![Themistocles (Tim) Assimes](https://profiles.stanford.edu/proxy/api/cap/profiles/6884/resources/profilephoto/350x350.1509552565630.jpg)
Themistocles (Tim) Assimes
Associate Professor of Medicine (Cardiovascular Medicine) and, by courtesy, of Epidemiology and Population Health
Medicine - Cardiovascular Medicine
Web page: http://web.stanford.edu/people/tassimes
Bio
I am a board-certified clinical cardiologist with a doctorate degree in Epidemiology & Biostatistics. I have been practicing medicine for nearly 30 years and I have over 20 years of experience conducting research. I was born and raised in Montreal, Canada, where I received my medical degree from McGill University in 1994. I then pursued training in surgery for nearly two years before switching into internal medicine. I completed my residency in internal medicine as well as a Master's degree in Epidemiology and Biostatistics at McGill under the supervision of Dr. Samy Suissa before moving to Stanford University in 2001 to pursue fellowship training in adult cardiology. During my fellowship and Instructorship years at Stanford University, I completed a PhD in Epidemiology and Biostatistics in pharmacoepidemiology once again under Dr. Suissa's supervision.
My principal research focus since moving to Stanford has been the identification of the genomic determinants of coronary heart disease (CHD) and risk factors of CHD. This transition in my research focus occurred thanks to the sage advice and unique opportunities provided to me by Dr. Thomas Quertermous, former chief of the Division of Cardiovascular Medicine and my primary mentor for many years after my arrival to Stanford. Since that transition, I have devoted a majority of my time performing advanced population based studies on the genomic causes of heart attacks and the common conditions that predispose people to heart attacks including high cholesterol, smoking, diabetes, obesity, high blood pressure, and insulin resistance. These research efforts go beyond the standard genetic variant association analyses and include analyses, interpretation, and integration of multi-omic data, construction and validation of polygenic scores, as well as Mendelian randomization, epigenetic association, and gene set enrichment analyses to help identify novel pathways of CHD in diverse populations.
In this context, I have heavily contributed to and/or led several translational team science endeavors at both the national and international level by representing Stanford in large consortia meta analyzing genomic data. These consortia include CARDIoGRAMplusC4D, GLGC, GIANT, GENESIS, TAICHI, and PAGE. I have also been an active Women's Health Initiative (WHI) investigator since 2010 serving as chair/co-chair of the WHI Genetics, Proteomics, and Biomarkers Scientific Interest Group and a member of the WHI Ancillary Studies Committee, while concurrently launching several genomic studies that have generated blood methylation, circulating miRNA, telomere lengths, and bulk RNA-seq resources within WHI. Through WHI, I have also served as a senior/key co-Investigator in NHLBI’s Trans-Omics for Precision Medicine (TOPMed) program where I have led whole genome sequencing projects related to CHD.
Starting in 2016, I became intricately involved in the Million Veteran Program (MVP) and have since served as a senior/key co-Investigator and/or a PI in multiple funded projects focused on the genetics of cardiometabolic traits. I also serve, or have served, as a co-chair of the MVP P&P Committee, the MVP CVD/Lipids Working Group, and the MVP COVID-19 Science Program Genomics and PRS Working Group. As a consequence of my heavy involvement in MVP, I was dually appointed (full-time) at the VA Palo Alto Healthcare System in 2018. In partnership with Dr. Phil Tsao, overall/national co-PI of the MVP, I hold key administrative positions and coordinate the local genomics research program within the newly formed Precision Health Service at the Palo Alto VA. Concurrently, I teach general cardiology as well as echocardiography to medical students, residents, and cardiology fellows-in-training at the Palo Alto VA Hospital echocardiography lab.
Academic Appointments
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Associate Professor, Medicine - Cardiovascular Medicine
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Associate Professor (By courtesy), Epidemiology and Population Health
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Member, Cardiovascular Institute
Administrative Appointments
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Clinical Lifelong Learning Committee, American Heart Association (2020 - 2024)
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Director, Medical and Population Genomics for Precision Medicine, VA Palo Alto Health Care System (2019 - Present)
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Program Committee, American Society of Human Genetics (2019 - 2022)
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Associate Director, Palo Alto Epidemiology Research and Information Center for Genomics, Palo Alto VA Hospital (2018 - Present)
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Steering Committee, Project Baseline (2017 - Present)
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Leadership Committee, Council of Genomic and Precision Medicine, American Heart Association (2016 - 2020)
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Membership and Communications Committee, Council of Epidemiology and Prevention, American Heart Organization (2016 - 2020)
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Steering Commitee, CARDIoGRAMplusC4D (http://www.cardiogramplusc4d.org/) (2012 - Present)
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Co-chair, Women's Health Initiative Scientific Interest Group for Genetics, Proteomics & Biomarkers (2010 - Present)
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Member, Ancillary Studies Committee, Women's Health Initiative (2010 - Present)
Honors & Awards
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Elected member, American Society of Clinical Investigation (01/01/2020)
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Genomic and Precision Medicine and Epidemiology Mid-Career Research Award and Lecturer, American Heart Association (04/30/2019)
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50+ Faces of Vanier College, Vanier College, Quebec, Canada (12/10/2018)
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Fellow of the American Heart Association (FAHA), council of Epidemiology and Prevention, American Heart Association (03/01/2016)
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Edwin L. Alderman award for excellence in Clinical Cardiovascular Research, Stanford University School of Medicine (2004, 2005)
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Fellow of the Royal College of Physicians of Canada, Royal College of Physicians and Surgeons of Canada (2000-2019)
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Chief Medical Resident, McGill University Medical Center - Royal Victoria Hospital (1999-2000)
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J.W. McConnell Scholarship, McGill Universtiy (1989-1994)
Professional Education
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MD, McGill University, Medicine (1994)
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Board Certified, American Board of Internal Medicine, Internal Medicine (not maintained beyond 2009) (1999)
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MS, McGill University, Epidemiology & Biostatistics (2001)
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Board Certified, American Board of Internal Medicine, Cardiovascular Medicine (2004)
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PhD, McGill University, Epidemiology & Biostatistics (2008)
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Testamur, National Board of Echocardiography, Adult Echocardiography (2022)
Current Research and Scholarly Interests
Our investigative focus is the design, conduct, analysis, and interpretation of human molecular epidemiology studies of complex cardiovascular disease (CVD) related traits. While we have focused on the study of coronary atherosclerosis, a condition that causes heart attacks, the number one cause of death worldwide, and risk factors for coronary atherosclerosis, we also examine many other traits related to cardiovascular disease. In addition to performing discovery and validation population genomic studies, we use contemporary genetic studies to gain important insight on the causal and mechanistic nature of associations between purported risk factors and adverse cardiovascular related health outcomes through instrumental variable analyses and genetic risk score association studies of intermediate phenotypes. Our group is also actively involved in studies assessing the clinical utility of novel genetic markers in isolation or in combination with other biomarkers. Lastly, we communicate the significance of genomic findings at the population level to molecular biologists who may lack a strong background in human genetics as well as human geneticists who lack a strong background in clinical medicine. Our group's broad translational knowledge base allows us to serve as a key collaborator in multidisciplinary investigative groups involved in the design and the interpretation of important functional experiments that will shed light on the biology behind these new genetic associations, as well as clinical trials the will help further delineate the utility of genomics in clinical practice.
If you are interested in working with us as a postdoctoral scholar, please check to see if we have any open positions at https://postdocs.stanford.edu/prospective/opportunities (search Assimes as last name). If you are interested in joining the team as a trainee in any other capacity, please do not hesitate to contact us as well.
Clinical Trials
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Personal Genomics for Preventive Cardiology
Not Recruiting
The purpose of this study is to see if providing information to a person on their inherited (genetic) risk of cardiovascular disease (CVD) helps to motivate that person to change their diet, lifestyle or medication regimen to alter their risk.
Stanford is currently not accepting patients for this trial. For more information, please contact Josh Knowles, 650-804-2526.
Projects
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Genome-wide association study of coronary artery disease in individuals of African ancestry, Vanderbilt University Medical Center (9/17/2020 - 8/31/2021)
Coronary artery disease (CAD) is a leading cause of death among adults in the United States. Its prevalence is highest in individuals of African ancestry. It has been estimated that genetic factors account for 26% to 69% of interindividual variation in CAD risk. Large-scale genome-wide association studies (GWAS) of CAD have mainly been conducted in populations of European ancestry and identified 161 independent loci so far. Few of the loci identified in European-ancestry populations have been replicated in populations of African ancestry. Large-scale GWAS of CAD in African-ancestry populations are lacking. This proposal will efficiently leverage the existing resources of the Population Architecture using Genomics and Epidemiology Consortium, Million Veteran Program and other established cohorts to create the largest-ever sample size for a genetic study of African- ancestry populations comprehensively phenotyped for CAD and related cardiometabolic traits. We propose to address the following Specific Aims.
Aim 1 will interrogate the genome using admixture mapping, univariate GWAS, multi-variate GWAS and trans-ethnic GWAS approaches to identify loci associated with CAD in African- ancestry populations.
Aim 2 will use phenome-wide association studies, variant-trait hierarchical clustering and integrative genomics methods to characterize CAD loci and gain insights into phenotypic, physiologic, and mechanistic impacts that underlie the pathophysiology of CAD.
Aim 3 will explore the public health impact and clinical relevance of CAD risk variants by constructing polygenic CAD risk scores and identifying pathogenic variants in Mendelian syndromes of CAD genes that are relevant to African-ancestry populations. The construction of population-specific polygenic risk scores and identification of rare and low-frequency pathogenic variants of large effect in Mendelian syndromes of CAD genes will facilitate quantification of CAD risk in individuals of African ancestry and potentially narrow the translational gap towards clinical use of genetic information across diverse populations. The comprehensive cross-trait associations of identified CAD risk loci will facilitate the discovery of subtypes of CAD. Both improved genetic CAD risk classifications and refined CAD sub-phenotyping would help with the implementation of precision medicine in CAD. The new biological insights elucidated from novel loci identified in African-ancestry populations may also be generalized to other populations for the diagnosis, prevention, and treatment of CAD.
Public Health Relevance
This study aims to identify and characterize genetic loci underlying coronary artery disease in populations of African ancestry. We will efficiently leverage the existing resources of the Population Architecture using Genomics and Epidemiology Consortium, Million Veteran Program and other established cohorts to create the largest-ever sample size for a study of an African-ancestry population comprehensively phenotyped for CAD and related cardiometabolic traits. The outcome of this study will provide a better understanding of the genetics of CAD and its risk factors in this high-risk population and has a strong likelihood of leading to measures that can help with the control and prevention of CAD in populations of African ancestry.Location
Nashville
Collaborators
- Yingchang Lu, Research Instructor in Medicine, Vanderbilt University Medical Center
- Themistocles Assimes, Stanford University School of Medicine
- Chor Yin (Maggie) Ng, Associate Professor, Division of Genetic Medicine, Vanderbilt University Medical Center
- Ruth Loos, PROFESSOR | Environmental Medicine & Public Health, Icahn School of Medicine, Mt Sinai
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Polygenic Risk Scores (PRS) for Diverse Populations - Bridging Research and Clinical Care, Fred Hutchison Cancer Research Center (8/1/2020 - 7/31/2024)
Cardiovascular disease (CVD) and its risk factors impose major societal burdens, are leading causes of morbidity, mortality, and disability. Precision medicine is uniquely positioned to address CVD and its risk factors, enabled by decades of investigation and billions of dollars of investment that have established their strong underlying genetic basis. Polygenic risk scores (PRS), the aggregation of risk variants into a single score, provides one such example. Research on PRS in CVD has transitioned from estimation to examining the clinical utility; i.e., determining when and how PRS adoption will occur and how similarly conceived environmental/lifestyle risk scores (ERS) can be used clinically in concert with PRS. However, the majority of participants included in large-scale CVD research have been of European ancestry (EA), limiting the global translation of genetic associations into clinical and public health applications relevant for all populations.
The PAGE consortium and others have demonstrated that EA-derived PRS are not directly translatable to racially/ethnically diverse populations. Statistical tools for PRS estimation and interpretation are founded on strong assumptions that are violated, and create bias, in the context of population structure that characterizes racially/ethnically diverse populations. These research gaps will exacerbate long-standing racial/ethnic disparities in CVD and its risk factors, underscoring the need for research that enables all groups to reap the benefits of PRS-enabled personalized prevention.
In this revised application, we address the limitations previously identified in our original application by leveraging high-quality, harmonized, and centrally available data from a network of cohorts and biobanks with linked electronic health records, capturing CVD and its risk factors. Through this effort, we will include over 1.5M non-European ancestry participants to develop and validate PRS for CVD-associated traits in racially/ethnically diverse populations. We will create the methods, resources, and best practices for the clinical and public health communities. This research will permit adoption and application of PRS for the detection, intervention, and treatment of CVD risk factors. Our ultimate goal is to reduce and prevent the burden of CVD in all populations. Our Specific Aims are (1) Creation of unbiased PRS: Develop and evaluate CVD PRS in combination with ERS in the large and racially/ethnically diverse PAGE study; and (2) Validation, calibration and dissemination: Externally validate and improve upon risk score models in biobanks and translate risk score models for improved access and understanding for the medical community.
We will build the next generation of methods, resources, and best-practices to empower appropriate development of PRS and subsequent prediction and clinical interrogation in CVD. Deliberate focus on non-EA populations will ensure that they are not the last to benefit in the new era of genomic medicine.Location
Fred Hutchison Cancer Center
Collaborators
- Charles Kooperberg, Professor and Program Head, Biostatistics Program, Public Health Sciences Division, Fred Hutch
- Kari North, Professor, Dept. of Epidemiology and Carolina Center of Genome Sciences, University of North Carolina
- Chris Cignoux, Associate Professor, University of Colorado Boulder
- Themistocles Assimes, Stanford University School of Medicine
- Christopher O'Donnell, Associate Professor of Medicine, Harvard Medical School & Chief of Cardiology, VA Boston Healthcare System, VA Boston Healthcare System
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New methods for constructing and evaluating polygenic scores, Stanford University School of Medicine (9/14/2020 - 6/30/2024)
In the last decade there has been major progress toward identifying the genetic bases of complex diseases and developing polygenic predictors for individuals who are at increased risk. Polygenic prediction models are now approaching the point of clinical relevance for several important diseases. However, since most of the polygenic risk is due to extremely large numbers of small-effect variants it is difficult to construct maximally efficient prediction models even using very large GWAS samples. At present, the largest samples are currently available for European ancestry individuals. Prediction models developed in these samples usually do not port well into other groups, although the precise reasons for the limited portability are not yet fully understood. In this project we will (1) measure the specific importance of different factors that contribute to the limited portability across groups; (2) implement and evaluate new statistical methods for computing polygenic predictors using joint inference across populations, and using functional information as priors; and (3) implement and evaluate new statistical methods for combining genetic information with other types of clinical data for prospective prediction in clinical settings. In summary our project will provide a framework of efficient statistical methods for polygenic prediction within and across populations.
Location
Stanford, CA
Collaborators
- Jonathan Pritchard, Stanford University School of Medicine
- Themistocles Assimes, Stanford University School of Medicine
- Stephen Montgomery, Associate Professor of Pathology, and of Genetics, Stanford University School of Medicine
- Molly Przeworski, Professor, Columbia - Biological Sciences
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Whole-genome sequencing analysis of coronary atherosclerosis and related traits, University of Texas Health Science Center Houston, Houston, TX, United States (3/17/2020 - 2/28/2025)
Genome-wide association studies have identified common single nucleotide variants at over 160 genetic loci associated with coronary artery disease (CAD) and subclinical atherosclerosis (coronary artery calcification, carotid intima media thickness, and carotid plaque). These discoveries have led to important insights into the pathways that contribute to subclinical atherosclerosis and CAD, as well as insights into the genetic architecture of atherosclerosis. For example, the heritability explained by common genetic variants for CAD appears to be concentrated in regulatory regions. Nevertheless, neither the genome-wide association studies nor exome sequencing studies performed to date have been able to examine both coding and non-coding variants across the allele frequency spectrum in relation to subclinical atherosclerosis and CAD. Furthermore, these studies have largely focused on European ancestry participants. Approaches that identify pleiotropic loci or quantify genetic correlation among phenotypes exist, but have not yet been applied to subclinical atherosclerosis and CAD. Genetic risk prediction studies based on common variants show promise with regards to improving primary prevention, but the extent to which adding low-frequency and rare variants to polygenic risk scores improves risk prediction is not known, nor have scores been developed and tested in those of non-European ancestry. A wealth of whole-genome sequencing (WGS) data has been generated by initiatives such as the National Heart, Lung, and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) program and the National Human Genome Research Institute (NHGRI) Centers for Common Disease Genomics (CCDG) program in populations from different ancestries. To expand our knowledge of genetic factors contributing to CAD and subclinical atherosclerosis phenotypes, we propose to use WGS data from TOPMed and CCDG (up to 101,295 individuals from diverse ancestries, of which 58% are non-European ancestry), with extended genomic coverage of low-frequency and rare genetic variants as well as more complex genetic variants such as structural variants. Findings from the WGS analysis will be replicated in several large-scale data sources, including exome sequencing data and genotype data imputed using TOPMed as the reference panel. Thus, we will examine genetic variation that has so far been missed, including structural variants. We will leverage the results of these analyses to explore the genetic architecture of subclinical atherosclerosis and CAD, investigate pleiotropy and genetic correlation between subclinical atherosclerosis and CAD and related cardiovascular traits, as well as assess the contribution of low-frequency and rare variants to risk prediction of CAD. Finally, we will create and test a polygenic risk score designed specifically for African ancestry population. This proposal brings together large-scale WGS datasets, clinical and subclinical atherosclerosis phenotypes, and exploits advances in genomic technologies and computational approaches. In doing so, we will advance the realization of precision medicine for CAD.
Location
Houston
Collaborators
- Paul Stefan De Vries, Assistant Professor, University of Texas Health Science Center Houston
- Themistocles Assimes, Stanford University School of Medicine
- Ron Do, ASSISTANT PROFESSOR | Genetics and Genomic Sciences, Icahn School of Medicine at Mt Sinai
- Danish Salaheen, Associate Professor of Medicine, Columbia University, Department of Medicine
- Jerome Rotter, Professor of Medicine, Los Angeles Biomedical Research Institute At Harbor-UCLA Medical Center
- Vasan S. Ramachandran, Professor of Medicine, Boston University School of Medicine
- Patricia A. Peyser, Professor, Epidemiology, University of Michigan School of Public Health
- Nathan O. Stitziel, Associate Professor of Medicine and Genetics, Washington University School of Medicine in St. Louis
For More Information:
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Genetics of Cardiometabolic Diseases in the VA Population, Veterans Health Administration (1/1/2017 - 9/30/2023)
Obesity, Type 2 diabetes (T2DM), and dyslipidemia are metabolic disorders that promote the development of coronary artery (CAD) and peripheral arterial disease (PAD). Collectively, these cardiometabolic conditions are leading causes of illness and death among Veterans. A substantial proportion of the variation in risk of clinical complications related to these conditions remains unexplained despite an understanding of the root factors involved. The VA Million Veteran Program (MVP) links information from Veterans’ electronic heath record (EHR) to biomarker data measured from blood and provides an unparalleled opportunity to further explore the genetic basis of cardiometabolic diseases. We propose to use the genome wide genotyping data from the first 200,000 participants in MVP linked to the EHR to uncover novel associations between genetic variation and risk of cardiometabolic disease. To perform this research, we have assembled a team of investigators with extensive experience in VA based clinical research and population genetics. Many members of our team have not only participated in, but also have led, the most productive international collaborations over the last 10 years that have studied the genetic basis of cardiometabolic diseases. Our consortium includes investigators from 5 VISNs based at Palo Alto, Philadelphia, Phoenix, Bedford, and Albany as well as from Stanford University and the University of Pennsylvania. In Aim 1, we will establish optimal definitions of five cardiometabolic traits: body mass index, blood levels of cholesterol, as well as diagnoses of Type 2 diabetes (T2DM), CAD, PAD, using EHR derived information on medical diagnoses and treatments, physical exam and lab measures, and medication usage. Preliminary results of our queries of VA EHR data using the most liberal definitions of the traits have identified approximately 160,000 participants with lipid measurements, 195,000 participants with measurements of body-mass index, 100,000 participants with T2DM or prediabetes, 46,000 participants with CAD, and 9,000 participants with PAD. For quantitative traits, we will derive and study not only single time point measures but also long term averages for each individual. For outcomes, we will optimize our definitions by assessing the relationship between established risk factors including phenotype specific genetic risk scores and case-control status. In Aim 2, we will perform a series of genome wide association studies to confirm known loci and to identify novel genetic variation associated with our traits of interest. We will also use the comprehensive VA EHR to examine for the presence of gene-environment interactions. Finally, in Aim 3, we will apply novel statistical algorithms that will improve our understanding of the genetic variation that contributes to the risk of cardiometabolic diseases in both the African American and the Hispanic American populations by leveraging similarities in the genetic architecture among different race/ethnic groups. Successful completion of this project will help us to more thoroughly comprehend the underlying causes of cardiometabolic disease and to develop novel therapies that are safe, effective, and personalized. These discoveries will also result in the more reliable identification of individuals at risk for these disorders, allowing for the more optimal delivery of primary prevention strategies within the VA population.
Location
3801 Miranda 94304
Collaborators
- Philip Tsao, Professor (Research) of Medicine (Cardiovascular Medicine), Stanford University School of Medicine
- Kyong-Mi Chang, Associate Professor of Medicine, University of Pennsylvania
- Themistocles Assimes, Stanford University School of Medicine
- Hua Tang, Professor of Genetics and, by courtesy, of Statistics, Stanford University School of Medicine
- Jennifer Lee, Professor, Stanford University School of Medicine
- Daniel Rader , Seymour Gray Professor of Molecular Medicine, University of Pennsylvania
- Scott Damrauer, Assistant Professor Of Surgery, University of Pennsylvania
- Manuel Rivas, Assistant Professor of Biomedical Data Science, Stanford University School of Medicine
For More Information:
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Efficient electronic phenotyping using APHRODITE in the Million Veteran Program, Palo Alto VA Health Care System (8/1/2019 - 7/31/2021)
The Million Veteran Program (MVP) is currently the largest biobank study in the world. The resource provides an unprecedented opportunity to identify the genetic causes of a variety of human diseases that disproportionally affect our veterans including diseases that affect the neurological, cardiovascular, pulmonary, gastrointestinal, endocrine, and musculoskeletal organs. Fast-paced technological progress over the last 10 years now allows us to reliably and densely profile individuals across their entire genome. Such data has already been generated and linked to a wide spectrum of human diseases and physiologic traits. However, many more links remain to be made which will provide the scientific community with additional important clues on the root causes of many life-threatening diseases as well as valuable insights on how to develop new drugs to treat or prevent these same diseases. The current challenge in making these additional discoveries is no longer the generation of high quality genetic data in large numbers but rather the organization and querying of very large and complex electronic health records (EHR) being leveraged by these large biobank studies. Until now, much effort and time has been expended to painstakingly develop and validate rules-based definitions to identify individuals with a specific disease, syndrome, or state across a variety of EHR platforms. However, the recent mapping of the VA corporate data warehouse to the Observational Medical Outcomes Partnership common data model (OMOP-CDM) provides us with unprecedented opportunities to apply new “electronic phenotyping” tools that can identify individuals with a specific disease, syndrome, or state in a much more efficient manner than rules-based methods. The goal of this proposal is to comprehensively test the ability of one of these new tools named APHRODITE (Automated PHenotype Routine for Observational Definition, Identification, Training and Evaluation) to identify established genetic links among MVP participants. APHRODITE was developed at Stanford by one of our co-investigators and uses state of the art machine learning algorithms to identify individuals with a condition in a fraction of the time it takes to identify them through rules-based definitions. The algorithm has shown great promise within the Stanford clinical data warehouse but requires validation in other EHR cohorts. In aim 1, we will test the accuracy of an APHRODITE classifier to that of a rules-based classifier for at least 5 diseases using gold-standard sets in the VA. In aim 2, we will test whether APHRODITE classifiers from aim 1 can be applied to MVP participants to replicate established genetic associations. If automated methods in APHRODITE perform equally well or better than rules-based methods for multiple diseases, automated methods may be leveraged for phenotypes where rules based methods may not exist, maximizing the efficiency of genetic discovery in MVP and facilitating rapid replication of findings within MVP in other EHRs mapped to the OMOP-CDM.
Location
Palo Alto Health Care System, Palo Alto
Collaborators
- Themistocles Assimes, Stanford University School of Medicine
- Jennifer Lee, Professor, Stanford University School of Medicine
- Philip Tsao, Professor (Research) of Medicine (Cardiovascular Medicine), Stanford University School of Medicine
- Scott Duvall, Director, VA Informatics and Computing Infrastructure, VA Salt Lake City Health Care System
- Julie Lynch, Investigator, Center for Healthcare Organization & Implementation Research, Veteran Affairs Administration
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Using census data linkages to study long-term impacts on disparities in DNA methylation, Stanford University School of Medicine (9/14/2018 - 9/13/2020)
A developing yet still inconclusive literature suggests that exposures early in life may play an important role in health disparities found at older ages. This literature suggests that early life environment may be a key place for intervening to reduce health disparities in the most cost-effective manner. A separate literature has suggested that environmental factors early in life have an important impact on patterns of DNA methylation that extend into old age. However, there remains a critical gap in knowledge of how DNA methylation may be a key underlying mechanism of linking early life exposures to racial/ethnic and socioeconomic disparities in chronic disease. This application seeks funding for innovative exploratory work to test whether linking current
longitudinal cohorts to historical individual level data from the 1940 U.S. Census at the time of childhood will offer a solution to answering this critical question. Our long-term goal is to understand the extent to which DNA methylation contributes to racial/ethnic and socioeconomic disparities in chronic disease incidence. The overall objective of this application is to test whether linkage to administrative data from the U.S. Census is an efficient and effective way of determining links between the early life environment and disparities in health due to changes in DNA methylation. Our central hypothesis, based on the literature and our prior research, is that early life household conditions will have a substantial impact on both racial/ethnic and socioeconomic
disparities in DNA methylation. To test this hypothesis we propose the following three specific aims: Aim 1: Link Women’s Health Initiative study participants to their childhood household data from the 1940 U.S. full population census, Aim 2: Test the association between early life household environment and racial/ethnic and socioeconomic differences in DNA methylation later in life, Aim 3: Perform quantitative bias analysis to assess the likelihood of bias due to differential linkage, survival, and study participation by race/ethnicity and socioeconomic position. The innovation of our proposed research is in testing a new approach to capturing the early life environment that does not rely on retrospective self-reports. If validated, our approach could be
applied to dozens of other currently available cohort studies with DNA methylation data that have participants who were alive in 1940. Critically, the 1940 U.S. census measures could then become a commonly used environmental metric applied across multiple studies facilitating large-scale meta-analyses of environmental impacts on health. Overall, we believe our innovative, exploratory study has the potential to guide a large number of future studies that will allow robust and useful estimates of how the early life environment contributes to differences in DNA methylation and subsequent chronic disease disparities. We believe our
approach represents a very cost-effective and efficient means to leverage currently available DNA methylation data to study the impact of the early life environment on health disparities.Location
Stanford University
Collaborators
- David Rehkopf, Stanford University School of Medicine
- Themistocles Assimes, Stanford University School of Medicine
- Mark Cullen, Professor, Stanford University School of Medicine
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Integrative multi-omics in whole genome studies of HLBS disorders, Stanford University School of Medicine (5/1/2018 - 4/30/2020)
Whole genome data will soon be available for tens to hundreds of thousands of individuals. This information is unprecedented in its ability to understand individual risk factors for disease. However, the volume of these data presents several major challenges to its interpretation. One powerful approach for interpreting genomes and identifying functional variants is to combine whole genome data with functional genomics or multi-omics data. Our research project focuses on multi-omics analyses in the TOPMED project to improve our understanding of individual and environmental genetic risk factors in heart, lung, blood and sleep (HLBS) disorders. In Aim 1, we will apply multi-omic outlier analysis to identify rare variants with large effects on multi-omics phenotypes. We will apply approaches we have developed in GTEx and SardiNIA that integrate genome and functional genomics data. Our premise is that rare genetic variants with large effects on -omics phenotypes will be strong candidates to contribute to an individual’s risk of genetic disease. Using these rare variants, we propose to improve understanding of the combined effects of common and rare variants in HLBS disorders. In Aim 2, we will apply and advance software we have developed to improve the mapping of gene-by-environment (GxE) and gene-by-gene (GxG) effects. Specifically, we have demonstrated that allele-specific signals have improved power for identifying both GxE and GxG genes and variants and we will apply our model to both transcriptome and methylome data in TOPMED to identify diverse hits for observed and latent environments. We will further conduct analyses to identify GxE hits for measured metabolites and, overall, with respect to differences in ancestry. Our premise is that GxE variants identified through multi-omics data analysis will define or modify genetic risk factors for HLBS and other disorders. The impact of discovered GxE and GxG variants will be evaluated through association analyses in the entire TOPMED cohort.
Our activities will bring new opportunities to study and understand both individual and gene-by-environment effects influencing disease risk. By leveraging multi-omics data, we will integrate rare variant and gene-by-environment analyses within TOPMED; an activity that would typically require enormous investment and hundreds of thousands of samples if conducted with only genetic data. All software, pipelines and research results developed by our group will be rapidly available on standard websites, in the Cloud and available to support collaborative efforts within TOPMED and the larger research community. Further, as our team has extensive experience with large-scale genomics and functional genomics analysis, we will provide assistance and effort in implementing world-class analytical pipelines and further complement TOPMED with data from GTEx, MoTrPAC, DGN, WHI and other project data to enhance the power of analyses. Our effort will provide multiple avenues, from rare variants to environmental genetics, to aid in interpreting whole genomes and the impact of genetic variation in health and diseaseLocation
Stanford, CA
Collaborators
- Stephen Montgomery, Associate Professor of Pathology, and of Genetics, Stanford University School of Medicine
- Themistocles Assimes, Stanford University School of Medicine
- Jonathan Pritchard, Stanford University School of Medicine
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Proteomic Determinants of direct measures of insulin sensitivity, Stanford University School of Medicine (4/1/2018 - 3/31/2023)
The consequences of insulin resistance (IR) include not only type 2 diabetes mellitus but also a cluster of metabolic abnormalities that double the risk of developing life-threatening complications of atherosclerosis including myocardial infarction, ischemic strokes, and peripheral arterial disease. The prevalence IR is increasing at an alarming rate as western populations become heavier and more sedentary. When one further considers the ongoing epidemiological transitions in developing countries in addition to the obesity epidemic in developed countries, the worldwide public health impact of IR is undoubtedly profound. Few pharmacological options exist that improve one’s insulin sensitivity and decrease the risk of complications from IR and recent genomic studies of surrogate measures of IR have yielded a disappointing number of new leads. Furthermore, a critical need exists for the development of more accurate blood-based diagnostic tests for IR. The long-term objective of the proposed research is to discover and validate novel protein markers of IR circulating in the blood of individuals who have undergone either one of the two ‘gold standard’ direct measures of insulin sensitivity: an insulin suppression test (IST) or a euglycemic clamp (EC). This information will be used to identify novel molecular pathways of IR that can be targeted pharmacologically and to develop statistical models that correlate highly with the degree of IR as estimated by direct measures of insulin sensitivity. In aim 1 of this proposal, the blood of 2100 white/European subjects who have undergone an IST at Stanford or an EC in the Relationship between Insulin Sensitivity and Cardiovascular Disease (RISC) and the Uppsala Longitudinal Study of Adult Men (ULSAM) studies will be measured for the presence of 981 proteins using an emerging platform that leverages novel technology referred to as the proximity extension assay. This technology allows for the accurate and reliable quantification of proteins in plasma down to the femtomolar or attomolar level. We will further validate the top signals identified in these subjects in an additional ~300 non-European subjects and a subset of 300 subjects from Stanford who underwent a second IST after weight loss or use of a thiazolidinedione. In aim 2, we will examine validated signals from Aim 1 for causality using the principal of Mendelian randomization, and we will quantify improvements afforded by validated markers over conventional measures in identifying subjects at risk of complications from IR. In aim 3, validated associations between proteins that appear causal in nature will be further examined through knockdown of the genes producing these proteins in human cell lines relevant to IR. These cell lines will include adipocytes, hepatocytes, and skeletal myocytes. This study is the largest study of the plasma proteome in relation to direct measures of insulin sensitivity ever proposed. Findings are expected to yield important mechanistic insights into the molecular basis of IR and provide the foundation for the development of a blood-based diagnostic test that can very reliably detect subjects at low or high risk of complications from IR.
Location
Stanford, CA
Collaborators
- Themistocles Assimes, Stanford University School of Medicine
- Erik Ingelsson, Stanford University School of Medicine
- Laura Lazzeroni, Stanford University School of Medicine
- Joshua Knowles, Stanford University School of Medicine
- Fahim Abbasi, Medicine - Cardiovascular Medicine
- John Petrie, Professor of Diabetic Medicine (Institute of Cardiovascular and Medical Sciences), University of Glasgow
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Whole Genome Sequence Analysis of Ischemic Stroke in the Women’s Health Initiative, Fred Hutchinson Cancer Research Center (4/5/2017 - 1/31/2021)
Stroke is among the understudied disorders despite its high burden to morbidity and mortality in the US. Ischemic stroke, which is due to cerebral vessel occlusion, accounts for 80% of cases. Ischemic stroke is a complex, multi-factorial disease, with heterogeneity by age, sex, and stroke subtype. A substantial proportion of stroke risk remains unexplained. The relatively low yield of stroke genetic studies to date may reflect the heterogeneous causes and clinical presentations of the various subtypes. Many of the studies participating in stroke GWAS have included have had little or no data available on stroke-specific risk factors or other CVD outcomes, which are key to understanding causal mechanisms and potential gene?environment interactions. Next generation sequencing (NGS) and multi-omics integrative biology research offer new opportunities in the way we research and understand stroke. Whole genome sequence (WGS) data, including both coding and functional non-coding variants, are required to identify the full spectrum of contributions of uncommon variants to stroke risk. Deep WGS data are currently being generated in over 11,000 WHI participants through the NHLBI TOPMed project, including over 4,000 ischemic stroke cases. Here we propose to apply innovative statistical approaches to perform a well-powered analysis to discover, replicate, and functionally characterize new loci (particularly rare or low frequency coding and non-coding regulatory variants) for ischemic stroke (and its subtypes) using WGS and imputation. Discovery will be performed in ~4,000 incident ischemic stroke cases and over 5,000 controls from WHI with WGS through TOPMed. Single variant and gene-based tests will be performed, prioritizing ~100 genomic regions based on prior GWAS and current epigenomic and proteomic analyses. Replication will be performed through state-of-the art WGS-based exome and GWAS imputation in up to ~77,000 additional ischemic stroke cases (and controls) obtained through UKBiobank, Million Veteran Program, and the SiGN and METASTROKE stroke genomics consortia. To assess the biologic mechanism of stroke-associated genetic loci, we will further test any newly identified stroke loci for association with: (1) a rich set of CVD risk factors and ~40 plasma biomarkers related to atherosclerosis, thrombosis, inflammation, and hormones available in WHI; (2) a new, commercial panel of 184 emerging biomarkers related to neurovascular disease and CVD in 2000 WHI TOPMed samples selected on the basis of genotype. Using casual inference methodology, we will perform mediation analyses to determine mechanistic relationships between genotype, intermediate biomarker phenotype, and stroke outcome.
Location
Seattle, WA
Collaborators
- Alexander Reiner, Professor, Department of Epidemiology , University of Washington
- Charles Kooberberg, Member and Program Head, Biostatistics Program, Fred Hutchinson Cancer Research Center
- Themistocles Assimes, Stanford University School of Medicine
- Rebecca Jackson, Professor of Medicine; Associate Dean for Clinical and Translational Research; Director, Center for Clinical and Translational Science, Ohio State University
- Paul Auer, Assistant Professor , University of Wisconsin-Milwaukee
- Braxton Dallam Mitchell Jr., Professor of Medicine and Epidemiology; Vice Division Chief, Endocrinol, Diabetes & Nutr, Univ of Maryland School of Medicine
- Sylvia Wassertheil-Smoller, Distinguished University Professor and Dorothy and William Manealoff Foundation and Molly Rosen Professor of Social Medicine Emerita, Albert Einstein College of Med
For More Information:
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The Baseline Study, Stanford University School of Medicine (6/1/2016 - Present)
To perform extensive phenotypic and integrative omic profiling of up to 10,000 newly enrolled individuals at risk of or with existing CHD or cancer.
Location
stanford, ca
Collaborators
- Sanjiv Gambhir, Professor, Stanford University School of Medicine
- Kenneth Mahaffey, Department of Medicine
- Themistocles Assimes, Stanford University School of Medicine
- Millie Das, Clinical Professor, Medicine - Oncology
- David Maron, Professor, Stanford University School of Medicine
- George Sledge, Stanford University School of Medicine
For More Information:
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Causal associations of circulating biomarkers with cardiovascular disease, Stanford University School of Medicine (2/1/2017 - 1/31/2020)
Cardiovascular diseases (CVD) comprise the global leading cause of morbidity and mortality, and in the United States, CVD account for more than one-third of all deaths, of which ~150,000 deaths per year occurs in individuals younger than 65 years. Over the past decades, hundreds of circulating biomarkers have been associated with CVD, but their relative importance and potential involvement in the actual disease processes have been less investigated. Using a very large cohort study that recently became available to the scientific community, we will deploy Mendelian randomization methods to study the causal role of biomarkers proposed to be associated with CVD. In 2006-2010, the UK Biobank recruited 502,650 participants aged 37-73 years to undergo physical measurements, detailed assessments about risk factors and future disease events, and sampling of blood, urine and saliva. Genome-wide genotyping on the UK Biobank Axiom Array (820,967 genetic markers) and measurement of 36 circulating biomarkers with relevance for CVD will be finished during 2016. We will study the associations of 36 circulating biomarkers representing coagulation and inflammation (fibrinogen, D-dimer, hsCRP, rheumatoid factor), glucose homeostasis (HbA1c, glucose, IGF-1), lipid metabolism (total cholesterol, LDL-C, HDL-C, triglycerides, ApoAI, ApoB, Lp(a)), liver function (ALT, AST, ALP, direct and total bilirubin, GGT, albumin, total protein), kidney function (creatinine, cystatin C, phosphate, urate, urea, urinary sodium, potassium, microalbumin and creatinine), reproductive system (SHBG, testosterone, oestradiol), and mineral metabolism (calcium, vitamin D) with incidence of coronary heart disease, stroke, heart failure, atrial fibrillation and type 2 diabetes in traditional observational multivariable-adjusted analyses. We will then perform genome-wide association studies (GWAS) of all 36 biomarkers to establish common genetic variation associated with respective biomarker. With a sample size of ~390,000 individuals, we will have excellent statistical power to uncover a substantial fraction of common genetic variants associated with the biomarkers. These associations will be used to develop robust instrumental variables. Finally, using instrumental variable analyses, we will study the causal roles of these circulating biomarkers for development of cardiovascular disease. The large sample size of the present study will allow for unprecedented possibilities of Mendelian randomization studies of CVD biomarkers with adequate statistical power and with low risk of pleiotropy. Knowledge about the causal roles of CVD-related biomarkers for development of coronary heart disease, stroke, heart failure, atrial fibrillation and type 2 diabetes will provide important insights regarding the etiological understanding of these diseases and accelerate new prevention strategies, including druggable targets.
Location
Stanford, CA
Collaborators
- Erik Ingelsson, Stanford University School of Medicine
- Themistocles Assimes, Stanford University School of Medicine
For More Information:
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The Epigenetics Leads To Age-Related Diseases (Gilga-Mesh) Network, University of California Los Angeles (10/1/2015 - 3/31/2018)
While life expectancy continues to rise, healthspan is not keeping pace because current disease treatments often decrease mortality without preventing the decline in overall health. It is crucial to understand how the underlying processes of aging affect susceptibility to chronic disease and related conditions. Epigenetic mechanisms have arguably become an important frontier in geroscience. We and others have shown that epigenetic biomarkers tend to be more strongly related with chronological age than existing biomarkers of aging. Importantly, we have recently demonstrated that epigenetic biomarkers of aging are prognostic of all-cause mortality in later life and correlate with measures of physical and cognitive fitness in older age. These data suggest that epigenetic mechanisms may play a role in mediating the effect of age on disease susceptibility. In this planning grant we lay out th framework needed to design a large-scale study that tests the overall hypothesis that epigenetic changes during aging collectively underlie aging as a risk factor for chronic diseases and degenerative conditions. We will generate preliminary results by leveraging existing epigenetic and phenotypic data available to our team of co-investigators and collaborators. These resources include data from the ENCODE project, various epigenetic data generated in multiple tissues, and richly phenotyped cohorts, such as the Baltimore Longitudinal Study of Aging (BLSA), InCHIANTI, the Women's Health Initiative, and the Lothian Birth Cohorts. We will evaluate different platforms for measuring epigenetic age, DNA methylation levels, chromatin states, and non-coding RNAs in terms of their relevance to our overall hypothesis, data quality, coverage, and price. While there exists a large body of literature on epigenetics and aging, our proposal is novel in terms of its breadth and depth: we will lay the groundwork for a study that investigates multiple epigenetic processes (DNA methylation, histone modifications, non-coding RNAs), multiple human tissues, multiple chronic conditions, at multiple time points using multiple well characterized human cohort studies and state-of-the-art statistical and bioinformatics techniques. Using pilot data from these and other studies, we will assess the reliability and precision of cutting-edge epigenetic measures and to estimate the resources needed for a future study. We will also assess to what extent epigenetic features in accessible human tissues (e.g., blood, buccal epithelium) can serve as surrogates for affected tissues and cell types. By organizing two workshops at UCLA, we will establish a research network comprised of leading researchers in the fields of aging research, epigenetics, epidemiology, genomics, and systems biology.
Location
Los Angeles
Collaborators
- Steven Horvath, Professor of Human Genetics & Biostatistics, University of California Los Angeles
- Themistocles Assimes, Stanford University School of Medicine
For More Information:
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Coronary Artery Disease Genetics in Large Sample of Taiwan Chinese, Harbor-UCLA Medical Center (10/1/2015 - 3/31/2018)
The major goal of this project is to conduct large-scale whole exome sequencing in multiple Taiwanese cohorts to identify novel genetic determinants of CAD related traits in Han Chinese. The main sponsor of this study is the Regeneron Genetics Center - Regeneron Pharmaceuticals
Location
Los Angeles, California
Collaborators
- Frederick Dewey, Senior Director and Head of the Translational Genetics , Regeneron Genetics Center
- Ida Chen, Professor of Pediatrics & Medicine, Harbor-UCLA Medical Center
- Jerome Rotter, Professor of Pediatrics, Medicine, and Human Genetics, Harbor-UCLA Medical Center
- Themistocles Assimes, Stanford University School of Medicine
- Thomas Quertermous, Professor, Stanford University School of Medicine
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Women's Health Initiative - Regional Centers 2015-2020, Stanford University School of Medicine (10/15/2015 - 10/14/2020)
This represents the third extension study of the WHI involving 5 additional years follow-up for cardiovascular, cancer and other health outcomes in participants and a continued leveraging of the bioresource to conduct genomic and other biomarker studies. This contract supports the western regional center based at Stanford University.
Location
Stanford, CA
Collaborators
- Marcia Stefanick, Stanford
- Themistocles Assimes, Stanford University School of Medicine
- Mark Hlatky, Stanford University School of Medicine
- Marco Perez, Associate Professor, Stanford University School of Medicine
For More Information:
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A pilot RNA-seq study among Long Life Study participants of the WHI, Stanford University School of Medicine (3/1/2015 - 8/31/2015)
RNAseq on whole blood from 100 participants of the Women's Health Initiative Long Life Study
Location
Stanford, CA
Collaborators
- Themistocles Assimes, Stanford University School of Medicine
- Stephen Montgomery, Associate Professor of Pathology, and of Genetics, Stanford University School of Medicine
For More Information:
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Determinants of Insulin mediated glucose update in South Asians, Stanford University School of Medicine (4/1/2011 - 1/31/2015)
The purpose of this award is to provide Dr. Themistocles (Tim) Assimes, Assistant Professor of Medicine at Stanford University, the support necessary to transition him from a junior investigator to an independent physician scientist studying the genetic determinants of various human complex traits related to cardiovascular medicine. Dr. Assimes is an adult cardiologist with an advanced degree in epidemiology and biostatistics and significant experience conducting human genetic studies using existing sample sets. Career development activities focus on consolidating his expertise by 1) designing and implementing his first human subjects clinical research study involving handling of biospecimens, 2) increasing his involvement in several international genetic epidemiology collaborations, and 3) attending didactic courses to expand his knowledge base in contemporary genetics, molecular biology, advanced statistical genetics and the pathophysiology of insulin resistance (IR). An advisory committee, which includes his mentors, Drs. Thomas Quertermous and Gerald Reaven, will carefully monitor his progress towards independence. The research proposal builds on ongoing efforts in the candidate’s division to identify the root causes of IR by studying South Asians, a racial/ethnic group known to be strongly predisposed to IR and its adverse consequences for unclear reasons. In this context, Specific Aim 1 proposes to quantify IR and its primary established determinants of adiposity and physical fitness in ~330 South Asians and ~100 white/Europeans using ‘gold standard’ measuring tools. These include an insulin suppression test to assess insulin mediated glucose uptake, DXA and abdominal MRI scans to determine total and regional body fat, pedometers to estimate current physical activity, and a symptom limited cardiopulmonary stress test to estimate maximum oxygen uptake (max VO2). A new research partnership between the non-profit South Asian Heart Center at El Camino Hospital, Mountain View, CA, and Division of Cardiovascular Medicine at Stanford University will facilitate recruitment. This aim will test the hypothesis that a predisposition to IR in South Asians is evident even after taking into account significant differences between the two racial/ethnic groups in adiposity and physical fitness not captured by more traditional methods of assessment of these variables (e.g., BMI and physical activity questionnaires). In Specific Aim 2, the candidate will perform genome wide genotyping in ~400 South Asians followed by gene/SNP set pathway analyses using innovative analytical techniques developed by collaborators at SAGE Bionetworks. The same analytical techniques will be applied to multiple other sample sets with GWAS and direct measures of IR representing 3 other race/ethnic groups including Europeans, East Asians, and Hispanics. This aim will compare and contrast pathways associated with IR across all groups and test the hypothesis that South Asians are more IR because they have inherited a relatively inefficient cellular mechanism of handling glucose compared to other racial/ethnic groups.
Location
Stanford, CA
Collaborators
- Themistocles Assimes, Stanford University School of Medicine
- Stephen Fortmann, Professor, Stanford University School of Medicine
- Fahim Abbasi, Medicine - Cardiovascular Medicine
- Latha Palaniappan, Center for Asian Health Research and Education
- Thomas Quertermous, Professor, Stanford University School of Medicine
- Philip Tsao, Professor (Research) of Medicine (Cardiovascular Medicine), Stanford University School of Medicine
- Gerald M Reaven, Professor Emeritus, Stanford University School of Medicine
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Utility of the Aviir risk score in predicting incident coronary heart disease in the WHI, Stanford University School of Medicine (8/1/2011 - 7/31/2013)
To test the ability of serum levels of 7 novel biomarkers to improve prediction for incident CHD over standard risk scores in the WHI observational study.
Location
Stanford, CA
Collaborators
- Themistocles Assimes, Stanford University School of Medicine
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A randomized trial of personal genomics for preventive cardiology, Stanford Research Pilot Grant, Innovation Awards in Population Medicine (5/1/2011 - 4/30/2012)
To test the hypothesis that giving patients information about their genetic risk of CAD will increase their adherence to therapy, behavior or help them affect lifestyle changes.
Location
Stanford, CA
Collaborators
- Joshua Knowles, Stanford University School of Medicine
- Themistocles Assimes, Stanford University School of Medicine
- John Ioannidis, Stanford University School of Medicine
- Michael McConnell, Stanford University School of Medicine
- Euan Ashley, Professor, Stanford University Cardiology
- Shirin Jimenez, Clinical Assistant Professor, Stanford University School of Medicine
For More Information:
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Integrative genomics and risk of CHD and related phenotypes in the Women’s Health Initiative, Stanford University School of Medicine (3/29/2013 - 3/28/2016)
To identify genomic signatures and pathways relevant to CHD and its risk factors through large scale methylation and circulating micro-RNA profiling in the WHI
Location
Stanford, CA
Collaborators
- Themistocles Assimes, Stanford University School of Medicine
- Devin Absher, Faculty Investigator, Hudson Alpha Institute for Biotechnology
- Philip Tsao, Professor (Research) of Medicine (Cardiovascular Medicine), Stanford University School of Medicine
- Steve Horvath, Professor of Human Genetics & Biostatistics, UCLA
For More Information:
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Whole Genome Association for Early Coronary Artery Disease and Related Phenotypes, Stanford University School of Medicine / Kaiser Permanente DOR (10/1/2006 - 7/31/2010)
Perform a whole genome association study on the ADVANCE study in search of novel genetic determinants of CAD and CAD risk factors.
Location
Stanford, CA
Collaborators
- Thomas Quertermous, Professor, Stanford University School of Medicine
- Themistocles Assimes, Stanford University School of Medicine
- Joshua Knowles, Stanford University School of Medicine
- Neil Risch, Professor, Division of Biostatistics / Director, Institute for Human Genetics, UCSF
- Alan Go, Director, Comprehensive Clinical Research Unit , Kaiser Permanente Northern California Division of Research
- Carlos Iribarren, Research Scientist, Kaiser Permanente Northern California Division of Research
For More Information:
2023-24 Courses
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Independent Studies (8)
- Directed Reading in Epidemiology
EPI 299 (Aut, Win, Spr, Sum) - Directed Reading in Medicine
MED 299 (Aut, Spr, Sum) - Early Clinical Experience in Medicine
MED 280 (Aut, Spr, Sum) - Graduate Research
EPI 399 (Aut, Win, Spr, Sum) - Graduate Research
MED 399 (Aut, Spr, Sum) - Medical Scholars Research
MED 370 (Aut, Spr, Sum) - Undergraduate Research
EPI 199 (Aut, Win, Spr, Sum) - Undergraduate Research
MED 199 (Aut, Win, Spr, Sum)
- Directed Reading in Epidemiology
Stanford Advisees
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Postdoctoral Faculty Sponsor
Ming Li Chen, Pik Fang Kho, Disha Sharma, Jiayan Zhou -
Postdoctoral Research Mentor
Alexa Barad Zayat, Daniel Panyard
Graduate and Fellowship Programs
All Publications
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A functional genomic framework to elucidate novel causal metabolic dysfunction-associated fatty liver disease genes.
Hepatology (Baltimore, Md.)
2024
Abstract
Metabolic dysfunction-associated fatty liver disease (MASLD) is the most prevalent chronic liver pathology in western countries, with serious public health consequences. Efforts to identify causal genes for MASLD have been hampered by the relative paucity of human data from gold-standard magnetic resonance quantification of hepatic fat. To overcome insufficient sample size, genome-wide association studies using MASLD surrogate phenotypes have been used, but only a small number of loci have been identified to date. In this study, we combined GWAS of MASLD composite surrogate phenotypes with genetic colocalization studies followed by functional in vitro screens to identify bona fide causal genes for MASLD.We used the UK Biobank to explore the associations of our novel MASLD score, and genetic colocalization to prioritize putative causal genes for in vitro validation. We created a functional genomic framework to study MASLD genes in vitro using CRISPRi. Our data identify VKORC1, TNKS, LYPLAL1 and GPAM as regulators of lipid accumulation in hepatocytes and suggest the involvement of VKORC1 in the lipid storage related to the development of MASLD.Complementary genetic and genomic approaches are useful for the identification of MASLD genes. Our data supports VKORC1 as a bona fide MASLD gene. We have established a functional genomic framework to study at scale putative novel MASLD genes from human genetic association studies.
View details for DOI 10.1097/HEP.0000000000001066
View details for PubMedID 39190705
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Genetically predicted lipoprotein(a) associates with coronary artery plaque severity independent of low-density lipoprotein cholesterol.
European journal of preventive cardiology
2024
Abstract
Elevated Lipoprotein(a) [Lp(a)] is a causal risk factor for atherosclerotic cardiovascular disease, but the mechanisms of risk are debated. Studies have found inconsistent associations between Lp(a) and measurements of atherosclerosis. We aimed to assess the relationship between Lp(a), low-density lipoprotein cholesterol (LDL-C) and coronary artery plaque severity.The study population consisted of participants of the Million Veteran Program who have undergone an invasive angiogram. The primary exposure was genetically predicted Lp(a), estimated by a polygenic score. Genetically predicted LDL-C was also assessed for comparison. The primary outcome was coronary artery plaque severity, categorized as normal, non-obstructive disease, 1-vessel disease, 2-vessel disease, and 3-vessel or left main disease.Among 18,927 adults of genetically inferred European ancestry and 4,039 adults of genetically inferred African ancestry, we observed consistent associations between genetically predicted Lp(a) and obstructive coronary plaque, with effect sizes trending upward for increasingly severe categories of disease. Associations were independent of risk factors, clinically measured LDL-C and genetically predicted LDL-C. However, we did not find strong or consistent evidence for an association between genetically predicted Lp(a) and risk for non-obstructive plaque.Genetically predicted Lp(a) is positively associated with coronary plaque severity independent of LDL-C, consistent with Lp(a) promoting atherogenesis. However, the effects of Lp(a) may be greater for progression of plaque to obstructive disease than for the initial development of non-obstructive plaque. A limitation of this study is that Lp(a) was estimated using genetic markers and could not be directly assayed, nor could apo(a) isoform size.
View details for DOI 10.1093/eurjpc/zwae271
View details for PubMedID 39158116
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Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
Science (New York, N.Y.)
2024; 385 (6706): eadj1182
Abstract
One of the justifiable criticisms of human genetic studies is the underrepresentation of participants from diverse populations. Lack of inclusion must be addressed at-scale to identify causal disease factors and understand the genetic causes of health disparities. We present genome-wide associations for 2068 traits from 635,969 participants in the Department of Veterans Affairs Million Veteran Program, a longitudinal study of diverse United States Veterans. Systematic analysis revealed 13,672 genomic risk loci; 1608 were only significant after including non-European populations. Fine-mapping identified causal variants at 6318 signals across 613 traits. One-third (n = 2069) were identified in participants from non-European populations. This reveals a broadly similar genetic architecture across populations, highlights genetic insights gained from underrepresented groups, and presents an extensive atlas of genetic associations.
View details for DOI 10.1126/science.adj1182
View details for PubMedID 39024449
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Digital Footprints of Obesity Treatment: GLP-1 Receptor Agonists and the Health Equity Divide.
Circulation
2024; 150 (3): 171-173
Abstract
Our research investigates the societal implications of access to glucagon-like peptide-1 (GLP-1) agonists, particularly in light of recent clinical trials demonstrating the efficacy of semaglutide in reducing cardiovascular mortality. A decade-long analysis of Google Trends indicates a significant increase in searches for GLP-1 agonists, primarily in North America. This trend contrasts with the global prevalence of obesity. Given the high cost of GLP-1 agonists, a critical question arises: Will this disparity in medication accessibility exacerbate the global health equity gap in obesity treatment? This viewpoint explores strategies to address the health equity gap exacerbated by this emerging medication. Because GLP-1 agonists hold the potential to become a cornerstone in obesity treatment, ensuring equitable access is a pressing public health concern.
View details for DOI 10.1161/CIRCULATIONAHA.124.069680
View details for PubMedID 39008562
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Increased BMI associated with decreased breastfeeding initiation in Million Veteran Program participants.
medRxiv : the preprint server for health sciences
2024
Abstract
Background: Breastfeeding has been associated with maternal and infant health benefits but has been inversely associated with body mass index (BMI) prepartum. Breastfeeding and BMI are both linked to socioeconomic factors.Methods: Data from parous female participants with available breastfeeding information from the Million Veteran Program cohort was included. BMI at enrollment and earliest BMI available were extracted, and polygenic scores (PGS) for BMI were calculated. We modeled breastfeeding for one month or more as a function of BMI at enrollment; earliest BMI where available pre-pregnancy; and PGS for BMI. We conducted Mendelian randomization for breastfeeding initiation using PGS as an instrumental variable.Results: A higher BMI predicted a lower likelihood of breastfeeding for one month or more in all analyses. A +5 kg/m 2 BMI pre-pregnancy was associated with a 24% reduced odds of breastfeeding, and a +5 kg/m 2 genetically predicted BMI was associated with a 17% reduced odds of breastfeeding.Conclusions: BMI predicts a lower likelihood of breastfeeding for one month or longer. Given the high success of breastfeeding initiation regardless of BMI in supportive environments as well as potential health benefits, patients with elevated BMI may benefit from additional postpartum breastfeeding support.
View details for DOI 10.1101/2024.07.02.24309047
View details for PubMedID 39006437
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Mendelian randomization analyses clarify the effects of height on cardiovascular diseases.
PloS one
2024; 19 (7): e0298786
Abstract
An inverse correlation between stature and risk of coronary artery disease (CAD) has been observed in several epidemiologic studies, and recent Mendelian randomization (MR) experiments have suggested causal association. However, the extent to which the effect estimated by MR can be explained by cardiovascular, anthropometric, lung function, and lifestyle-related risk factors is unclear, with a recent report suggesting that lung function traits could fully explain the height-CAD effect. To clarify this relationship, we utilized a well-powered set of genetic instruments for human stature, comprising >1,800 genetic variants for height and CAD. In univariable analysis, we confirmed that a one standard deviation decrease in height (~6.5 cm) was associated with a 12.0% increase in the risk of CAD, consistent with previous reports. In multivariable analysis accounting for effects from up to 12 established risk factors, we observed a >3-fold attenuation in the causal effect of height on CAD susceptibility (3.7%, p = 0.02). However, multivariable analyses demonstrated independent effects of height on other cardiovascular traits beyond CAD, consistent with epidemiologic associations and univariable MR experiments. In contrast with published reports, we observed minimal effects of lung function traits on CAD risk in our analyses, indicating that these traits are unlikely to explain the residual association between height and CAD risk. In sum, these results suggest the impact of height on CAD risk beyond previously established cardiovascular risk factors is minimal and not explained by lung function measures.
View details for DOI 10.1371/journal.pone.0298786
View details for PubMedID 38959188
View details for PubMedCentralID PMC11221663
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Design and Pilot Results from Million Veteran Program Return Of Actionable Genetic Results (MVP-ROAR) Study.
American heart journal
2024
Abstract
As a mega-biobank linked to a national healthcare system, the Million Veteran Program (MVP) can directly improve the health care of participants. To determine the feasibility and outcomes of returning medically actionable genetic results to MVP participants, the program launched the MVP Return Of Actionable Results (MVP-ROAR) Study, with familial hypercholesterolemia (FH) as an exemplar actionable condition.The MVP-ROAR Study consists of a completed single-arm pilot phase and an ongoing randomized clinical trial (RCT), in which MVP participants are recontacted and invited to receive clinical confirmatory gene sequencing testing and a telegenetic counseling intervention. The primary outcome of the RCT is 6-month change in low-density lipoprotein cholesterol (LDL-C) between participants receiving results at baseline and those receiving results after 6 months.The pilot developed processes to identify and recontact participants nationally with probable pathogenic variants in low-density lipoprotein receptor (LDLR) on the MVP genotype array, invite them to clinical confirmatory gene sequencing, and deliver a telegenetic counseling intervention. Among participants in the pilot phase, 8 (100%) had active statin prescriptions after 6 months. Results were shared with 16 first-degree family members. Six-month ΔLDL-C (low-density lipoprotein cholesterol) after the genetic counseling intervention was -37 mg/dL (95% CI: -12 to -61; p=0.03). The ongoing RCT will determine between-arm differences in this primary outcome.While underscoring the importance of clinical confirmation of research results, the pilot phase of the MVP-ROAR Study marks a turning point in MVP and demonstrates the feasibility of returning genetic results to participants and their providers. The ongoing RCT will contribute to understanding how such a program might improve patient health care and outcomes.
View details for DOI 10.1016/j.ahj.2024.04.021
View details for PubMedID 38762090
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Identifying therapeutic targets for cancer among 2074 circulating proteins and risk of nine cancers.
Nature communications
2024; 15 (1): 3621
Abstract
Circulating proteins can reveal key pathways to cancer and identify therapeutic targets for cancer prevention. We investigate 2,074 circulating proteins and risk of nine common cancers (bladder, breast, endometrium, head and neck, lung, ovary, pancreas, kidney, and malignant non-melanoma) using cis protein Mendelian randomisation and colocalization. We conduct additional analyses to identify adverse side-effects of altering risk proteins and map cancer risk proteins to drug targets. Here we find 40 proteins associated with common cancers, such as PLAUR and risk of breast cancer [odds ratio per standard deviation increment: 2.27, 1.88-2.74], and with high-mortality cancers, such as CTRB1 and pancreatic cancer [0.79, 0.73-0.85]. We also identify potential adverse effects of protein-altering interventions to reduce cancer risk, such as hypertension. Additionally, we report 18 proteins associated with cancer risk that map to existing drugs and 15 that are not currently under clinical investigation. In sum, we identify protein-cancer links that improve our understanding of cancer aetiology. We also demonstrate that the wider consequence of any protein-altering intervention on well-being and morbidity is required to interpret any utility of proteins as potential future targets for therapeutic prevention.
View details for DOI 10.1038/s41467-024-46834-3
View details for PubMedID 38684708
View details for PubMedCentralID 7294238
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Development and utility of a clinical research informatics application for participant recruitment and workflow management for a return of results pilot trial in familial hypercholesterolemia in the Million Veteran Program.
JAMIA open
2024; 7 (1): ooae020
Abstract
Objective: The development of clinical research informatics tools and workflow processes associated with re-engaging biobank participants has become necessary as genomic repositories increasingly consider the return of actionable research results.Materials and Methods: Here we describe the development and utility of an informatics application for participant recruitment and enrollment management for the Veterans Affairs Million Veteran Program Return Of Actionable Results Study, a randomized controlled pilot trial returning individual genetic results associated with familial hypercholesterolemia.Results: The application is developed in Python-Flask and was placed into production in November 2021. The application includes modules for chart review, medication reconciliation, participant contact and biospecimen logging, survey recording, randomization, and documentation of genetic counseling and result disclosure. Three primary users, a genetic counselor and two research coordinators, and 326 Veteran participants have been integrated into the system as of February 23, 2023. The application has successfully handled 3367 task requests involving greater than 95000 structured data points. Specifically, application users have recorded 326 chart reviews, 867 recruitment telephone calls, 158 telephone-based surveys, and 61 return of results genetic counseling sessions, among other available study tasks.Conclusion: The development of usable, customizable, and secure informatics tools will become increasingly important as large genomic repositories begin to return research results at scale. Our work provides a proof-of-concept for developing and using such tools to aid in managing the return of results process within a national biobank.
View details for DOI 10.1093/jamiaopen/ooae020
View details for PubMedID 38464744
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Multi-Ancestry Polygenic Risk Score for Coronary Heart Disease Based on an Ancestrally Diverse Genome-Wide Association Study and Population-Specific Optimization.
Circulation. Genomic and precision medicine
2024: e004272
Abstract
Predictive performance of polygenic risk scores (PRS) varies across populations. To facilitate equitable clinical use, we developed PRS for coronary heart disease (CHD; PRSCHD) for 5 genetic ancestry groups.We derived ancestry-specific and multi-ancestry PRSCHD based on pruning and thresholding and continuous shrinkage priors (polygenic risk score for CHD developed using ancestry-based continuous shrinkage methods) applied to summary statistics from the largest multi-ancestry genome-wide association study meta-analysis for CHD to date, including 1.1 million participants from 5 major genetic ancestry groups. Following training and optimization in the Million Veteran Program, we evaluated the best-performing PRSCHD in 176 988 individuals across 9 diverse cohorts.Multi-ancestry polygenic risk score for CHD developed using pruning and thresholding methods and polygenic risk score for CHD developed using ancestry-based continuous shrinkage methods outperformed ancestry-specific Polygenic risk score for CHD developed using pruning and thresholding methods and polygenic risk score for CHD developed using ancestry-based continuous shrinkage methods across a range of tuning values. Two best-performing multi-ancestry PRSCHD (ie, polygenic risk score for CHD developed using pruning and thresholding methods optimized using a multi-ancestry population and polygenic risk score for CHD developed using ancestry-based continuous shrinkage methods optimized using a multi-ancestry population) and 1 ancestry-specific (PRSCSxEUR) were taken forward for validation. Polygenic risk score for CHD developed using pruning and thresholding methods (PT) optimized using a multi-ancestry population demonstrated the strongest association with CHD in individuals of South Asian genetic ancestry and European genetic ancestry (odds ratio per 1 SD [95% CI, 2.75 [2.41-3.14], 1.65 [1.59-1.72]), followed by East Asian genetic ancestry (1.56 [1.50-1.61]), Hispanic/Latino genetic ancestry (1.38 [1.24-1.54]), and African genetic ancestry (1.16 [1.11-1.21]). Polygenic risk score for CHD developed using ancestry-based continuous shrinkage methods optimized using a multi-ancestry population showed the strongest associations in South Asian genetic ancestry (2.67 [2.38-3.00]) and European genetic ancestry (1.65 [1.59-1.71]), lower in East Asian genetic ancestry (1.59 [1.54-1.64]), Hispanic/Latino genetic ancestry (1.51 [1.35-1.69]), and the lowest in African genetic ancestry (1.20 [1.15-1.26]).The use of summary statistics from a large multi-ancestry genome-wide meta-analysis improved the performance of PRSCHD in most ancestry groups compared with single-ancestry methods. Despite the use of one of the largest and most diverse sets of training and validation cohorts to date, improvement of predictive performance was limited in African genetic ancestry. This highlights the need for larger Genome-wide association study datasets of underrepresented populations to enhance the performance of PRSCHD.
View details for DOI 10.1161/CIRCGEN.123.004272
View details for PubMedID 38380516
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A functional genomic framework to elucidate novel causal non-alcoholic fatty liver disease genes.
medRxiv : the preprint server for health sciences
2024
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver pathology in western countries, with serious public health consequences. Efforts to identify causal genes for NAFLD have been hampered by the relative paucity of human data from gold-standard magnetic resonance quantification of hepatic fat. To overcome insufficient sample size, genome-wide association studies using NAFLD surrogate phenotypes have been used, but only a small number of loci have been identified to date. In this study, we combined GWAS of NAFLD composite surrogate phenotypes with genetic colocalization studies followed by functional in vitro screens to identify bona fide causal genes for NAFLD.We used the UK Biobank to explore the associations of our novel NAFLD score, and genetic colocalization to prioritize putative causal genes for in vitro validation. We created a functional genomic framework to study NAFLD genes in vitro using CRISPRi. Our data identify VKORC1, TNKS, LYPLAL1 and GPAM as regulators of lipid accumulation in hepatocytes and suggest the involvement of VKORC1 in the lipid storage related to the development of NAFLD.Complementary genetic and genomic approaches are useful for the identification of NAFLD genes. Our data supports VKORC1 as a bona fide NAFLD gene. We have established a functional genomic framework to study at scale putative novel NAFLD genes from human genetic association studies.
View details for DOI 10.1101/2024.02.03.24302258
View details for PubMedID 38352379
View details for PubMedCentralID PMC10863038
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Diet Quality and Epigenetic Aging in the Women's Health Initiative.
Journal of the Academy of Nutrition and Dietetics
2024
Abstract
Higher diet quality scores are associated with a lower risk for many chronic diseases and all-cause mortality; however, it is unclear if diet quality is associated with aging biology.This study aimed to examine the association between diet quality and a measure of biological aging - epigenetic aging.A cross-sectional data analysis was used to examine the association between three diet quality scores based on self-reported food frequency questionnaire (FFQ) data and five measures of epigenetic aging based on DNA methylation (DNAm) data from peripheral blood.This study included 4,500 postmenopausal women recruited from multiple sites across the United States (1993-1998), aged 50-79 years, with FFQ and DNAm data available from the Women's Health Initiative (WHI) baseline visit.Five established epigenetic aging measures were generated from HumanMethylation450 Beadchip DNAm data, including AgeAccelHannum, AgeAccelHorvath, AgeAccelPheno, AgeAccelGrim, and DunedinPACE.Linear mixed models were used to test for associations between three diet quality scores [Healthy Eating Index (HEI-2015), Dietary Approaches to Stop Hypertension (DASH), and alternate Mediterranean (aMED) diet scores] and epigenetic aging measures, adjusted for age, race and ethnicity, education, tobacco smoking, physical activity, WHI sub-study from which DNAm data were obtained, and DNAm-based estimates of leukocyte proportions.HEI-2015, DASH, and aMED scores were all inversely associated with AgeAccelPheno, AgeAccelGrim, and DunedinPACE (p<0.05), with the largest effects with DunedinPACE. A one-standard deviation (SD) increment in diet quality scores was associated with a decrement (Beta ± SE) in DunedinPACE z-score of -0.097 ± 0.014 (p = 9.70E-13) for HEI-2015, -0.107 ± 0.014 (p = 1.53E-14) for DASH, and -0.068 ± 0.013 (p = 2.31E-07) for aMED.In postmenopausal women, diet quality scores were inversely associated with DNAm-based measures of biological aging, particularly DunedinPACE.
View details for DOI 10.1016/j.jand.2024.01.002
View details for PubMedID 38215906
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Cardiorespiratory Fitness and Risk of Heart Failure with Preserved Ejection Fraction.
European journal of heart failure
2023
Abstract
Preventive strategies for heart failure (HF) with preserved ejection fraction (HFpEF) include pharmacotherapies and lifestyle modifications. However, the association between cardiorespiratory fitness (CRF) assessed objectively by a standardized exercise treadmill test (ETT) and the risk of HFpEF has not been evaluated. Thus, we evaluated the association between CRF and HFpEF incidence.We assessed CRF in US Veterans (624,551 men; mean age 61.2 ± 9.7 years and 43,179 women; mean age 55.0±8.9 years) by a standardized ETT performed between 1999-2020 across US Veterans Affairs Medical Centers. All had no evidence of HF or myocardial infarction prior to completion of the ETT. We assigned participants to one of five age-and-gender-specific CRF categories (quintiles) based on peak metabolic equivalents (METs) achieved during the ETT and four categories based on CRF changes in those with two ETT evaluations (n=139,434) ≥1.0 year apart. During the median follow-up of 10.1 years (IQR 6.0-14.3 years), providing 6,879,229 person-years, there were 16,493 HFpEF events with an average annual rate of 2.4 events per 1,000 person-years. The adjusted risk of HFpEF decreased across CRF categories as CRF increased, independent of comorbidities. For fit individuals (≥10.5 METs) the hazard ratio (HR) was 0.48 (95% CI 0.46-0.51) compared with least fit (≤ 4.9 METs; referent). Being unfit carried the highest risk (HR, 2.88; 95% CI, 2.67-3.11) of any other comorbidity. The risk of unfit individuals who became fit was 37% lower (HR 0.63, 95% CI 0.57-0.71), compared to those who remained unfit.Higher CRF levels are independently associated with lower HRpEF in a dose-response manner. Changes in CRF reflected proportional changes in HFpEF risk, suggesting that the HFpEF risk was modulated by CRF. This article is protected by copyright. All rights reserved.
View details for DOI 10.1002/ejhf.3117
View details for PubMedID 38152843
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Mendelian randomization analyses suggest a causal role for circulating GIP and IL-1RA levels in homeostatic model assessment-derived measures of β-cell function and insulin sensitivity in Africans without type 2 diabetes.
Genome medicine
2023; 15 (1): 108
Abstract
In vitro and in vivo studies have shown that certain cytokines and hormones may play a role in the development and progression of type 2 diabetes (T2D). However, studies on their role in T2D in humans are scarce. We evaluated associations between 11 circulating cytokines and hormones with T2D among a population of sub-Saharan Africans and tested for causal relationships using Mendelian randomization (MR) analyses.We used logistic regression analysis adjusted for age, sex, body mass index, and recruitment country to regress levels of 11 cytokines and hormones (adipsin, leptin, visfatin, PAI-1, GIP, GLP-1, ghrelin, resistin, IL-6, IL-10, IL-1RA) on T2D among Ghanaians, Nigerians, and Kenyans from the Africa America Diabetes Mellitus study including 2276 individuals with T2D and 2790 non-T2D individuals. Similar linear regression models were fitted with homeostatic modelling assessments of insulin sensitivity (HOMA-S) and β-cell function (HOMA-B) as dependent variables among non-T2D individuals (n = 2790). We used 35 genetic variants previously associated with at least one of these 11 cytokines and hormones among non-T2D individuals as instrumental variables in univariable and multivariable MR analyses. Statistical significance was set at 0.0045 (0.05/11 cytokines and hormones).Circulating GIP and IL-1RA levels were associated with T2D. Nine of the 11 cytokines and hormones (exceptions GLP-1 and IL-6) were associated with HOMA-S, HOMA-B, or both among non-T2D individuals. Two-stage least squares MR analysis provided evidence for a causal effect of GIP and IL-RA on HOMA-S and HOMA-B in multivariable analyses (GIP ~ HOMA-S β = - 0.67, P-value = 1.88 × 10-6 and HOMA-B β = 0.59, P-value = 1.88 × 10-5; IL-1RA ~ HOMA-S β = - 0.51, P-value = 8.49 × 10-5 and HOMA-B β = 0.48, P-value = 5.71 × 10-4). IL-RA was partly mediated via BMI (30-34%), but GIP was not. Inverse variance weighted MR analysis provided evidence for a causal effect of adipsin on T2D (multivariable OR = 1.83, P-value = 9.79 × 10-6), though these associations were not consistent in all sensitivity analyses.The findings of this comprehensive MR analysis indicate that circulating GIP and IL-1RA levels are causal for reduced insulin sensitivity and increased β-cell function. GIP's effect being independent of BMI suggests that circulating levels of GIP could be a promising early biomarker for T2D risk. Our MR analyses do not provide conclusive evidence for a causal role of other circulating cytokines in T2D among sub-Saharan Africans.
View details for DOI 10.1186/s13073-023-01263-7
View details for PubMedID 38049854
View details for PubMedCentralID 6523054
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Whole-genome sequencing uncovers two loci for coronary artery calcification and identifies ARSE as a regulator of vascular calcification
NATURE CARDIOVASCULAR RESEARCH
2023; 2 (12): 1159-+
View details for DOI 10.1038/s44161-023-00375-y
View details for Web of Science ID 001124837200021
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Whole-genome sequencing uncovers two loci for coronary artery calcification and identifies ARSE as a regulator of vascular calcification.
Nature cardiovascular research
2023; 2 (12): 1159-1172
Abstract
Coronary artery calcification (CAC) is a measure of atherosclerosis and a well-established predictor of coronary artery disease (CAD) events. Here we describe a genome-wide association study (GWAS) of CAC in 22,400 participants from multiple ancestral groups. We confirmed associations with four known loci and identified two additional loci associated with CAC (ARSE and MMP16), with evidence of significant associations in replication analyses for both novel loci. Functional assays of ARSE and MMP16 in human vascular smooth muscle cells (VSMCs) demonstrate that ARSE is a promoter of VSMC calcification and VSMC phenotype switching from a contractile to a calcifying or osteogenic phenotype. Furthermore, we show that the association of variants near ARSE with reduced CAC is likely explained by reduced ARSE expression with the G allele of enhancer variant rs5982944. Our study highlights ARSE as an important contributor to atherosclerotic vascular calcification, and a potential drug target for vascular calcific disease.
View details for DOI 10.1038/s44161-023-00375-y
View details for PubMedID 38817323
View details for PubMedCentralID PMC11138106
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Plasma Protein Profiling of Incident Cardiovascular Diseases: A Multisample Evaluation.
Circulation. Genomic and precision medicine
2023: e004233
Abstract
Proteomic profiling could potentially disclose new pathophysiological pathways for cardiovascular diseases (CVD) and improve prediction at the individual level. We therefore aimed to study the plasma protein profile associated with the incidence of different CVDs.Plasma levels of 245 proteins suspected to be linked to CVD or metabolism were measured in 4 Swedish prospective population-based cohorts (SIMPLER [Swedish Infrastructure for Medical Population-Based Life-Course and Environmental Research], ULSAM (Uppsala Longitudinal Study of Adult Men), EpiHealth, and POEM [Prospective Investigation of Obesity, Energy Production, and Metabolism]) comprising 11 869 individuals, free of CVD diagnoses at baseline. Our primary CVD outcome was defined by a combined end point that included either incident myocardial infarction, stroke, or heart failure.Using a discovery/validation approach, 42 proteins were associated with our primary composite end point occurring in 1163 subjects. In separate meta-analyses for each of the 3 CVD outcomes, 49 proteins were related to myocardial infarction, 34 to ischemic stroke, and 109 to heart failure. Thirteen proteins were related to all 3 outcomes. Of those, urokinase plasminogen activator surface receptor, adrenomedullin, and KIM-1 (kidney injury molecule 1) were also related to several markers of subclinical CVD in Prospective Investigation of Obesity, Energy production and Metabolism, reflecting myocardial or arterial pathologies. In prediction analysis, a lasso selection of 11 proteins in ULSAM improved the discrimination of CVD by 3.3% (P<0.0001) in SIMPLER when added to traditional risk factors.Protein profiling in multiple samples disclosed several new proteins to be associated with subsequent myocardial infarction, stroke, and heart failure, suggesting common pathophysiological pathways for these diseases. KIM-1, urokinase plasminogen activator surface receptor, and adrenomedullin were novel early markers of CVD. A selection of 11 proteins improved the discrimination of CVD.
View details for DOI 10.1161/CIRCGEN.123.004233
View details for PubMedID 38014560
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C-X-C Motif Chemokine Ligand 12 is a Primary Determinant of Coronary Artery Dominance
LIPPINCOTT WILLIAMS & WILKINS. 2023
View details for DOI 10.1161/circ.148.suppl_1.16503
View details for Web of Science ID 001157891306224
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CXCL12 regulates coronary artery dominance in diverse populations and links development to disease.
medRxiv : the preprint server for health sciences
2023
Abstract
Mammalian cardiac muscle is supplied with blood by right and left coronary arteries that form branches covering both ventricles of the heart. Whether branches of the right or left coronary arteries wrap around to the inferior side of the left ventricle is variable in humans and termed right or left dominance. Coronary dominance is likely a heritable trait, but its genetic architecture has never been explored. Here, we present the first large-scale multi-ancestry genome-wide association study of dominance in 61,043 participants of the VA Million Veteran Program, including over 10,300 Africans and 4,400 Admixed Americans. Dominance was moderately heritable with ten loci reaching genome wide significance. The most significant mapped to the chemokine CXCL12 in both Europeans and Africans. Whole-organ imaging of human fetal hearts revealed that dominance is established during development in locations where CXCL12 is expressed. In mice, dominance involved the septal coronary artery, and its patterning was altered with Cxcl12 deficiency. Finally, we linked human dominance patterns with coronary artery disease through colocalization, genome-wide genetic correlation and Mendelian Randomization analyses. Together, our data supports CXCL12 as a primary determinant of coronary artery dominance in humans of diverse backgrounds and suggests that developmental patterning of arteries may influence one's susceptibility to ischemic heart disease.
View details for DOI 10.1101/2023.10.27.23297507
View details for PubMedID 37961706
View details for PubMedCentralID PMC10635223
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CYP2C19 Polymorphisms and Clinical Outcomes Following Percutaneous Coronary Intervention (PCI) in the Million Veterans Program.
medRxiv : the preprint server for health sciences
2023
Abstract
CYP2C19 loss-of-function (LOF) alleles decrease the antiplatelet effect of clopidogrel following percutaneous coronary intervention (PCI) in patients presenting with acute coronary syndrome (ACS). The impact of genotype in stable ischemic heart disease (SIHD) is unclear.Determine the association of CYP2C19 genotype with major adverse cardiac events (MACE) after PCI for ACS or SIHD.Million Veterans Program (MVP) participants age <65 years with a PCI documented in the VA Clinical Assessment, Reporting and Tracking (CART) Program between 1/1/2009 to 9/30/2017, treated with clopidogrel were included. Time to MACE defined as the composite of all-cause death, stroke or myocardial infarction within 12 months following PCI.Among 4,461 Veterans (mean age 59.1 ± 5.1 years, 18% Black); 44% had ACS, 56% had SIHD and 29% carried a CYP2C19 LOF allele. 301 patients (6.7%) experienced MACE while being treated with clopidogrel, 155 (7.9%) in the ACS group and 146 (5.9%) in the SIHD group. Overall, MACE was not significantly different between LOF carriers vs. noncarriers (adjusted hazard ratio [HR] 1.18, confidence interval [95%CI] 0.97-1.45, p=0.096). Among patients presenting with ACS, MACE risk in LOF carriers versus non-carriers was numerically higher (HR 1.30, 95%CI 0.98-1.73, p=0.067). There was no difference in MACE risk in patients with SIHD (HR 1.09, 95%CI 0.82-1.44; p=0.565).CYP2C19 LOF carriers presenting with ACS treated with clopidogrel following PCI experienced a numerically greater elevated risk of MACE events. CYP2C19 LOF genotype is not associated with MACE among patients presenting with SIHD.
View details for DOI 10.1101/2023.10.25.23297578
View details for PubMedID 37961335
View details for PubMedCentralID PMC10635203
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Multi-ancestry genome-wide study identifies effector genes and druggable pathways for coronary artery calcification.
Nature genetics
2023
Abstract
Coronary artery calcification (CAC), a measure of subclinical atherosclerosis, predicts future symptomatic coronary artery disease (CAD). Identifying genetic risk factors for CAC may point to new therapeutic avenues for prevention. Currently, there are only four known risk loci for CAC identified from genome-wide association studies (GWAS) in the general population. Here we conducted the largest multi-ancestry GWAS meta-analysis of CAC to date, which comprised 26,909 individuals of European ancestry and 8,867 individuals of African ancestry. We identified 11 independent risk loci, of which eight were new for CAC and five had not been reported for CAD. These new CAC loci are related to bone mineralization, phosphate catabolism and hormone metabolic pathways. Several new loci harbor candidate causal genes supported by multiple lines of functional evidence and are regulators of smooth muscle cell-mediated calcification ex vivo and in vitro. Together, these findings help refine the genetic architecture of CAC and extend our understanding of the biological and potential druggable pathways underlying CAC.
View details for DOI 10.1038/s41588-023-01518-4
View details for PubMedID 37770635
View details for PubMedCentralID 3033741
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Assessing efficiency of fine-mapping obesity-associated variants through leveraging ancestry architecture and functional annotation using PAGE and UKBB cohorts.
Human genetics
2023
Abstract
Inadequate representation of non-European ancestry populations in genome-wide association studies (GWAS) has limited opportunities to isolate functional variants. Fine-mapping in multi-ancestry populations should improve the efficiency of prioritizing variants for functional interrogation. To evaluate this hypothesis, we leveraged ancestry architecture to perform comparative GWAS and fine-mapping of obesity-related phenotypes in European ancestry populations from the UK Biobank (UKBB) and multi-ancestry samples from the Population Architecture for Genetic Epidemiology (PAGE) consortium with comparable sample sizes. In the investigated regions with genome-wide significant associations for obesity-related traits, fine-mapping in our ancestrally diverse sample led to 95% and 99% credible sets (CS) with fewer variants than in the European ancestry sample. Lead fine-mapped variants in PAGE regions had higher average coding scores, and higher average posterior probabilities for causality compared to UKBB. Importantly, 99% CS in PAGE loci contained strong expression quantitative trait loci (eQTLs) in adipose tissues or harbored more variants in tighter linkage disequilibrium (LD) with eQTLs. Leveraging ancestrally diverse populations with heterogeneous ancestry architectures, coupled with functional annotation, increased fine-mapping efficiency and performance, and reduced the set of candidate variants for consideration for future functional studies. Significant overlap in genetic causal variants across populations suggests generalizability of genetic mechanisms underpinning obesity-related traits across populations.
View details for DOI 10.1007/s00439-023-02593-7
View details for PubMedID 37658231
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Carriers of rare damaging CCR2 genetic variants are at lower risk of atherosclerotic disease.
medRxiv : the preprint server for health sciences
2023
Abstract
The CCL2/CCR2 axis governs monocyte trafficking and recruitment to atherosclerotic lesions. Human genetic analyses and population-based studies support an association between circulating CCL2 levels and atherosclerosis. Still, it remains unknown whether pharmacological targeting of CCR2, the main CCL2 receptor, would provide protection against human atherosclerotic disease.In whole-exome sequencing data from 454,775 UK Biobank participants (40-69 years), we identified predicted loss-of-function (LoF) or damaging missense (REVEL score >0.5) variants within the CCR2 gene. We prioritized variants associated with lower monocyte count (p<0.05) and tested associations with vascular risk factors and risk of atherosclerotic disease over a mean follow-up of 14 years. The results were replicated in a pooled cohort of three independent datasets (TOPMed, deCODE and Penn Medicine BioBank; total n=441,445) and the effect of the most frequent damaging variant was experimentally validated.A total of 45 predicted LoF or damaging missense variants were identified in the CCR2 gene, 4 of which were also significantly associated with lower monocyte count, but not with other white blood cell counts. Heterozygous carriers of these variants were at a lower risk of a combined atherosclerosis outcome, showed a lower burden of atherosclerosis across four vascular beds, and were at a lower lifetime risk of coronary artery disease and myocardial infarction. There was no evidence of association with vascular risk factors including LDL-cholesterol, blood pressure, glycemic status, or C-reactive protein. Using a cAMP assay, we found that cells transfected with the most frequent CCR2 damaging variant (3:46358273:T:A, M249K, 547 carriers, frequency: 0.14%) show a decrease in signaling in response to CCL2. The associations of the M249K variant with myocardial infarction were consistent across cohorts (ORUKB: 0.62 95%CI: 0.39-0.96; ORexternal: 0.64 95%CI: 0.34-1.19; ORpooled: 0.64 95%CI: 0.450.90). In a phenome-wide association study, we found no evidence for higher risk of common infections or mortality among carriers of damaging CCR2 variants.Heterozygous carriers of damaging CCR2 variants have a lower burden of atherosclerosis and lower lifetime risk of myocardial infarction. In conjunction with previous evidence from experimental and epidemiological studies, our findings highlight the translational potential of CCR2-targeting as an atheroprotective approach.
View details for DOI 10.1101/2023.08.14.23294063
View details for PubMedID 37645892
View details for PubMedCentralID PMC10462211
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Proteomic analysis of 92 circulating proteins and their effects in cardiometabolic diseases.
Clinical proteomics
2023; 20 (1): 31
Abstract
Human plasma contains a wide variety of circulating proteins. These proteins can be important clinical biomarkers in disease and also possible drug targets. Large scale genomics studies of circulating proteins can identify genetic variants that lead to relative protein abundance.We conducted a meta-analysis on genome-wide association studies of autosomal chromosomes in 22,997 individuals of primarily European ancestry across 12 cohorts to identify protein quantitative trait loci (pQTL) for 92 cardiometabolic associated plasma proteins.We identified 503 (337 cis and 166 trans) conditionally independent pQTLs, including several novel variants not reported in the literature. We conducted a sex-stratified analysis and found that 118 (23.5%) of pQTLs demonstrated heterogeneity between sexes. The direction of effect was preserved but there were differences in effect size and significance. Additionally, we annotate trans-pQTLs with nearest genes and report plausible biological relationships. Using Mendelian randomization, we identified causal associations for 18 proteins across 19 phenotypes, of which 10 have additional genetic colocalization evidence. We highlight proteins associated with a constellation of cardiometabolic traits including angiopoietin-related protein 7 (ANGPTL7) and Semaphorin 3F (SEMA3F).Through large-scale analysis of protein quantitative trait loci, we provide a comprehensive overview of common variants associated with plasma proteins. We highlight possible biological relationships which may serve as a basis for further investigation into possible causal roles in cardiometabolic diseases.
View details for DOI 10.1186/s12014-023-09421-0
View details for PubMedID 37550624
View details for PubMedCentralID PMC10405520
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Genetic insights into resting heart rate and its role in cardiovascular disease.
Nature communications
2023; 14 (1): 4646
Abstract
Resting heart rate is associated with cardiovascular diseases and mortality in observational and Mendelian randomization studies. The aims of this study are to extend the number of resting heart rate associated genetic variants and to obtain further insights in resting heart rate biology and its clinical consequences. A genome-wide meta-analysis of 100 studies in up to 835,465 individuals reveals 493 independent genetic variants in 352 loci, including 68 genetic variants outside previously identified resting heart rate associated loci. We prioritize 670 genes and in silico annotations point to their enrichment in cardiomyocytes and provide insights in their ECG signature. Two-sample Mendelian randomization analyses indicate that higher genetically predicted resting heart rate increases risk of dilated cardiomyopathy, but decreases risk of developing atrial fibrillation, ischemic stroke, and cardio-embolic stroke. We do not find evidence for a linear or non-linear genetic association between resting heart rate and all-cause mortality in contrast to our previous Mendelian randomization study. Systematic alteration of key differences between the current and previous Mendelian randomization study indicates that the most likely cause of the discrepancy between these studies arises from false positive findings in previous one-sample MR analyses caused by weak-instrument bias at lower P-value thresholds. The results extend our understanding of resting heart rate biology and give additional insights in its role in cardiovascular disease development.
View details for DOI 10.1038/s41467-023-39521-2
View details for PubMedID 37532724
View details for PubMedCentralID PMC10397318
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Systems Age: A single blood methylation test to quantify aging heterogeneity across 11 physiological systems.
bioRxiv : the preprint server for biology
2023
Abstract
Individuals, organs, tissues, and cells age in diverse ways throughout the lifespan. Epigenetic clocks attempt to quantify differential aging between individuals, but they typically summarize aging as a single measure, ignoring within-person heterogeneity. Our aim was to develop novel systems-based methylation clocks that, when assessed in blood, capture aging in distinct physiological systems. We combined supervised and unsupervised machine learning methods to link DNA methylation, system-specific clinical chemistry and functional measures, and mortality risk. This yielded a panel of 11 system-specific scores- Heart, Lung, Kidney, Liver, Brain, Immune, Inflammatory, Blood, Musculoskeletal, Hormone, and Metabolic. Each system score predicted a wide variety of outcomes, aging phenotypes, and conditions specific to the respective system, and often did so more strongly than existing epigenetic clocks that report single global measures. We also combined the system scores into a composite Systems Age clock that is predictive of aging across physiological systems in an unbiased manner. Finally, we showed that the system scores clustered individuals into unique aging subtypes that had different patterns of age-related disease and decline. Overall, our biological systems based epigenetic framework captures aging in multiple physiological systems using a single blood draw and assay and may inform the development of more personalized clinical approaches for improving age-related quality of life.
View details for DOI 10.1101/2023.07.13.548904
View details for PubMedID 37503069
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A multi-ancestry polygenic risk score improves risk prediction for coronary artery disease.
Nature medicine
2023
Abstract
Identification of individuals at highest risk of coronary artery disease (CAD)-ideally before onset-remains an important public health need. Prior studies have developed genome-wide polygenic scores to enable risk stratification, reflecting the substantial inherited component to CAD risk. Here we develop a new and significantly improved polygenic score for CAD, termed GPSMult, that incorporates genome-wide association data across five ancestries for CAD (>269,000 cases and >1,178,000 controls) and ten CAD risk factors. GPSMult strongly associated with prevalent CAD (odds ratio per standard deviation 2.14, 95% confidence interval 2.10-2.19, P<0.001) in UK Biobank participants of European ancestry, identifying 20.0% of the population with 3-fold increased risk and conversely 13.9% with 3-fold decreased risk as compared with those in the middle quintile. GPSMult was also associated with incident CAD events (hazard ratio per standard deviation 1.73, 95% confidence interval 1.70-1.76, P<0.001), identifying 3% of healthy individuals with risk of future CAD events equivalent to those with existing disease and significantly improving risk discrimination and reclassification. Across multiethnic, external validation datasets inclusive of 33,096, 124,467, 16,433 and 16,874 participants of African, European, Hispanic and South Asian ancestry, respectively, GPSMult demonstrated increased strength of associations across all ancestries and outperformed all available previously published CAD polygenic scores. These data contribute a new GPSMult for CAD to the field and provide a generalizable framework for how large-scale integration of genetic association data for CAD and related traits from diverse populations can meaningfully improve polygenic risk prediction.
View details for DOI 10.1038/s41591-023-02429-x
View details for PubMedID 37414900
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Contemporary Polygenic Scores of Low-Density Lipoprotein Cholesterol and Coronary Artery Disease Predict Coronary Atherosclerosis in Adolescents and Young Adults.
Circulation. Genomic and precision medicine
2023: e004047
View details for DOI 10.1161/CIRCGEN.122.004047
View details for PubMedID 37409455
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Diversity and Scale: Genetic Architecture of 2,068 Traits in the VA Million Veteran Program.
medRxiv : the preprint server for health sciences
2023
Abstract
Genome-wide association studies (GWAS) have underrepresented individuals from non-European populations, impeding progress in characterizing the genetic architecture and consequences of health and disease traits. To address this, we present a population-stratified phenome-wide GWAS followed by a multi-population meta-analysis for 2,068 traits derived from electronic health records of 635,969 participants in the Million Veteran Program (MVP), a longitudinal cohort study of diverse U.S. Veterans genetically similar to the respective African (121,177), Admixed American (59,048), East Asian (6,702), and European (449,042) superpopulations defined by the 1000 Genomes Project. We identified 38,270 independent variants associating with one or more traits at experiment-wide P<4.6×10-11 significance; fine-mapping 6,318 signals identified from 613 traits to single-variant resolution. Among these, a third (2,069) of the associations were found only among participants genetically similar to non-European reference populations, demonstrating the importance of expanding diversity in genetic studies. Our work provides a comprehensive atlas of phenome-wide genetic associations for future studies dissecting the architecture of complex traits in diverse populations.
View details for DOI 10.1101/2023.06.28.23291975
View details for PubMedID 37425708
View details for PubMedCentralID PMC10327290
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Plasma proteomic signatures of a direct measure of insulin sensitivity in two population cohorts.
Diabetologia
2023
Abstract
The euglycaemic-hyperinsulinaemic clamp (EIC) is the reference standard for the measurement of whole-body insulin sensitivity but is laborious and expensive to perform. We aimed to assess the incremental value of high-throughput plasma proteomic profiling in developing signatures correlating with the M value derived from the EIC.We measured 828 proteins in the fasting plasma of 966 participants from the Relationship between Insulin Sensitivity and Cardiovascular disease (RISC) study and 745 participants from the Uppsala Longitudinal Study of Adult Men (ULSAM) using a high-throughput proximity extension assay. We used the least absolute shrinkage and selection operator (LASSO) approach using clinical variables and protein measures as features. Models were tested within and across cohorts. Our primary model performance metric was the proportion of the M value variance explained (R2).A standard LASSO model incorporating 53 proteins in addition to routinely available clinical variables increased the M value R2 from 0.237 (95% CI 0.178, 0.303) to 0.456 (0.372, 0.536) in RISC. A similar pattern was observed in ULSAM, in which the M value R2 increased from 0.443 (0.360, 0.530) to 0.632 (0.569, 0.698) with the addition of 61 proteins. Models trained in one cohort and tested in the other also demonstrated significant improvements in R2 despite differences in baseline cohort characteristics and clamp methodology (RISC to ULSAM: 0.491 [0.433, 0.539] for 51 proteins; ULSAM to RISC: 0.369 [0.331, 0.416] for 67 proteins). A randomised LASSO and stability selection algorithm selected only two proteins per cohort (three unique proteins), which improved R2 but to a lesser degree than in standard LASSO models: 0.352 (0.266, 0.439) in RISC and 0.495 (0.404, 0.585) in ULSAM. Reductions in improvements of R2 with randomised LASSO and stability selection were less marked in cross-cohort analyses (RISC to ULSAM R2 0.444 [0.391, 0.497]; ULSAM to RISC R2 0.348 [0.300, 0.396]). Models of proteins alone were as effective as models that included both clinical variables and proteins using either standard or randomised LASSO. The single most consistently selected protein across all analyses and models was IGF-binding protein 2.A plasma proteomic signature identified using a standard LASSO approach improves the cross-sectional estimation of the M value over routine clinical variables. However, a small subset of these proteins identified using a stability selection algorithm affords much of this improvement, especially when considering cross-cohort analyses. Our approach provides opportunities to improve the identification of insulin-resistant individuals at risk of insulin resistance-related adverse health consequences.
View details for DOI 10.1007/s00125-023-05946-z
View details for PubMedID 37329449
View details for PubMedCentralID 5866840
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A Multi-Ancestry Polygenic Risk Score for Coronary Heart Disease Based on an Ancestrally Diverse Genome-Wide Association Study and Population-Specific Optimization.
medRxiv : the preprint server for health sciences
2023
Abstract
Predictive performance of polygenic risk scores (PRS) varies across populations. To facilitate equitable clinical use, we developed PRS for coronary heart disease (PRSCHD) for 5 genetic ancestry groups.We derived ancestry-specific and multi-ancestry PRSCHD based on pruning and thresholding (PRSP+T) and continuous shrinkage priors (PRSCSx) applied on summary statistics from the largest multi-ancestry genome-wide meta-analysis for CHD to date, including 1.1 million participants from 5 continental populations. Following training and optimization of PRSCHD in the Million Veteran Program, we evaluated predictive performance of the best performing PRSCHD in 176,988 individuals across 9 cohorts of diverse genetic ancestry.Multi-ancestry PRSP+T outperformed ancestry specific PRSP+T across a range of tuning values. In training stage, for all ancestry groups, PRSCSx performed better than PRSP+T and multi-ancestry PRS outperformed ancestry-specific PRS. In independent validation cohorts, the selected multi-ancestry PRSP+T demonstrated the strongest association with CHD in individuals of South Asian (SAS) and European (EUR) ancestry (OR per 1SD[95% CI]; 2.75[2.41-3.14], 1.65[1.59-1.72]), followed by East Asian (EAS) (1.56[1.50-1.61]), Hispanic/Latino (HIS) (1.38[1.24-1.54]), and weakest in African (AFR) ancestry (1.16[1.11-1.21]). The selected multi-ancestry PRSCSx showed stronger associacion with CHD in comparison within each ancestry group where the association was strongest in SAS (2.67[2.38-3.00]) and EUR (1.65[1.59-1.71]), progressively decreasing in EAS (1.59[1.54-1.64]), HIS (1.51[1.35-1.69]), and lowest in AFR (1.20[1.15-1.26]).Utilizing diverse summary statistics from a large multi-ancestry genome-wide meta-analysis led to improved performance of PRSCHD in most ancestry groups compared to single-ancestry methods. Improvement of predictive performance was limited, specifically in AFR and HIS, despite use of one of the largest and most diverse set of training and validation cohorts to date. This highlights the need for larger GWAS datasets of AFR and HIS individuals to enhance performance of PRSCHD.
View details for DOI 10.1101/2023.06.02.23290896
View details for PubMedID 37609230
View details for PubMedCentralID PMC10441485
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Mendelian randomization analyses clarify the effects of height on cardiovascular diseases.
medRxiv : the preprint server for health sciences
2023
Abstract
An inverse correlation between stature and risk of coronary artery disease (CAD) has been observed in several epidemiologic studies, and recent Mendelian randomization (MR) experiments have suggested causal association. However, the extent to which the effect estimated by MR can be explained by established cardiovascular risk factors is unclear, with a recent report suggesting that lung function traits could fully explain the height-CAD effect. To clarify this relationship, we utilized a well-powered set of genetic instruments for human stature, comprising >1,800 genetic variants for height and CAD. In univariable analysis, we confirmed that a one standard deviation decrease in height (~6.5 cm) was associated with a 12.0% increase in the risk of CAD, consistent with previous reports. In multivariable analysis accounting for effects from up to 12 established risk factors, we observed a >3-fold attenuation in the causal effect of height on CAD susceptibility (3.7%, p = 0.02). However, multivariable analyses demonstrated independent effects of height on other cardiovascular traits beyond CAD, consistent with epidemiologic associations and univariable MR experiments. In contrast with published reports, we observed minimal effects of lung function traits on CAD risk in our analyses, indicating that these traits are unlikely to explain the residual association between height and CAD risk. In sum, these results suggest the impact of height on CAD risk beyond previously established cardiovascular risk factors is minimal and not explained by lung function measures.
View details for DOI 10.1101/2021.12.16.21267869
View details for PubMedID 37205563
View details for PubMedCentralID PMC10187353
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Cardiovascular Disease Risk Assessment Using Traditional Risk Factors and Polygenic Risk Scores in the Million Veteran Program.
JAMA cardiology
2023
Abstract
Importance: Primary prevention of atherosclerotic cardiovascular disease (ASCVD) relies on risk stratification. Genome-wide polygenic risk scores (PRSs) are proposed to improve ASCVD risk estimation.Objective: To determine whether genome-wide PRSs for coronary artery disease (CAD) and acute ischemic stroke improve ASCVD risk estimation with traditional clinical risk factors in an ancestrally diverse midlife population.Design, Setting, and Participants: This was a prognostic analysis of incident events in a retrospectively defined longitudinal cohort conducted from January 1, 2011, to December 31, 2018. Included in the study were adults free of ASCVD and statin naive at baseline from the Million Veteran Program (MVP), a mega biobank with genetic, survey, and electronic health record data from a large US health care system. Data were analyzed from March 15, 2021, to January 5, 2023.Exposures: PRSs for CAD and ischemic stroke derived from cohorts of largely European descent and risk factors, including age, sex, systolic blood pressure, total cholesterol, high-density lipoprotein (HDL) cholesterol, smoking, and diabetes status.Main Outcomes and Measures: Incident nonfatal myocardial infarction (MI), ischemic stroke, ASCVD death, and composite ASCVD events.Results: A total of 79 151 participants (mean [SD] age, 57.8 [13.7] years; 68 503 male [86.5%]) were included in the study. The cohort included participants from the following harmonized genetic ancestry and race and ethnicity categories: 18 505 non-Hispanic Black (23.4%), 6785 Hispanic (8.6%), and 53 861 non-Hispanic White (68.0%) with a median (5th-95th percentile) follow-up of 4.3 (0.7-6.9) years. From 2011 to 2018, 3186 MIs (4.0%), 1933 ischemic strokes (2.4%), 867 ASCVD deaths (1.1%), and 5485 composite ASCVD events (6.9%) were observed. CAD PRS was associated with incident MI in non-Hispanic Black (hazard ratio [HR], 1.10; 95% CI, 1.02-1.19), Hispanic (HR, 1.26; 95% CI, 1.09-1.46), and non-Hispanic White (HR, 1.23; 95% CI, 1.18-1.29) participants. Stroke PRS was associated with incident stroke in non-Hispanic White participants (HR, 1.15; 95% CI, 1.08-1.21). A combined CAD plus stroke PRS was associated with ASCVD deaths among non-Hispanic Black (HR, 1.19; 95% CI, 1.03-1.17) and non-Hispanic (HR, 1.11; 95% CI, 1.03-1.21) participants. The combined PRS was also associated with composite ASCVD across all ancestry groups but greater among non-Hispanic White (HR, 1.20; 95% CI, 1.16-1.24) than non-Hispanic Black (HR, 1.11; 95% CI, 1.05-1.17) and Hispanic (HR, 1.12; 95% CI, 1.00-1.25) participants. Net reclassification improvement from adding PRS to a traditional risk model was modest for the intermediate risk group for composite CVD among men (5-year risk >3.75%, 0.38%; 95% CI, 0.07%-0.68%), among women, (6.79%; 95% CI, 3.01%-10.58%), for age older than 55 years (0.25%; 95% CI, 0.03%-0.47%), and for ages 40 to 55 years (1.61%; 95% CI, -0.07% to 3.30%).Conclusions and Relevance: Study results suggest that PRSs derived predominantly in European samples were statistically significantly associated with ASCVD in the multiancestry midlife and older-age MVP cohort. Overall, modest improvement in discrimination metrics were observed with addition of PRSs to traditional risk factors with greater magnitude in women and younger age groups.
View details for DOI 10.1001/jamacardio.2023.0857
View details for PubMedID 37133828
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Genetics Of Physical Activity And Risk Of Cardiovascular Disease
LIPPINCOTT WILLIAMS & WILKINS. 2023
View details for DOI 10.1161/atvb.43.suppl_1.560
View details for Web of Science ID 001138201700315
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Circulating lipoprotein lipids and colorectal cancer risk: A Mendelian randomization analysis from the GECCO consortium
AMER ASSOC CANCER RESEARCH. 2023
View details for DOI 10.1158/1538-7445.AM2023-5223
View details for Web of Science ID 001008499104092
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Cardiovascular Disease and Mortality in Black Women Carrying the Amyloidogenic V122I Transthyretin Gene Variant.
JACC. Heart failure
2023
Abstract
Long-term data on cardiovascular disease (CVD) and mortality in female carriers of the transthyretin (TTR) V122I (pV142I) variant, one of the most common variants of hereditary transthyretin cardiac amyloidosis, are sparse and the effects of blood pressure, heart rate, body mass index, and physical activity on CVD outcomes remain largely unknown.The aim was to first examine the relationship of TTR V122I (pV142I) carrier status with CVD and mortality and second to investigate the effects of blood pressure, heart rate, body mass index, and physical activity in a large cohort of postmenopausal women.The study population consisted of 9,862 non-Hispanic Black/African American women, 9,529 noncarriers and 333 TTR V122I carriers, enrolled in the Women's Health Initiative at 40 centers in the United States. Women were generally healthy and postmenopausal at the time of enrollment (1993-1998). CVD was defined as a composite endpoint consisting of coronary heart disease, stroke, acute heart failure or CVD death, and all-cause mortality. CVD cases were based on self-reported annual mailed health updates. All information was centrally adjudicated by trained physicians. HRs and 95% CIs were obtained from adjusted Cox proportional hazards models.Among 9,862 Black female participants (mean age: 62 years [IQR: 56-67 years]), the population frequency of the TTR V122I variant was 3.4% (333 variant carriers and 9,529 noncarriers). During a mean follow-up of 16.1 years (IQR: 9.7-22.2 years), incident CVD occurred in 2,229 noncarriers and 96 carriers, whereas 2,689 noncarriers and 108 carriers died. In adjusted models including demographic, lifestyle, and medical history covariates, TTR V122I carriers were at higher risk of the composite endpoint CVD (HR: 1.52; 95% CI: 1.22-1.88), acute heart failure (HR: 2.21; 95% CI: 1.53-3.18), coronary heart disease (HR: 1.80; 95% CI: 1.30-2.47), CVD death (HR: 1.70; 95% CI: 1.26-2.30), and all-cause mortality (HR: 1.28; 95% CI: 1.04-1.56). The authors found a significant interaction by age but not by blood pressure, heart rate, body mass index, or physical activity.Black female TTR V122I (pV142I) carriers have a higher CVD and all-cause mortality risk compared to noncarriers. In case of clinical suspicion of amyloidosis, they should be screened for TTR V122I (pV142I) carrier status to ensure early treatment onset.
View details for DOI 10.1016/j.jchf.2023.02.003
View details for PubMedID 36930136
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Evaluation of the Association Between Circulating IL-1β and Other Inflammatory Cytokines and Incident Atrial Fibrillation in a Cohort of Postmenopausal Women.
American heart journal
2023
Abstract
Inflammatory cytokines play a role in atrial fibrillation (AF). Interleukin (IL)-1β, which is targeted in the treatment of ischemic heart disease, has not been well-studied in relation to AF.Postmenopausal women from the Women's Health Initiative were included. Cox proportional hazards regression models were used to evaluate the association between log-transformed baseline cytokine levels and future AF incidence. Models were adjusted for body mass index, age, race, education, hypertension, diabetes, hyperlipidemia, current smoking, and history of coronary heart disease, congestive heart failure, or peripheral artery disease.Of 16,729 women, 3,943 developed AF over an average of 8.5 years. Racial and ethnic groups included White (77.4%), Black/African-American (16.1%), Asian (2.7%), American Indian/Alaska Native (1.0%), and Hispanic (5.5%). Baseline IL-1β log continuous levels were not significantly associated with incident AF (HR 0.86 per 1 log (pg/mL) increase, p=0.24), similar to those of other inflammatory cytokines, IL-7, IL-8, IL-10, IGF-1, and TNF-α. There were significant associations between C-reactive protein (CRP) and IL-6 with incident AF.In this large cohort of postmenopausal women, there was no significant association between IL-1β and incident AF, although downstream effectors, CRP and IL-6, were associated with incident AF.
View details for DOI 10.1016/j.ahj.2023.01.010
View details for PubMedID 36646198
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Epigenome-wide meta-analysis of BMI in nine cohorts: Examining the utility of epigenetically predicted BMI.
American journal of human genetics
2023
Abstract
This study sought to examine the association between DNA methylation and body mass index (BMI) and the potential of BMI-associated cytosine-phosphate-guanine (CpG) sites to provide information about metabolic health. We pooled summary statistics from six trans-ethnic epigenome-wide association studies (EWASs) of BMI representing nine cohorts (n = 17,034), replicated these findings in the Women's Health Initiative (WHI, n = 4,822), and developed an epigenetic prediction score of BMI. In the pooled EWASs, 1,265 CpG sites were associated with BMI (p < 1E-7) and 1,238 replicated in the WHI (FDR < 0.05). We performed several stratified analyses to examine whether these associations differed between individuals of European and African descent, as defined by self-reported race/ethnicity. We found that five CpG sites had a significant interaction with BMI by race/ethnicity. To examine the utility of the significant CpG sites in predicting BMI, we used elastic net regression to predict log-normalized BMI in the WHI (80% training/20% testing). This model found that 397 sites could explain 32% of the variance in BMI in the WHI test set. Individuals whose methylome-predicted BMI overestimated their BMI (high epigenetic BMI) had significantly higher glucose and triglycerides and lower HDL cholesterol and LDL cholesterol compared to accurately predicted BMI. Individuals whose methylome-predicted BMI underestimated their BMI (low epigenetic BMI) had significantly higher HDL cholesterol and lower glucose and triglycerides. This study confirmed 553 and identified 685 CpG sites associated with BMI. Participants with high epigenetic BMI had poorer metabolic health, suggesting that the overestimation may be driven in part by cardiometabolic derangements characteristic of metabolic syndrome.
View details for DOI 10.1016/j.ajhg.2022.12.014
View details for PubMedID 36649705
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Whole genome sequence analysis of apparent treatment resistant hypertension status in participants from the Trans-Omics for Precision Medicine program.
Frontiers in genetics
2023; 14: 1278215
Abstract
Introduction: Apparent treatment-resistant hypertension (aTRH) is characterized by the use of four or more antihypertensive (AHT) classes to achieve blood pressure (BP) control. In the current study, we conducted single-variant and gene-based analyses of aTRH among individuals from 12 Trans-Omics for Precision Medicine cohorts with whole-genome sequencing data. Methods: Cases were defined as individuals treated for hypertension (HTN) taking three different AHT classes, with average systolic BP ≥ 140 or diastolic BP ≥ 90mmHg, or four or more medications regardless of BP (n = 1,705). A normotensive control group was defined as individuals with BP < 140/90mmHg (n = 22,079), not on AHT medication. A second control group comprised individuals who were treatment responsive on one AHT medication with BP < 140/ 90mmHg (n = 5,424). Logistic regression with kinship adjustment using the Scalable and Accurate Implementation of Generalized mixed models (SAIGE) was performed, adjusting for age, sex, and genetic ancestry. We assessed variants using SKAT-O in rare-variant analyses. Single-variant and gene-based tests were conducted in a pooled multi-ethnicity stratum, as well as self-reported ethnic/racial strata (European and African American). Results: One variant in the known HTN locus, KCNK3, was a top finding in the multi-ethnic analysis (p = 8.23E-07) for the normotensive control group [rs12476527, odds ratio (95% confidence interval) = 0.80 (0.74-0.88)]. This variant was replicated in the Vanderbilt University Medical Center's DNA repository data. Aggregate gene-based signals included the genes AGTPBP, MYL4, PDCD4, BBS9, ERG, and IER3. Discussion: Additional work validating these loci in larger, more diverse populations, is warranted to determine whether these regions influence the pathobiology of aTRH.
View details for DOI 10.3389/fgene.2023.1278215
View details for PubMedID 38162683
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Genomics and phenomics of body mass index reveals a complex disease network.
Nature communications
2022; 13 (1): 7973
Abstract
Elevated body mass index (BMI) is heritable and associated with many health conditions that impact morbidity and mortality. The study of the genetic association of BMI across a broad range of common disease conditions offers the opportunity to extend current knowledge regarding the breadth and depth of adiposity-related diseases. We identify 906 (364 novel) and 41 (6 novel) genome-wide significant loci for BMI among participants of European (N~1.1 million) and African (N~100,000) ancestry, respectively. Using a BMI genetic risk score including 2446 variants, 316 diagnoses are associated in the Million Veteran Program, with 96.5% showing increased risk. A co-morbidity network analysis reveals seven disease communities containing multiple interconnected diseases associated with BMI as well as extensive connections across communities. Mendelian randomization analysis confirms numerous phenotypes across a breadth of organ systems, including conditions of the circulatory (heart failure, ischemic heart disease, atrial fibrillation), genitourinary (chronic renal failure), respiratory (respiratory failure, asthma), musculoskeletal and dermatologic systems that are deeply interconnected within and across the disease communities. This work shows that the complex genetic architecture of BMI associates with a broad range of major health conditions, supporting the need for comprehensive approaches to prevent and treat obesity.
View details for DOI 10.1038/s41467-022-35553-2
View details for PubMedID 36581621
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Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis.
Genome biology
2022; 23 (1): 268
Abstract
Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery.To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3-5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism.Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.
View details for DOI 10.1186/s13059-022-02837-1
View details for PubMedID 36575460
View details for PubMedCentralID PMC9793579
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Genetic evidence for causal relationships between age at natural menopause and the risk of ageing-associated adverse health outcomes.
International journal of epidemiology
2022
Abstract
A later age at natural menopause (ANM) has been linked to several ageing-associated traits including an increased risk of breast and endometrial cancer and a decreased risk of lung cancer, osteoporosis and Alzheimer disease. However, ANM is also related to several proxies for overall health that may confound these associations.We investigated the causal association of ANM with these clinical outcomes using Mendelian randomization (MR). Participants and outcomes analysed were restricted to post-menopausal females. We conducted a one-sample MR analysis in both the Women's Health Initiative and UK Biobank. We further analysed and integrated several additional data sets of post-menopausal women using a two-sample MR design. We used ≤55 genetic variants previously discovered to be associated with ANM as our instrumental variable.A 5-year increase in ANM was causally associated with a decreased risk of osteoporosis [odds ratio (OR) = 0.80, 95% CI (0.70-0.92)] and fractures (OR = 0.76, 95% CI, 0.62-0.94) as well as an increased risk of lung cancer (OR = 1.35, 95% CI, 1.06-1.71). Other associations including atherosclerosis-related outcomes were null.Our study confirms that the decline in bone density with menopause causally translates into fractures and osteoporosis. Additionally, this is the first causal epidemiological analysis to our knowledge to find an increased risk of lung cancer with increasing ANM. This finding is consistent with molecular and epidemiological studies suggesting oestrogen-dependent growth of lung tumours.
View details for DOI 10.1093/ije/dyac215
View details for PubMedID 36409989
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Fibromuscular Dysplasia and Abdominal Aortic Aneurysms Are Dimorphic Sex-Specific Diseases With Shared Complex Genetic Architecture.
Circulation. Genomic and precision medicine
2022: e003496
Abstract
BACKGROUND: The risk of arterial diseases may be elevated among family members of individuals having multifocal fibromuscular dysplasia (FMD). We sought to investigate the risk of arterial diseases in families of individuals with FMD.METHODS: Family histories for 73 probands with FMD were obtained, which included an analysis of 463 total first-degree relatives focusing on FMD and related arterial disorders. A polygenic risk score for FMD (PRSFMD) was constructed from prior genome-wide association findings of 584 FMD cases and 7139 controls and evaluated for association with an abdominal aortic aneurysm (AAA) in a cohort of 9693 AAA cases and 294049 controls. A previously published PRSAAA was also assessed among the FMD cases and controls.RESULTS: 9.3% (43) of all first-degree relatives of probands were diagnosed with FMD, aneurysms, and dissections. Aneurysmal disease occurred in 60.5% of affected relatives and 5.6% of all relatives. Among 227 female first-degree relatives of probands, 4.8% (11) had FMD, representing a relative risk (RR)FMD of 1.5 ([95% CI, 0.75-2.8]; P=0.19) compared with the estimated population prevalence of 3.3%, though not of statistical significance. 11% (8 of 72) of FMD proband fathers had AAAs resulting in a RRAAA of 2.3 ([95% CI, 1.12-4.6]; P=0.014) compared with population estimates. The PRSFMD was found to be associated with an AAA (odds ratio, 1.03 [95% CI, 1.01-1.05]; P=2.6*10-3), and the PRSAAA was found to be associated with FMD (odds ratio, 1.53 [95% CI, 1.2-1.9]; P=9.0*10-5) as well.CONCLUSIONS: FMD and AAAs seem to be sex-dimorphic manifestations of a heritable arterial disease with a partially shared complex genetic architecture. Excess risk of having an AAA according to a family history of FMD may justify screening in family members of individuals having FMD.
View details for DOI 10.1161/CIRCGEN.121.003496
View details for PubMedID 36374587
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A Large-Scale Genome-Wide Association Study of Angiographically Determined Burden of Coronary Atherosclerosis in a Genetically Diverse Population
LIPPINCOTT WILLIAMS & WILKINS. 2022
View details for Web of Science ID 000890856907176
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A saturated map of common genetic variants associated with human height.
Nature
2022
Abstract
Common single-nucleotide polymorphisms (SNPs) are predicted to collectively explain 40-50% of phenotypic variation in human height, but identifying the specific variants and associated regions requires huge sample sizes1. Here, using data from a genome-wide association study of 5.4million individuals of diverse ancestries, we showthat 12,111 independent SNPs that are significantly associated with height account for nearly all of the common SNP-based heritability. These SNPs are clustered within 7,209 non-overlapping genomic segments with a mean size of around 90kb, covering about 21% of the genome. The density of independent associations varies across the genome and the regions of increased density are enriched for biologically relevant genes. In out-of-sample estimation and prediction, the 12,111 SNPs (or all SNPs in the HapMap 3 panel2) account for 40% (45%) of phenotypic variance in populations of European ancestry but only around 10-20% (14-24%) in populations of other ancestries. Effect sizes, associated regions and gene prioritization are similar across ancestries, indicating that reduced prediction accuracy is likely to be explained by linkage disequilibrium and differences in allele frequency within associated regions. Finally, we show that the relevant biological pathways are detectable with smaller sample sizes than are needed to implicate causal genes and variants. Overall, this study provides a comprehensive map of specific genomic regions that contain the vast majority of common height-associated variants. Although this map is saturated for populations of European ancestry, further research is needed to achieve equivalent saturation in other ancestries.
View details for DOI 10.1038/s41586-022-05275-y
View details for PubMedID 36224396
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The Contribution of Rare Variants to the Heritability of Coronary Artery Disease Based on 38,544 Whole Genome Sequences from the NHLBI TOPMed Program
WILEY. 2022: 527
View details for Web of Science ID 000850044000144
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A translational genomics approach identifies IL10RB as the top candidate gene target for COVID-19 susceptibility.
NPJ genomic medicine
2022; 7 (1): 52
Abstract
Recent efforts have identified genetic loci that are associated with coronavirus disease 2019 (COVID-19) infection rates and disease outcome severity. Translating these genetic findings into druggable genes that reduce COVID-19 host susceptibility is a critical next step. Using a translational genomics approach that integrates COVID-19 genetic susceptibility variants, multi-tissue genetically regulated gene expression (GReX), and perturbagen signatures, we identified IL10RB as the top candidate gene target for COVID-19 host susceptibility. In a series of validation steps, we show that predicted GReX upregulation of IL10RB and higher IL10RB expression in COVID-19 patient blood is associated with worse COVID-19 outcomes and that in vitro IL10RB overexpression is associated with increased viral load and activation of disease-relevant molecular pathways.
View details for DOI 10.1038/s41525-022-00324-x
View details for PubMedID 36064543
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Understanding the comorbidity between posttraumatic stress severity and coronary artery disease using genome-wide information and electronic health records.
Molecular psychiatry
2022
Abstract
The association between coronary artery disease (CAD) and posttraumatic stress disorder (PTSD) contributes to the high morbidity and mortality observed for these conditions. To understand the dynamics underlying PTSD-CAD comorbidity, we investigated large-scale genome-wide association (GWA) statistics from the Million Veteran Program (MVP), the UK Biobank (UKB), the Psychiatric Genomics Consortium, and the CARDIoGRAMplusC4D Consortium. We observed a genetic correlation of CAD with PTSD case-control and quantitative outcomes, ranging from 0.18 to 0.32. To investigate possible cause-effect relationships underlying these genetic correlations, we performed a two-sample Mendelian randomization (MR) analysis, observing a significant bidirectional relationship between CAD and PTSD symptom severity. Genetically-determined PCL-17 (PTSD 17-item Checklist) total score was associated with increased CAD risk (odds ratio=1.04; 95% confidence interval, 95% CI=1.01-1.06). Conversely, CAD genetic liability was associated with reduced PCL-17 total score (beta=-0.42; 95% CI=-0.04 to -0.81). Because of these opposite-direction associations, we conducted a pleiotropic meta-analysis to investigate loci with concordant vs. discordant effects on PCL-17 and CAD, observing that concordant-effect loci were enriched for molecular pathways related to platelet amyloid precursor protein (beta=1.53, p=2.97*10-7) and astrocyte activation regulation (beta=1.51, p=2.48*10-6) while discordant-effect loci were enriched for biological processes related to lipid metabolism (e.g., triglyceride-rich lipoprotein particle clearance, beta=2.32, p=1.61*10-10). To follow up these results, we leveraged MVP and UKB electronic health records (EHR) to assess longitudinal changes in the association between CAD and posttraumatic stress severity. This EHR-based analysis highlighted that earlier CAD diagnosis is associated with increased PCL-total score later in life, while lower PCL total score was associated with increased risk of a later CAD diagnosis (Mann-Kendall trend test: MVP tau=0.932, p<2*10-16; UKB tau=0.376, p=0.005). In conclusion, both our genetically-informed analyses and our EHR-based follow-up investigation highlighted a bidirectional relationship between PTSD and CAD where multiple pleiotropic mechanisms are likely to be involved.
View details for DOI 10.1038/s41380-022-01735-z
View details for PubMedID 35986173
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Identification of genetic correlates of coronary artery disease in diverse ancestral populations
NATURE MEDICINE
2022: 1548-1549
View details for DOI 10.1038/s41591-022-01915-y
View details for Web of Science ID 000838479400001
View details for PubMedID 35948628
View details for PubMedCentralID PMC9364856
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A multi-layer functional genomic analysis to understand noncoding genetic variation in lipids.
American journal of human genetics
2022; 109 (8): 1366-1387
Abstract
A major challenge of genome-wide association studies (GWASs) is to translate phenotypic associations into biological insights. Here, we integrate a large GWAS on blood lipids involving 1.6 million individuals from five ancestries with a wide array of functional genomic datasets to discover regulatory mechanisms underlying lipid associations. We first prioritize lipid-associated genes with expression quantitative trait locus (eQTL) colocalizations and then add chromatin interaction data to narrow the search for functional genes. Polygenic enrichment analysis across 697 annotations from a host of tissues and cell types confirms the central role of the liver in lipid levels and highlights the selective enrichment of adipose-specific chromatin marks in high-density lipoprotein cholesterol and triglycerides. Overlapping transcription factor (TF) binding sites with lipid-associated loci identifies TFs relevant in lipid biology. In addition, we present an integrative framework to prioritize causal variants at GWAS loci, producing a comprehensive list of candidate causal genes and variants with multiple layers of functional evidence. We highlight two of the prioritized genes, CREBRF and RRBP1, which show convergent evidence across functional datasets supporting their roles in lipid biology.
View details for DOI 10.1016/j.ajhg.2022.06.012
View details for PubMedID 35931049
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Large-scale genome-wide association study of coronary artery disease in genetically diverse populations.
Nature medicine
2022
Abstract
We report a genome-wide association study (GWAS) of coronary artery disease (CAD) incorporating nearly a quarter of a million cases, in which existing studies are integrated with data from cohorts of white, Black and Hispanic individuals from the Million Veteran Program. We document near equivalent heritability of CAD across multiple ancestral groups, identify 95 novel loci, including nine on the X chromosome, detect eight loci of genome-wide significance in Black and Hispanic individuals, and demonstrate that two common haplotypes at the 9p21 locus are responsible for risk stratification in all populations except those of African origin, in which these haplotypes are virtually absent. Moreover, in the largest GWAS for angiographically derived coronary atherosclerosis performed to date, we find 15 loci of genome-wide significance that robustly overlap with established loci for clinical CAD. Phenome-wide association analyses of novel loci and polygenic risk scores (PRSs) augment signals related to insulin resistance, extend pleiotropic associations of these loci to include smoking and family history, and precisely document the markedly reduced transferability of existing PRSs to Black individuals. Downstream integrative analyses reinforce the critical roles of vascular endothelial, fibroblast, and smooth muscle cells in CAD susceptibility, but also point to a shared biology between atherosclerosis and oncogenesis. This study highlights the value of diverse populations in further characterizing the genetic architecture of CAD.
View details for DOI 10.1038/s41591-022-01891-3
View details for PubMedID 35915156
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Race and Ethnicity Stratification for Polygenic Risk Score Analyses May Mask Disparities in Hispanics.
Circulation
2022; 146 (3): 265-267
View details for DOI 10.1161/CIRCULATIONAHA.122.059162
View details for PubMedID 35861770
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Use of Polygenic Risk Scores for Coronary Heart Disease in Ancestrally Diverse Populations.
Current cardiology reports
2022
Abstract
PURPOSE OF REVIEW: A polygenic risk score (PRS) is a measure of genetic liability to a disease and is typically normally distributed in a population. Individuals in the upper tail of thisdistribution often have relative risk equivalent to that of monogenic form of the disease. The majority of currently available PRSs for coronary heart disease (CHD) have been generated from cohorts of European ancestry (EUR) and vary in their applicability to other ancestry groups. In this report, we review the performance of PRSs for CHD across different ancestries and efforts to reduce variability in performance including novel population and statistical genetics approaches.RECENT FINDINGS: PRSs for CHD perform robustly in EUR populations but lag in performance in non-EUR groups, particularly individuals of African ancestry. Several large consortia have been established to enable genomic studies in diverse ancestry groups and develop methods to improve PRS performance in multi-ancestry contexts as well as admixed individuals. These include fine-mapping to ascertain causal variants, trans ancestry meta-analyses, and ancestry deconvolution in admixed individuals. PRSs are being used in the clinical setting but enthusiasm has been tempered by the variable performance in non-EUR ancestry groups. Increasing diversity in genomic association studies and continued innovation in methodological approaches are needed to improve PRS performance in non-EUR individuals for equitable implementation of genomic medicine.
View details for DOI 10.1007/s11886-022-01734-0
View details for PubMedID 35796859
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Genetic interactions drive heterogeneity in causal variant effect sizes for gene expression and complex traits.
American journal of human genetics
2022
Abstract
Despite the growing number of genome-wide association studies (GWASs), it remains unclear to what extent gene-by-gene and gene-by-environment interactions influence complex traits in humans. The magnitude of genetic interactions in complex traits has been difficult to quantify because GWASs are generally underpowered to detect individual interactions of small effect. Here, we develop a method to test for genetic interactions that aggregates information across all trait-associated loci. Specifically, we test whether SNPs in regions of European ancestry shared between European American and admixed African American individuals have the same causal effect sizes. We hypothesize that in African Americans, the presence of genetic interactions will drive the causal effect sizes of SNPs in regions of European ancestry to be more similar to those of SNPs in regions of African ancestry. We apply our method to two traits: gene expression in 296 African Americans and 482 European Americans in the Multi-Ethnic Study of Atherosclerosis (MESA) and low-density lipoprotein cholesterol (LDL-C) in 74K African Americans and 296K European Americans in the Million Veteran Program (MVP). We find significant evidence for genetic interactions in our analysis of gene expression; for LDL-C, we observe a similar point estimate, although this is not significant, most likely due to lower statistical power. These results suggest that gene-by-gene or gene-by-environment interactions modify the effect sizes of causal variants in human complex traits.
View details for DOI 10.1016/j.ajhg.2022.05.014
View details for PubMedID 35716666
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Insights From a Large-Scale Whole-Genome Sequencing Study of Systolic Blood Pressure, Diastolic Blood Pressure, and Hypertension.
Hypertension (Dallas, Tex. : 1979)
2022: 101161HYPERTENSIONAHA12219324
Abstract
BACKGROUND: The availability of whole-genome sequencing data in large studies has enabled the assessment of coding and noncoding variants across the allele frequency spectrum for their associations with blood pressure.METHODS: We conducted a multiancestry whole-genome sequencing analysis of blood pressure among 51456 Trans-Omics for Precision Medicine and Centers for Common Disease Genomics program participants (stage-1). Stage-2 analyses leveraged array data from UK Biobank (N=383145), Million Veteran Program (N=318891), and Reasons for Geographic and Racial Differences in Stroke (N=10643) participants, along with whole-exome sequencing data from UK Biobank (N=199631) participants.RESULTS: Two blood pressure signals achieved genome-wide significance in meta-analyses of stage-1 and stage-2 single variant findings (P<5*10-8). Among them, a rare intergenic variant at novel locus, LOC100506274, was associated with lower systolic blood pressure in stage-1 (beta [SE]=-32.6 [6.0]; P=4.99*10-8) but not stage-2 analysis (P=0.11). Furthermore, a novel common variant at the known INSR locus was suggestively associated with diastolic blood pressure in stage-1 (beta [SE]=-0.36 [0.07]; P=4.18*10-7) and attained genome-wide significance in stage-2 (beta [SE]=-0.29 [0.03]; P=7.28*10-23). Nineteen additional signals suggestively associated with blood pressure in meta-analysis of single and aggregate rare variant findings (P<1*10-6 and P<1*10-4, respectively).DISCUSSION: We report one promising but unconfirmed rare variant for blood pressure and, more importantly, contribute insights for future blood pressure sequencing studies. Our findings suggest promise of aggregate analyses to complement single variant analysis strategies and the need for larger, diverse samples, and family studies to enable robust rare variant identification.
View details for DOI 10.1161/HYPERTENSIONAHA.122.19324
View details for PubMedID 35652341
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A multiancestry genome-wide association study of unexplained chronic ALT elevation as a proxy for nonalcoholic fatty liver disease with histological and radiological validation.
Nature genetics
2022
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a growing cause of chronic liver disease. Using a proxy NAFLD definition of chronic elevation of alanine aminotransferase (cALT) levels without other liver diseases, we performed a multiancestry genome-wide association study (GWAS) in the Million Veteran Program (MVP) including 90,408 cALT cases and 128,187 controls. Seventy-seven loci exceeded genome-wide significance, including 25 without prior NAFLD or alanine aminotransferase associations, with one additional locus identified in European American-only and two in African American-only analyses (P<5 * 10-8). External replication in histology-defined NAFLD cohorts (7,397 cases and 56,785 controls) or radiologic imaging cohorts (n=44,289) replicated 17 single-nucleotide polymorphisms (SNPs) (P<6.5 * 10-4), of which 9 were new (TRIB1, PPARG, MTTP, SERPINA1, FTO, IL1RN, COBLL1, APOH and IFI30). Pleiotropy analysis showed that 61 of 77 multiancestry and all 17 replicated SNPs were jointly associated with metabolic and/or inflammatory traits, revealing a complex model of genetic architecture. Our approach integrating cALT, histology and imaging reveals new insights into genetic liability to NAFLD.
View details for DOI 10.1038/s41588-022-01078-z
View details for PubMedID 35654975
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A multi-population phenome-wide association study of genetically-predicted height in the Million Veteran Program.
PLoS genetics
2022; 18 (6): e1010193
Abstract
BACKGROUND: Height has been associated with many clinical traits but whether such associations are causal versus secondary to confounding remains unclear in many cases. To systematically examine this question, we performed a Mendelian Randomization-Phenome-wide association study (MR-PheWAS) using clinical and genetic data from a national healthcare system biobank.METHODS AND FINDINGS: Analyses were performed using data from the US Veterans Affairs (VA) Million Veteran Program in non-Hispanic White (EA, n = 222,300) and non-Hispanic Black (AA, n = 58,151) adults in the US. We estimated height genetic risk based on 3290 height-associated variants from a recent European-ancestry genome-wide meta-analysis. We compared associations of measured and genetically-predicted height with phenome-wide traits derived from the VA electronic health record, adjusting for age, sex, and genetic principal components. We found 345 clinical traits associated with measured height in EA and an additional 17 in AA. Of these, 127 were associated with genetically-predicted height at phenome-wide significance in EA and 2 in AA. These associations were largely independent from body mass index. We confirmed several previously described MR associations between height and cardiovascular disease traits such as hypertension, hyperlipidemia, coronary heart disease (CHD), and atrial fibrillation, and further uncovered MR associations with venous circulatory disorders and peripheral neuropathy in the presence and absence of diabetes. As a number of traits associated with genetically-predicted height frequently co-occur with CHD, we evaluated effect modification by CHD status of genetically-predicted height associations with risk factors for and complications of CHD. We found modification of effects of MR associations by CHD status for atrial fibrillation/flutter but not for hypertension, hyperlipidemia, or venous circulatory disorders.CONCLUSIONS: We conclude that height may be an unrecognized but biologically plausible risk factor for several common conditions in adults. However, more studies are needed to reliably exclude horizontal pleiotropy as a driving force behind at least some of the MR associations observed in this study.
View details for DOI 10.1371/journal.pgen.1010193
View details for PubMedID 35653334
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High heritability of ascending aortic diameter and trans-ancestry prediction of thoracic aortic disease.
Nature genetics
2022
Abstract
Enlargement of the aorta is an important risk factor for aortic aneurysm and dissection, a leading cause of morbidity in the developed world. Here we performed automated extraction of ascending aortic diameter from cardiac magnetic resonance images of 36,021 individuals from the UK Biobank, followed by genome-wide association. We identified lead variants across 41 loci, including genes related to cardiovascular development (HAND2, TBX20) and Mendelian forms of thoracic aortic disease (ELN, FBN1). A polygenic score significantly predicted prevalent risk of thoracic aortic aneurysm and the need for surgical intervention for patients with thoracic aneurysm across multiple ancestries within the UK Biobank, FinnGen, the Penn Medicine Biobank and the Million Veterans Program (MVP). Additionally, we highlight the primary causal role of blood pressure in reducing aortic dilation using Mendelian randomization. Overall, our findings provide a roadmap for using genetic determinants of human anatomy to understand cardiovascular development while improving prediction of diseases of the thoracic aorta.
View details for DOI 10.1038/s41588-022-01070-7
View details for PubMedID 35637384
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Integration of rare expression outlier-associated variants improves polygenic risk prediction.
American journal of human genetics
2022
Abstract
Polygenic risk scores (PRSs) quantify the contribution of multiple genetic loci to an individual's likelihood of a complex trait or disease. However, existing PRSs estimate this likelihood with common genetic variants, excluding the impact of rare variants. Here, we report on a method to identify rare variants associated with outlier gene expression and integrate their impact into PRS predictions for body mass index (BMI), obesity, and bariatric surgery. Between the top and bottom 10%, we observed a 20.8% increase in risk for obesity (p= 3*10-14), 62.3% increase in risk for severe obesity (p= 1*10-6), and median 5.29 years earlier onset for bariatric surgery (p=0.008), as a function of expression outlier-associated rare variant burden when controlling for common variant PRS. We show that these predictions were more significant than integrating the effects of rare protein-truncating variants (PTVs), observing a mean 19% increase in phenotypic variance explained with expression outlier-associated rare variants when compared with PTVs (p= 2*10-15). We replicated these findings by using data from the Million Veteran Program and demonstrated that PRSs across multiple traits and diseases can benefit from the inclusion of expression outlier-associated rare variants identified through population-scale transcriptome sequencing.
View details for DOI 10.1016/j.ajhg.2022.04.015
View details for PubMedID 35588732
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Gaseous air pollutants and DNA methylation in a methylome-wide association study of an ethnically and environmentally diverse population of U.S. adults.
Environmental research
2022: 113360
Abstract
Epigenetic mechanisms may underlie air pollution-health outcome associations. We estimated gaseous air pollutant-DNA methylation (DNAm) associations using twelve subpopulations within Women's Health Initiative (WHI) and Atherosclerosis Risk in Communities (ARIC) cohorts (n = 8397; mean age 61.3 years; 83% female; 46% African-American, 46% European-American, 8% Hispanic/Latino). We used geocoded participant address-specific mean ambient carbon monoxide (CO), nitrogen oxides (NO2; NOx), ozone (O3), and sulfur dioxide (SO2) concentrations estimated over the 2-, 7-, 28-, and 365-day periods before collection of blood samples used to generate Illumina 450 k array leukocyte DNAm measurements. We estimated methylome-wide, subpopulation- and race/ethnicity-stratified pollutant-DNAm associations in multi-level, linear mixed-effects models adjusted for sociodemographic, behavioral, meteorological, and technical covariates. We combined stratum-specific estimates in inverse variance-weighted meta-analyses and characterized significant associations (false discovery rate; FDR<0.05) at Cytosine-phosphate-Guanine (CpG) sites without among-strata heterogeneity (PCochran's Q > 0.05). We attempted replication in the Cooperative Health Research in Region of Augsburg (KORA) study and Normative Aging Study (NAS). We observed a -0.3 (95% CI: -0.4, -0.2) unit decrease in percent DNAm per interquartile range (IQR, 7.3 ppb) increase in 28-day mean NO2 concentration at cg01885635 (chromosome 3; regulatory region 290 bp upstream from ZNF621; FDR = 0.03). At intragenic sites cg21849932 (chromosome 20; LIME1; intron 3) and cg05353869 (chromosome 11; KLHL35; exon 2), we observed a -0.3 (95% CI: -0.4, -0.2) unit decrease (FDR = 0.04) and a 1.2 (95% CI: 0.7, 1.7) unit increase (FDR = 0.04), respectively, in percent DNAm per IQR (17.6 ppb) increase in 7-day mean ozone concentration. Results were not fully replicated in KORA and NAS. We identified three CpG sites potentially susceptible to gaseous air pollution-induced DNAm changes near genes relevant for cardiovascular and lung disease. Further harmonized investigations with a range of gaseous pollutants and averaging durations are needed to determine the effect of gaseous air pollutants on DNA methylation and ultimately gene expression.
View details for DOI 10.1016/j.envres.2022.113360
View details for PubMedID 35500859
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Mendelian randomization supports bidirectional causality between telomere length and clonal hematopoiesis of indeterminate potential.
Science advances
2022; 8 (14): eabl6579
Abstract
Human genetic studies support an inverse causal relationship between leukocyte telomere length (LTL) and coronary artery disease (CAD), but directionally mixed effects for LTL and diverse malignancies. Clonal hematopoiesis of indeterminate potential (CHIP), characterized by expansion of hematopoietic cells bearing leukemogenic mutations, predisposes both hematologic malignancy and CAD. TERT (which encodes telomerase reverse transcriptase) is the most significantly associated germline locus for CHIP in genome-wide association studies. Here, we investigated the relationship between CHIP, LTL, and CAD in the Trans-Omics for Precision Medicine (TOPMed) program (n = 63,302) and UK Biobank (n = 47,080). Bidirectional Mendelian randomization studies were consistent with longer genetically imputed LTL increasing propensity to develop CHIP, but CHIP then, in turn, hastens to shorten measured LTL (mLTL). We also demonstrated evidence of modest mediation between CHIP and CAD by mLTL. Our data promote an understanding of potential causal relationships across CHIP and LTL toward prevention of CAD.
View details for DOI 10.1126/sciadv.abl6579
View details for PubMedID 35385311
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Genetic Landscape of the ACE2 Coronavirus Receptor.
Circulation
2022
Abstract
Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiologic agent of COVID-19, enters human cells using the angiotensin-converting enzyme 2 (ACE2) protein as a receptor. ACE2 is thus key to the infection and treatment of the coronavirus. ACE2 is highly expressed in the heart, respiratory and gastrointestinal tracts, playing important regulatory roles in the cardiovascular and other biologic systems. However, the genetic basis of the ACE2 protein levels is not well understood. Methods: We conduct so far the largest genome-wide association meta-analysis of plasma ACE2 levels in over 28,000 individuals of the SCALLOP Consortium. We summarize the cross-sectional epidemiologic correlates of circulating ACE2. Using the summary-statistics-based high-definition likelihood method, we estimate relevant genetic correlations with cardiometabolic phenotypes, COVID-19, and other human complex traits and diseases. We perform causal inference of soluble ACE2 on vascular disease outcomes and COVID-19 disease severity using Mendelian randomization. We also perform in silico functional analysis by integrating with other types of omics data. Results: We identified ten loci, including eight novel, capturing 30% of the protein's heritability. We detected that plasma ACE2 was genetically correlated with vascular diseases, severe COVID-19, and a wide range of human complex diseases and medications. An X-chromosome cis-pQTL-based Mendelian randomization analysis suggested a causal effect of elevated ACE2 levels on COVID-19 severity (odds ratio (OR), 1.63; 95% CI, 1.10 to 2.42; P = 0.01), hospitalization (OR, 1.52; 95% CI, 1.05 to 2.21; P = 0.03), and infection (OR, 1.60; 95% CI, 1.08 to 2.37; P = 0.02). Tissue- and cell-type-specific transcriptomic and epigenomic analysis revealed that the ACE2 regulatory variants were enriched for DNA methylation sites in blood immune cells. Conclusions: Human plasma ACE2 shares a genetic basis with cardiovascular disease, COVID-19, and other related diseases. The genetic architecture of the ACE2 protein is mapped, providing a useful resource for further biological and clinical studies on this coronavirus receptor.
View details for DOI 10.1161/CIRCULATIONAHA.121.057888
View details for PubMedID 35387486
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Whole Genome Sequence Analysis Of Apparent Treatment Resistant Hypertension Status In Participants From The Trans-omics For Precision Medicine Program
LIPPINCOTT WILLIAMS & WILKINS. 2022
View details for DOI 10.1161/circ.145.suppl_1.018
View details for Web of Science ID 000805839700018
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Rare coding variants in RCN3 are associated with blood pressure.
BMC genomics
2022; 23 (1): 148
Abstract
BACKGROUND: While large genome-wide association studies have identified nearly one thousand loci associated with variation in blood pressure, rare variant identification is still a challenge. In family-based cohorts, genome-wide linkage scans have been successful in identifying rare genetic variants for blood pressure. This study aims to identify low frequency and rare genetic variants within previously reported linkage regions on chromosomes 1 and 19 in African American families from the Trans-Omics for Precision Medicine (TOPMed) program. Genetic association analyses weighted by linkage evidence were completed with whole genome sequencing data within and across TOPMed ancestral groups consisting of 60,388 individuals of European, African, East Asian, Hispanic, and Samoan ancestries.RESULTS: Associations of low frequency and rare variants in RCN3 and multiple other genes were observed for blood pressure traits in TOPMed samples. The association of low frequency and rare coding variants in RCN3 was further replicated in UK Biobank samples (N=403,522), and reached genome-wide significance for diastolic blood pressure (p=2.01*10-7).CONCLUSIONS: Low frequency and rare variants in RCN3 contributes blood pressure variation. This study demonstrates that focusing association analyses in linkage regions greatly reduces multiple-testing burden and improves power to identify novel rare variants associated with blood pressure traits.
View details for DOI 10.1186/s12864-022-08356-4
View details for PubMedID 35183128
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Genome-wide and phenome-wide analysis of ideal cardiovascular health in the VA Million Veteran Program.
PloS one
2022; 17 (5): e0267900
Abstract
BACKGROUND: Genetic studies may help identify causal pathways; therefore, we sought to identify genetic determinants of ideal CVH and their association with CVD outcomes in the multi-population Veteran Administration Million Veteran Program.METHODS: An ideal health score (IHS) was calculated from 3 clinical factors (blood pressure, total cholesterol, and blood glucose levels) and 3 behavioral factors (smoking status, physical activity, and BMI), ascertained at baseline. Multi-population genome-wide association study (GWAS) was performed on IHS and binary ideal health using linear and logistic regression, respectively. Using the genome-wide significant SNPs from the IHS GWAS, we created a weighted IHS polygenic risk score (PRSIHS) which was used (i) to conduct a phenome-wide association study (PheWAS) of associations between PRSIHS and ICD-9 phenotypes and (ii) to further test for associations with mortality and selected CVD outcomes using logistic and Cox regression and, as an instrumental variable, in Mendelian Randomization.RESULTS: The discovery and replication cohorts consisted of 142,404 (119,129 European American (EUR); 16,495 African American (AFR)), and 45,766 (37,646 EUR; 5,366 AFR) participants, respectively. The mean age was 65.8 years (SD = 11.2) and 92.7% were male. Overall, 4.2% exhibited ideal CVH based on the clinical and behavioral factors. In the multi-population meta-analysis, variants at 17 loci were associated with IHS and each had known GWAS associations with multiple components of the IHS. PheWAS analysis in 456,026 participants showed that increased PRSIHS was associated with a lower odds ratio for many CVD outcomes and risk factors. Both IHS and PRSIHS measures of ideal CVH were associated with significantly less CVD outcomes and CVD mortality.CONCLUSION: A set of high interest genetic variants contribute to the presence of ideal CVH in a multi-ethnic cohort of US Veterans. Genetically influenced ideal CVH is associated with lower odds of CVD outcomes and mortality.
View details for DOI 10.1371/journal.pone.0267900
View details for PubMedID 35613103
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Interactions of physical activity, muscular fitness, adiposity, and genetic risk for NAFLD.
Hepatology communications
2022
Abstract
Genetic predisposition and unhealthy lifestyle are risk factors for nonalcoholic fatty liver disease (NAFLD). We investigated whether the genetic risk of NAFLD is modified by physical activity, muscular fitness, and/or adiposity. In up to 242,524 UK Biobank participants without excessive alcohol intake or known liver disease, we examined cross-sectional interactions and joint associations of physical activity, muscular fitness, body mass index (BMI), and a genetic risk score (GRS) with alanine aminotransferase (ALT) levels and the proxy definition for suspected NAFLD of ALT levels > 30 U/L in women and >40 U/L in men. Genetic predisposition to NAFLD was quantified using a GRS consisting of 68 loci known to be associated with chronically elevated ALT. Physical activity was assessed using accelerometry, and muscular fitness was estimated by measuring handgrip strength. We found that increased physical activity and grip strength modestly attenuate genetic predisposition to elevation in ALT levels, whereas higher BMI markedly amplifies it (all p values < 0.001). Among those with normal weight and high level of physical activity, the odds of suspected NAFLD were 1.6-fold higher in those with high versus low genetic risk (reference group). In those with high genetic risk, the odds of suspected NAFLD were 12-fold higher in obese participants with low physical activity versus those with normal weight and high physical activity (odds ratio for NAFLD = 19.2 and 1.6, respectively, vs. reference group). Conclusion: In individuals with high genetic predisposition for NAFLD, maintaining a normal body weight and increased physical activity may reduce the risk of NAFLD.
View details for DOI 10.1002/hep4.1932
View details for PubMedID 35293152
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Broad clinical manifestations of polygenic risk for coronary artery disease in the Women's Health Initiative.
Communications medicine
2022; 2: 108
Abstract
Background: The genetic basis for coronary artery disease (CAD) risk is highly complex. Genome-wide polygenic risk scores (PRS) can help to quantify that risk, but the broader impacts of polygenic risk for CAD are not well characterized.Methods: We measured polygenic risk for CAD using the meta genomic risk score, a previously validated genome-wide PRS, in a subset of genotyped participants from the Women's Health Initiative and applied a phenome-wide association study framework to assess associations between the PRS and a broad range of blood biomarkers, clinical measurements, and health outcomes.Results: Polygenic risk for CAD is associated with a variety of biomarkers, clinical measurements, behaviors, and diagnoses related to traditional risk factors, as well as risk-enhancing factors. Analysis of adjudicated outcomes shows a graded association between atherosclerosis related outcomes, with the highest odds ratios being observed for the most severe manifestations of CAD. We find associations between increased polygenic risk for CAD and decreased risk for incident breast and lung cancer, with replication of the breast cancer finding in an external cohort. Genetic correlation and two-sample Mendelian randomization suggest that breast cancer association is likely due to horizontal pleiotropy, while the association with lung cancer may be causal.Conclusion: Polygenic risk for CAD has broad clinical manifestations, reflected in biomarkers, clinical measurements, behaviors, and diagnoses. Some of these associations may represent direct pathways between genetic risk and CAD while others may reflect pleiotropic effects independent of CAD risk.
View details for DOI 10.1038/s43856-022-00171-y
View details for PubMedID 36034645
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Coronary Artery Disease Risk of Familial Hypercholesterolemia Genetic Variants Independent of Clinically Observed Longitudinal Cholesterol Exposure.
Circulation. Genomic and precision medicine
2022: CIRCGEN121003501
Abstract
Familial hypercholesterolemia (FH) genetic variants confer risk for coronary artery disease independent of LDL-C (low-density lipoprotein cholesterol) when considering a single measurement. In real clinical settings, longitudinal LDL-C data are often available through the electronic health record. It is unknown whether genetic testing for FH variants provides additional risk-stratifying information once longitudinal LDL-C is considered.We used the extensive electronic health record data available through the Million Veteran Program to conduct a nested case-control study. The primary outcome was coronary artery disease, derived from electronic health record codes for acute myocardial infarction and coronary revascularization. Incidence density sampling was used to match case/control exposure windows, defined by the date of the first LDL-C measurement to the date of the first coronary artery disease code of the index case. Adjustments for the first, maximum, or mean LDL-C were analyzed. FH variants in LDLR, APOB, and PCSK9 were assessed by custom genotype array.In a cohort of 23 091 predominantly prevalent cases at enrollment and 230 910 matched controls, FH variant carriers had an increased risk for coronary artery disease (odds ratio [OR], 1.53 [95% CI, 1.24-1.89]). Adjusting for mean LDL-C led to the greatest attenuation of the risk estimate, but significant risk remained (odds ratio, 1.33 [95% CI, 1.08-1.64]). The degree of attenuation was not affected by the number and the spread of LDL-C measures available.The risk associated with carrying an FH variant cannot be fully captured by the LDL-C data available in the electronic health record, even when considering multiple LDL-C measurements spanning more than a decade.
View details for DOI 10.1161/CIRCGEN.121.003501
View details for PubMedID 35143253
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ZEB2 Shapes the Epigenetic Landscape of Atherosclerosis.
Circulation
2022
Abstract
Background: Smooth muscle cells (SMC) transition into a number of different phenotypes during atherosclerosis, including those that resemble fibroblasts and chondrocytes, and make up the majority of cells in the atherosclerotic plaque. To better understand the epigenetic and transcriptional mechanisms that mediate these cell state changes, and how they relate to risk for coronary artery disease (CAD), we have investigated the causality and function of transcription factors (TFs) at genome wide associated loci. Methods: We employed CRISPR-Cas 9 genome and epigenome editing to identify the causal gene and cell(s) for a complex CAD GWAS signal at 2q22.3. Subsequently, single-cell epigenetic and transcriptomic profiling in murine models and human coronary artery smooth muscle cells were employed to understand the cellular and molecular mechanism by which this CAD risk gene exerts its function. Results: CRISPR-Cas 9 genome and epigenome editing showed that the complex CAD genetic signals within a genomic region at 2q22.3 lie within smooth muscle long-distance enhancers for ZEB2, a TF extensively studied in the context of epithelial mesenchymal transition (EMT) in development and cancer. ZEB2 regulates SMC phenotypic transition through chromatin remodeling that obviates accessibility and disrupts both Notch and TGFβ signaling, thus altering the epigenetic trajectory of SMC transitions. SMC specific loss of ZEB2 resulted in an inability of transitioning SMCs to turn off contractile programing and take on a fibroblast-like phenotype, but accelerated the formation of chondromyocytes, mirroring features of high-risk atherosclerotic plaques in human coronary arteries. Conclusions: These studies identify ZEB2 as a new CAD GWAS gene that affects features of plaque vulnerability through direct effects on the epigenome, providing a new thereapeutic approach to target vascular disease.
View details for DOI 10.1161/CIRCULATIONAHA.121.057789
View details for PubMedID 34990206
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Associations between DNA methylation and BMI vary by metabolic health status: a potential link to disparate cardiovascular outcomes.
Clinical epigenetics
1800; 13 (1): 230
Abstract
BACKGROUND: Body mass index (BMI), a well-known risk factor for poor cardiovascular outcomes, is associated with differential DNA methylation (DNAm). Similarly, metabolic health has also been associated with changes in DNAm. It is unclear how overall metabolic health outside of BMI may modify the relationship between BMI and methylation profiles, and what consequences this may have on downstream cardiovascular disease. The purpose of this study was to identify cytosine-phosphate-guanine (CpG) sites at which the association between BMI and DNAm could be modified by overall metabolic health.RESULTS: The discovery study population was derived from three Women's Health Initiative (WHI) ancillary studies (n=3977) and two Atherosclerosis Risk in Communities (ARIC) ancillary studies (n=3520). Findings were validated in the Multi-Ethnic Study of Atherosclerosis (MESA) cohort (n=1200). Generalized linear models regressed methylation beta values on the interaction between BMI and metabolic health Z score(BMI*MHZ) adjusted for BMI, MHZ, cell composition, chip number and location, study characteristics, top three ancestry principal components, smoking, age, ethnicity (WHI), and sex (ARIC). Among the 429,566 sites examined, differential associations between BMI*MHZ and DNAm were identified at 22 CpG sites (FDR q<0.05), with one site replicated in MESA (cg18989722, in theTRAPPC9gene). Three of the 22 sites were associated with incident coronary heart disease (CHD) in WHI. For each 0.01 unit increase in DNAm beta value, the risk of incident CHD increased by 9% in one site and decreased by 6-10% in two sites over 25years.CONCLUSIONS: Differential associations between DNAm and BMI by MHZ were identified at 22 sites, one of which was validated (cg18989722) and three of which were predictive of incident CHD. These sites are located in several genes related to NF-kappa-B signaling, suggesting a potential role for inflammation between DNA methylation and BMI-associated metabolic health.
View details for DOI 10.1186/s13148-021-01194-3
View details for PubMedID 34937574
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The power of genetic diversity in genome-wide association studies of lipids.
Nature
2021
Abstract
Increased blood lipid levels are heritable risk factors of cardiovascular disease with varied prevalence worldwide owing to different dietary patterns and medication use1. Despite advances in prevention and treatment, in particular through reducing low-density lipoprotein cholesterol levels2, heart disease remains the leading cause of death worldwide3. Genome-wideassociation studies (GWAS) of blood lipid levels have led to important biological and clinical insights, as well as new drug targets, for cardiovascular disease. However, most previous GWAS4-23 have been conducted in European ancestry populations and may have missed genetic variants that contribute to lipid-level variation in other ancestry groups. These include differences in allele frequencies, effect sizes and linkage-disequilibrium patterns24. Here we conduct a multi-ancestry, genome-wide genetic discovery meta-analysis of lipid levels in approximately 1.65million individuals, including 350,000 of non-European ancestries. We quantify the gain in studying non-European ancestries and provide evidence to support the expansion of recruitment of additional ancestries, even with relatively small sample sizes. We find that increasing diversity rather than studying additional individuals of European ancestry results in substantial improvements in fine-mapping functional variants and portability of polygenic prediction (evaluated in approximately295,000 individuals from 7ancestry groupings). Modest gains in the number of discovered loci and ancestry-specific variants were also achieved. As GWAS expand emphasis beyond the identification of genes and fundamental biology towards the use of genetic variants for preventive and precision medicine25, we anticipate that increased diversity of participants will lead to more accurate and equitable26 application of polygenic scores in clinical practice.
View details for DOI 10.1038/s41586-021-04064-3
View details for PubMedID 34887591
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Large-Scale Plasma Protein Profiling of Incident Myocardial Infarction, Ischemic Stroke, and Heart Failure.
Journal of the American Heart Association
2021: e023330
Abstract
Background We recently reported a link between plasma levels of 2 of 84 cardiovascular disease (CVD)-related proteins and the 3 major CVDs, myocardial infarction, ischemic stroke, and heart failure. The present study investigated whether measurement of almost 10 times the number of proteins could lead to discovery of additional risk markers for CVD. Methods and Results We measured 742 proteins using the proximity extension assay in 826 male participants of ULSAM (Uppsala Longitudinal Study of Adult Men) who were free from CVD at the age of 70years. Cox proportional hazards models were adjusted for age only, as well as all traditional risk factors. During a 12.5-year median follow-up (maximal, 22.0years), 283 incident CVDs occurred. Forty-one proteins were significantly (false discovery rate <0.05) related to the combined end point of incident CVD, with N-terminal pro-brain natriuretic peptide as the top finding, while 53 proteins were related to incident myocardial infarction. A total of 13 and 16 proteins were significantly related to incident ischemic stroke and heart failure, respectively. Growth differentiation factor 15, 4-disulfide core domain protein 2, and kidney injury molecule were related to all of the 3 major CVD outcomes. A lasso selection of 11 proteins improved discrimination of incident CVD by 5.0% (P=0.0038). Conclusions Large-scale proteomics seem useful for the discovery of new risk markers for CVD and to improve risk prediction in an elderly population of men. Further studies are needed to replicate the findings in independent samples of both men and women of different ages.
View details for DOI 10.1161/JAHA.121.023330
View details for PubMedID 34845919
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Prediction of Incident Atherosclerotic Cardiovascular Disease Using Traditional and Polygenic Risk Score Modeling: The Million Veteran Program Experience
LIPPINCOTT WILLIAMS & WILKINS. 2021
View details for Web of Science ID 000752020002284
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Zeb2 Shapes the Epigenetic Landscape of Atherosclerosis and Modulates the Risk of Myocardial Infarction
LIPPINCOTT WILLIAMS & WILKINS. 2021
View details for Web of Science ID 000752020000395
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Whole-Genome Sequencing Association Analyses of Stroke and Its Subtypes in Ancestrally Diverse Populations From Trans-Omics for Precision Medicine Project.
Stroke
2021: STROKEAHA120031792
Abstract
BACKGROUND AND PURPOSE: Stroke is the leading cause of death and long-term disability worldwide. Previous genome-wide association studies identified 51 loci associated with stroke (mostly ischemic) and its subtypes among predominantly European populations. Using whole-genome sequencing in ancestrally diverse populations from the Trans-Omics for Precision Medicine (TOPMed) Program, we aimed to identify novel variants, especially low-frequency or ancestry-specific variants, associated with all stroke, ischemic stroke and its subtypes (large artery, cardioembolic, and small vessel), and hemorrhagic stroke and its subtypes (intracerebral and subarachnoid).METHODS: Whole-genome sequencing data were available for 6833 stroke cases and 27 116 controls, including 22 315 European, 7877 Black, 2616 Hispanic/Latino, 850 Asian, 54 Native American, and 237 other ancestry participants. In TOPMed, we performed single variant association analysis examining 40 million common variants and aggregated association analysis focusing on rare variants. We also combined TOPMed European populations with over 28 000 additional European participants from the UK BioBank genome-wide array data through meta-analysis.RESULTS: In the single variant association analysis in TOPMed, we identified one novel locus 13q33 for large artery at whole-genome-wide significance (P<5.00*10-9) and 4 novel loci at genome-wide significance (P<5.00*10-8), all of which need confirmation in independent studies. Lead variants in all 5 loci are low-frequency but are more common in non-European populations. An aggregation of synonymous rare variants within the gene C6orf26 demonstrated suggestive evidence of association for hemorrhagic stroke (P<3.11*10-6). By meta-analyzing European ancestry samples in TOPMed and UK BioBank, we replicated several previously reported stroke loci including PITX2, HDAC9, ZFHX3, and LRCH1.CONCLUSIONS: We represent the first association analysis for stroke and its subtypes using whole-genome sequencing data from ancestrally diverse populations. While our findings suggest the potential benefits of combining whole-genome sequencing data with populations of diverse genetic backgrounds to identify possible low-frequency or ancestry-specific variants, they also highlight the need to increase genome coverage and sample sizes.
View details for DOI 10.1161/STROKEAHA.120.031792
View details for PubMedID 34727735
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A GENOME-WIDE ASSOCIATION STUDY OF CHRONIC ALT-BASED NAFLD IN THE MILLION VETERAN PROGRAM WITH HISTOLOGICAL AND RADIOLOGICAL VALIDATION
WILEY. 2021: 6A-7A
View details for Web of Science ID 000707188000010
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A Missense Variant in the IL-6 Receptor and Protection from Peripheral Artery Disease.
Circulation research
2021
View details for DOI 10.1161/CIRCRESAHA.121.319589
View details for PubMedID 34547901
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Multi-trait Gwas Of Atherosclerosis Detects Novel Loci And Potential Therapeutic Targets
LIPPINCOTT WILLIAMS & WILKINS. 2021
View details for DOI 10.1161/atvb.41.suppl_1.MP16
View details for Web of Science ID 000861072500017
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DXA Versus Clinical Measures of Adiposity as Predictors of Cardiometabolic Diseases and All-Cause Mortality in Postmenopausal Women.
Mayo Clinic proceedings
2021
Abstract
OBJECTIVE: To investigate whether dual-energy x-ray absorptiometry (DXA) estimates of adiposity improve risk prediction for cardiometabolic diseases over traditional surrogates, body mass index (BMI), waist circumference (WC), and waist-to-hip ratio (WHR) in older women.PATIENTS AND METHODS: We analyzed up to 9744 postmenopausal women aged 50 to 79 years participating in the Women's Health Initiative who underwent a DXA scan and were free of cardiovascular disease and diabetes at baseline (October 1993 to December 1998) and followed through September 2015. Baseline BMI, WC, WHR, and DXA-derived percent total-body and trunk fat (%TrF) were incorporated into multivariable Cox proportional hazards models to estimate the risk of incident diabetes, atherosclerosis-related cardiovascular diseases (ASCVDs), heart failure, and death. Concordance probability estimates assessed the relative discriminatory value between pairs of adiposity measures.RESULTS: A total of 1327 diabetes cases, 1266 atherosclerotic cardiovascular disease (ASCVD) cases, 292 heart failure cases, and 1811 deaths from any cause accrued during a median follow-up of up to 17.2 years. The largest hazard ratio observed per 1 standard deviation increase of an adiposity measure was for %TrF and diabetes (1.77; 95% CI, 1.66-1.88) followed by %TrF and broadly defined ASCVD (1.22; 95% CI, 1.15-1.30). These hazard ratios remained significant for both diabetes (1.47; 95% CI, 1.37-1.57) and ASCVD (1.22; 95% CI, 1.14-1.31) even after adjusting for the best traditional surrogate measure of adiposity, WC. Percentage of trunk fat was also the only adiposity measure to demonstrate statistically significant improved concordance probability estimates over BMI, WC, and WHR for diabetes and ASCVD (all P<0.05).CONCLUSION: DXA-derived estimates of abdominal adiposity in postmenopausal women may allow for substantially improved risk prediction of diabetes over standard clinical risk models. Larger DXA studies with complete lipid biomarker profiles and clinical trials are needed before firm conclusions can be made.
View details for DOI 10.1016/j.mayocp.2021.04.027
View details for PubMedID 34479738
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The Propagation of Racial Disparities in Cardiovascular Genomics Research.
Circulation. Genomic and precision medicine
2021: CIRCGEN121003178
Abstract
Genomics research has improved our understanding of the genetic basis for human traits and diseases. This progress is now being translated into clinical care as we move toward a future of precision medicine. Many hope that expanded use of genomic testing will improve disease screening, diagnosis, risk stratification, and treatment. In many respects, cardiovascular medicine is leading this charge. However, most cardiovascular genomics research has been conducted in populations of primarily European ancestry. This bias has critical downstream effects. Here, we review the current disparities in cardiovascular genomics research, and we outline how these disparities propagate forward through all phases of the translational pipeline. If not adequately addressed, biases in genomics research will further compound the existing health disparities that face underrepresented and marginalized populations.
View details for DOI 10.1161/CIRCGEN.121.003178
View details for PubMedID 34461749
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Associations of Genetically Predicted Lipoprotein (a) Levels with Cardiovascular Traits in Individuals of European and African Ancestry.
Circulation. Genomic and precision medicine
2021
Abstract
Background - Lipoprotein (a) [Lp(a)] levels are higher in individuals of African ancestry (AA) than in individuals of European ancestry (EA). We examined associations of genetically predicted Lp(a) levels with 1) atherosclerotic cardiovascular disease (ASCVD) subtypes: coronary heart disease (CHD), cerebrovascular disease (CVD), peripheral artery disease (PAD), and abdominal aortic aneurysm (AAA); and 2) non-ASCVD phenotypes, stratified by ancestry. Methods - We performed 1) Mendelian randomization (MR) analyses for previously reported cardiovascular associations, and 2) phenome-wide MR (MR-PheWAS) analyses for novel associations. Analyses were stratified by ancestry in electronic MEdical Records and GEnomics, United Kingdom Biobank, and Million Veteran Program cohorts separately and in a combined cohort of 804,507 EA and 103,580 AA participants. Results - In MR analyses using the combined cohort, a 1-standard deviation (SD) genetic increase in Lp(a) level was associated with ASCVD subtypes in EA - odds ratio and 95% confidence interval for CHD 1.28(1.16-1.41); CVD 1.14(1.07-1.21); PAD 1.22(1.11-1.34); AAA 1.28(1.17-1.40); in AA the effect estimate was lower than in EA and nonsignificant for CHD 1.11(0.99-1.24) and CVD 1.06(0.99-1.14) but similar for PAD 1.16(1.01-1.33) and AAA 1.34(1.11-1.62). In EA, a 1-SD genetic increase in Lp(a) level was associated with aortic valve disorders 1.34(1.10-1.62), mitral valve disorders 1.18(1.09-1.27), congestive heart failure 1.12(1.05-1.19), and chronic kidney disease 1.07(1.01-1.14). In AA no significant associations were noted for aortic valve disorders 1.08(0.94-1.25), mitral valve disorders 1.02(0.89-1.16), congestive heart failure 1.02(0.95-1.10), or chronic kidney disease 1.05(0.99-1.12). MR-PheWAS identified novel associations in EA with arterial thromboembolic disease, non-aortic aneurysmal disease, atrial fibrillation, cardiac conduction disorders, and hypertension. Conclusions - Many cardiovascular associations of genetically increased Lp(a) that were significant in EA were not significant in AA. Lp(a) was associated with ASCVD in four major arterial beds in EA but only with PAD and AAA in AA. Additional, novel cardiovascular associations were detected in EA.
View details for DOI 10.1161/CIRCGEN.120.003354
View details for PubMedID 34282949
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A multi-ethnic epigenome-wide association study of leukocyte DNA methylation and blood lipids.
Nature communications
2021; 12 (1): 3987
Abstract
Here we examine the association between DNA methylation in circulating leukocytes and blood lipids in a multi-ethnic sample of 16,265 subjects. We identify 148, 35, and 4 novel associations among Europeans, African Americans, and Hispanics, respectively, and an additional 186 novel associations through a trans-ethnic meta-analysis. We observe a high concordance in the direction of effects across racial/ethnic groups, a high correlation of effect sizes between high-density lipoprotein and triglycerides, a modest overlap of associations with epigenome-wide association studies of other cardio-metabolic traits, and a largely non-overlap with lipid loci identified to date through genome-wide association studies. Thirty CpGs reached significance in at least 2 racial/ethnic groups including 7 that showed association with the expression of an annotated gene. CpGs annotated to CPT1A showed evidence of being influenced by triglycerides levels. DNA methylation levels of circulating leukocytes show robust and consistent association with blood lipid levels across multiple racial/ethnic groups.
View details for DOI 10.1038/s41467-021-23899-y
View details for PubMedID 34183656
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Association of the transthyretin variant V122I with polyneuropathy among individuals of African ancestry.
Scientific reports
2021; 11 (1): 11645
Abstract
Hereditary transthyretin-mediated (hATTR) amyloidosis is an underdiagnosed, progressively debilitating disease caused by mutations in the transthyretin (TTR) gene. V122I, a common pathogenic TTR mutation, is found in 3-4% of individuals of African ancestry in the United States and has been associated with cardiomyopathy and heart failure. To better understand the phenotypic consequences of carrying V122I, we conducted a phenome-wide association study scanning 427 ICD diagnosis codes in UK Biobank participants of African ancestry (n=6062). Significant associations were tested for replication in the Penn Medicine Biobank (n=5737) and the Million Veteran Program (n=82,382). V122I was significantly associated with polyneuropathy in the UK Biobank (odds ratio [OR]=6.4, 95% confidence interval [CI] 2.6-15.6, p=4.2*10-5), which was replicated in the Penn Medicine Biobank (OR=1.6, 95% CI 1.2-2.4, p=6.0*10-3) and Million Veteran Program (OR=1.5, 95% CI 1.2-1.8, p=1.8*10-4). Polyneuropathy prevalence among V122I carriers was 2.1%, 9.0%, and 4.8% in the UK Biobank, Penn Medicine Biobank, and Million Veteran Program, respectively. The cumulative incidence of common hATTR amyloidosis manifestations (carpal tunnel syndrome, polyneuropathy, cardiomyopathy, heart failure) was significantly enriched in V122I carriers compared with non-carriers (HR=2.8, 95% CI 1.7-4.5, p=2.6*10-5) in the UK Biobank, with 37.4% of V122I carriers having at least one of these manifestations by age 75. Our findings show that V122I carriers are at increased risk of polyneuropathy. These results also emphasize the underdiagnosis of disease in V122I carriers with a significant proportion of subjects showing phenotypic changes consistent with hATTR amyloidosis. Greater understanding of the manifestations associated with V122I is critical for earlier diagnosis and treatment.
View details for DOI 10.1038/s41598-021-91113-6
View details for PubMedID 34079032
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Clonal hematopoiesis associated with epigenetic aging and clinical outcomes.
Aging cell
2021: e13366
Abstract
Clonal hematopoiesis of indeterminate potential (CHIP) is a common precursor state for blood cancers that most frequently occurs due to mutations in the DNA-methylation modifying enzymes DNMT3A or TET2. We used DNA-methylation array and whole-genome sequencing data from four cohorts together comprising 5522 persons to study the association between CHIP, epigenetic clocks, and health outcomes. CHIP was strongly associated with epigenetic age acceleration, defined as the residual after regressing epigenetic clock age on chronological age, in several clocks, ranging from 1.31years (GrimAge, p<8.6*10-7 ) to 3.08years (EEAA, p<3.7*10-18 ). Mutations in most CHIP genes except DNA-damage response genes were associated with increases in several measures of age acceleration. CHIP carriers with mutations in multiple genes had the largest increases in age acceleration and decrease in estimated telomere length. Finally, we found that ~40% of CHIP carriers had acceleration >0 in both Hannum and GrimAge (referred to as AgeAccelHG+). This group was at high risk of all-cause mortality (hazard ratio 2.90, p<4.1*10-8 ) and coronary heart disease (CHD) (hazard ratio 3.24, p<9.3*10-6 ) compared to those who were CHIP-/AgeAccelHG-. In contrast, the other ~60% of CHIP carriers who were AgeAccelHG- were not at increased risk of these outcomes. In summary, CHIP is strongly linked to age acceleration in multiple clocks, and the combination of CHIP and epigenetic aging may be used to identify a population at high risk for adverse outcomes and who may be a target for clinical interventions.
View details for DOI 10.1111/acel.13366
View details for PubMedID 34050697
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BROAD CLINICAL MANIFESTATIONS OF POLYGENIC RISK FOR CORONARY ARTERY DISEASE IN THE WOMEN'S HEALTH INITIATIVE
ELSEVIER SCIENCE INC. 2021: 1511
View details for Web of Science ID 000647487501519
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Epigenetically mediated electrocardiographic manifestations of sub-chronic exposures to ambient particulate matter air pollution in the Women's Health Initiative and Atherosclerosis Risk in Communities Study.
Environmental research
2021: 111211
Abstract
BACKGROUND: Short-duration exposure to ambient particulate matter (PM) air pollution is associated with cardiac autonomic dysfunction and prolonged ventricular repolarization. However, associations with sub-chronic exposures to coarser particulates are relatively poorly characterized as are molecular mechanisms underlying their potential relationships with cardiovascular disease.MATERIALS AND METHODS: We estimated associations between monthly mean concentrations of PM < 10mum and 2.5-10mum in diameter (PM10; PM2.5-10) with time-domain measures of heart rate variability (HRV) and QT interval duration (QT) among U.S. women and men in the Women's Health Initiative and Atherosclerosis Risk in Communities Study (nHRV = 82,107; nQT = 76,711). Then we examined mediation of the PM-HRV and PM-QT associations by DNA methylation (DNAm) at three Cytosine-phosphate-Guanine (CpG) sites (cg19004594, cg24102420, cg12124767) with known sensitivity to monthly mean PM concentrations in a subset of the participants (nHRV = 7,169; nQT = 6,895). After multiply imputing missing PM, electrocardiographic and covariable data, we estimated associations using attrition-weighted, linear, mixed, longitudinal models adjusting for sociodemographic, behavioral, meteorological, and clinical characteristics. We assessed mediation by estimating the proportions of PM-HRV and PM-QT associations mediated by DNAm.RESULTS: We found little evidence of PM-HRV association, PM-QT association, or mediation by DNAm.CONCLUSIONS: The findings suggest that among racially/ethnically and environmentally diverse U.S. populations, sub-chronic exposures to coarser particulates may not exert appreciable, epigenetically mediated effects on cardiac autonomic function or ventricular repolarization. Further investigation in better-powered studies is warranted, with additional focus on shorter duration exposures to finer particulates and non-electrocardiographic outcomes among relatively susceptible populations.
View details for DOI 10.1016/j.envres.2021.111211
View details for PubMedID 33895111
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Association Between Genetic Variation in Blood Pressure and Increased Lifetime Risk of Peripheral Artery Disease.
Arteriosclerosis, thrombosis, and vascular biology
2021: ATVBAHA120315482
Abstract
OBJECTIVE: We aimed to estimate the effect of blood pressure (BP) traits and BP-lowering medications (via genetic proxies) on peripheral artery disease. Approach and Results: Genome-wide association studies summary statistics were obtained for BP, peripheral artery disease (PAD), and coronary artery disease. Causal effects of BP on PAD were estimated by 2-sample Mendelian randomization using a range of pleiotropy-robust methods. Increased systolic BP (SBP), diastolic BP, mean arterial pressure (MAP), and pulse pressure each significantly increased risk of PAD (SBP odds ratio [OR], 1.20 [1.16-1.25] per 10 mmHg increase, P=1*10-24; diastolic BP OR, 1.27 [1.18-1.35], P=4*10-11; MAP OR, 1.26 [1.19-1.33], P=6*10-16; pulse pressure OR, 1.31 [1.24-1.39], P=9*10-23). The effects of SBP, diastolic BP, and MAP were greater for coronary artery disease than PAD (SBP ratio of Ors, 1.06 [1.0-1.12], P=0.04; MAP ratio of OR, 1.15 [1.06-1.26], P=8.6*10-4; diastolic BP ratio of OR, 1.21 [1.08-1.35], P=6.9*10-4). Considered jointly, both pulse pressure and MAP directly increased risk of PAD (pulse pressure OR, 1.26 [1.17-1.35], P=3*10-10; MAP OR, 1.14 [1.06-1.23], P=2*10-4). The effects of antihypertensive medications were estimated using genetic instruments. SBP-lowering via beta-blocker (OR, 0.74 per 10 mmHg decrease in SBP [95% CI, 0.65-0.84]; P=5*10-6), loop diuretic (OR, 0.66 [0.48-0.91], P=0.01), and thiazide diuretic (OR, 0.57 [0.41-0.79], P=6*10-4) associated variants were protective of PAD.CONCLUSIONS: Higher BP is likely to cause PAD. BP-lowering through beta blockers, loop diuretics, and thiazide diuretics (as proxied by genetic variants) was associated with decreased risk of PAD. Future study is needed to clarify the specific mechanisms by which BP influences PAD.
View details for DOI 10.1161/ATVBAHA.120.315482
View details for PubMedID 33853351
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Mendelian randomisation identifies alternative splicing of the FAS death receptor as a mediator of severe COVID-19.
medRxiv : the preprint server for health sciences
2021
Abstract
Severe COVID-19 is characterised by immunopathology and epithelial injury. Proteomic studies have identified circulating proteins that are biomarkers of severe COVID-19, but cannot distinguish correlation from causation. To address this, we performed Mendelian randomisation (MR) to identify proteins that mediate severe COVID-19. Using protein quantitative trait loci (pQTL) data from the SCALLOP consortium, involving meta-analysis of up to 26,494 individuals, and COVID-19 genome-wide association data from the Host Genetics Initiative, we performed MR for 157 COVID-19 severity protein biomarkers. We identified significant MR results for five proteins: FAS, TNFRSF10A, CCL2, EPHB4 and LGALS9. Further evaluation of these candidates using sensitivity analyses and colocalization testing provided strong evidence to implicate the apoptosis-associated cytokine receptor FAS as a causal mediator of severe COVID-19. This effect was specific to severe disease. Using RNA-seq data from 4,778 individuals, we demonstrate that the pQTL at the FAS locus results from genetically influenced alternate splicing causing skipping of exon 6. We show that the risk allele for very severe COVID-19 increases the proportion of transcripts lacking exon 6, and thereby increases soluble FAS. Soluble FAS acts as a decoy receptor for FAS-ligand, inhibiting apoptosis induced through membrane-bound FAS. In summary, we demonstrate a novel genetic mechanism that contributes to risk of severe of COVID-19, highlighting a pathway that may be a promising therapeutic target.
View details for DOI 10.1101/2021.04.01.21254789
View details for PubMedID 33851187
View details for PubMedCentralID PMC8043484
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Plasma Proteomics to Predict Insulin-mediated Glucose Disposal/Uptake
W B SAUNDERS CO-ELSEVIER INC. 2021: 41
View details for DOI 10.1016/j.metabol.2020.154568
View details for Web of Science ID 000614658000102
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Multi-trait association studies discover pleiotropic loci between Alzheimer's disease and cardiometabolic traits.
Alzheimer's research & therapy
2021; 13 (1): 34
Abstract
BACKGROUND: Identification of genetic risk factors that are shared between Alzheimer's disease (AD) and other traits, i.e., pleiotropy, can help improve our understanding of the etiology of AD and potentially detect new therapeutic targets. Previous epidemiological correlations observed between cardiometabolic traits and AD led us to assess the pleiotropy between these traits.METHODS: We performed a set of bivariate genome-wide association studies coupled with colocalization analysis to identify loci that are shared between AD and eleven cardiometabolic traits. For each of these loci, we performed colocalization with Genotype-Tissue Expression (GTEx) project expression quantitative trait loci (eQTL) to identify candidate causal genes.RESULTS: We identified three previously unreported pleiotropic trait associations at known AD loci as well as four novel pleiotropic loci. One associated locus was tagged by a low-frequency coding variant in the gene DOCK4 and is potentially implicated in its alternative splicing. Colocalization with GTEx eQTL data identified additional candidate genes for the loci we detected, including ACE, the target of the hypertensive drug class of ACE inhibitors. We found that the allele associated with decreased ACE expression in brain tissue was also associated with increased risk of AD, providing human genetic evidence of a potential increase in AD risk from use of an established anti-hypertensive therapeutic.CONCLUSION: Our results support a complex genetic relationship between AD and these cardiometabolic traits, and the candidate causal genes identified suggest that blood pressure and immune response play a role in the pleiotropy between these traits.
View details for DOI 10.1186/s13195-021-00773-z
View details for PubMedID 33541420
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Genetics of 35 blood and urine biomarkers in the UK Biobank.
Nature genetics
2021
Abstract
Clinical laboratory tests are a critical component of the continuum of care. We evaluate the genetic basis of 35 blood and urine laboratory measurements in the UK Biobank (n=363,228 individuals). We identify 1,857 loci associated with at least one trait, containing 3,374 fine-mapped associations and additional sets of large-effect (>0.1s.d.) protein-altering, human leukocyte antigen (HLA) and copy number variant (CNV) associations. Through Mendelian randomization (MR) analysis, we discover 51 causal relationships, including previously known agonistic effects of urate on gout and cystatin C on stroke. Finally, we develop polygenic risk scores (PRSs) for each biomarker and build 'multi-PRS' models for diseases using 35 PRSs simultaneously, which improved chronic kidney disease, type 2 diabetes, gout and alcoholic cirrhosis genetic risk stratification in an independent dataset (FinnGen; n=135,500) relative to single-disease PRSs. Together, our results delineate the genetic basis of biomarkers and their causal influences on diseases and improve genetic risk stratification for common diseases.
View details for DOI 10.1038/s41588-020-00757-z
View details for PubMedID 33462484
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Genetics of Smoking and Risk of Atherosclerotic Cardiovascular Diseases: A Mendelian Randomization Study.
JAMA network open
2021; 4 (1): e2034461
Abstract
Importance: Smoking is associated with atherosclerotic cardiovascular disease, but the relative contribution to each subtype (coronary artery disease [CAD], peripheral artery disease [PAD], and large-artery stroke) remains less well understood.Objective: To determine the association between genetic liability to smoking and risk of CAD, PAD, and large-artery stroke.Design, Setting, and Participants: Mendelian randomization study using summary statistics from genome-wide associations of smoking (UK Biobank; up to 462 690 individuals), CAD (Coronary Artery Disease Genome Wide Replication and Meta-analysis plus the Coronary Artery Disease Genetics Consortium; up to 60 801 cases, 123 504 controls), PAD (VA Million Veteran Program; up to 24 009 cases, 150 983 controls), and large-artery stroke (MEGASTROKE; up to 4373 cases, 406 111 controls). This study was conducted using summary statistic data from large, previously described cohorts. Review of those publications does not reveal the total recruitment dates for those cohorts. Data analyses were conducted from August 2019 to June 2020.Exposures: Genetic liability to smoking (as proxied by genetic variants associated with lifetime smoking index).Main Outcomes and Measures: Risk (odds ratios [ORs]) of CAD, PAD, and large-artery stroke.Results: Genetic liability to smoking was associated with increased risk of PAD (OR, 2.13; 95% CI, 1.78-2.56; P=3.6*10-16), CAD (OR, 1.48; 95% CI, 1.25-1.75; P=4.4*10-6), and stroke (OR, 1.40; 95% CI, 1.02-1.92; P=.04). Genetic liability to smoking was associated with greater risk of PAD than risk of large-artery stroke (ratio of ORs, 1.52; 95% CI, 1.05-2.19; P=.02) or CAD (ratio of ORs, 1.44; 95% CI, 1.12-1.84; P=.004). The association between genetic liability to smoking and atherosclerotic cardiovascular diseases remained independent from the effects of smoking on traditional cardiovascular risk factors.Conclusions and Relevance: In this mendelian randomization analysis of data from large studies of atherosclerotic cardiovascular diseases, genetic liability to smoking was a strong risk factor for CAD, PAD, and stroke, although the estimated association was strongest between smoking and PAD. The association between smoking and atherosclerotic cardiovascular disease was independent of traditional cardiovascular risk factors.
View details for DOI 10.1001/jamanetworkopen.2020.34461
View details for PubMedID 33464320
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Chromosome Xq23 is associated with lower atherogenic lipid concentrations and favorable cardiometabolic indices.
Nature communications
2021; 12 (1): 2182
Abstract
Autosomal genetic analyses of blood lipids have yielded key insights for coronary heart disease (CHD). However, X chromosome genetic variation is understudied for blood lipids in large sample sizes. We now analyze genetic and blood lipid data in a high-coverage whole X chromosome sequencing study of 65,322 multi-ancestry participants and perform replication among 456,893 European participants. Common alleles on chromosome Xq23 are strongly associated with reduced total cholesterol, LDL cholesterol, and triglycerides (min P=8.5*10-72), with similar effects for males and females. Chromosome Xq23 lipid-lowering alleles are associated with reduced odds for CHD among 42,545 cases and 591,247 controls (P=1.7*10-4), and reduced odds for diabetes mellitus type 2 among 54,095 cases and 573,885 controls (P=1.4*10-5). Although we observe an association with increased BMI, waist-to-hip ratio adjusted for BMI is reduced, bioimpedance analyses indicate increased gluteofemoral fat, and abdominal MRI analyses indicate reduced visceral adiposity. Co-localization analyses strongly correlate increased CHRDL1 gene expression, particularly in adipose tissue, with reduced concentrations of blood lipids.
View details for DOI 10.1038/s41467-021-22339-1
View details for PubMedID 33846329
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Alcohol use and cardiometabolic risk in the UK Biobank: A Mendelian randomization study.
PloS one
2021; 16 (8): e0255801
Abstract
Observational studies suggest alcohol use promotes the development of some adverse cardiometabolic traits but protects against others including outcomes related to coronary artery disease. We used Mendelian randomization (MR) to explore causal relationships between the degree of alcohol consumption and several cardiometabolic traits in the UK Biobank. Using the well-established ADH1B Arg47His variant (rs1229984) and up to 24 additional SNPs recently found to be associated with alcohol consumption in an independent dataset as instruments, we conducted two-stage least squares and inverse weighted variance MR analyses, both as one-sample analyses in the UK Biobank and as two-sample analyses in external consortia. In the UK Biobank inverse variance weighted analyses, we found that one additional drink of alcohol per day was positively associated with systolic blood pressure (beta = 2.65 mmHg [1.40, 3.89]), hemorrhagic stroke (OR = 2.25 [1.41, 3.60]), and atrial fibrillation (OR = 1.26 [1.07, 1.48]), which were replicated in multivariable analyses. Alcohol was also associated with all cardiovascular disease and all-cause death. A positive association with myocardial infarction did not replicate in multivariable analysis, with suggestive mediation through blood pressure; similarly, a positive association between alcohol use with type 2 diabetes was mitigated by BMI in multivariable analysis. Findings were generally null in replication with two-sample analyses. Alcohol was not protective for any disease outcome with any analysis method, dataset, or strata. Stratifications by sex and smoking in the UK Biobank revealed higher point estimates of risk for several outcomes for men and mixed results for smoking strata, but no statistically significant heterogeneity. Our results are consistent with an overall harmful and/or null effect of alcohol on cardiometabolic health at all levels of use and suggest that even moderate alcohol use should not be promoted as a part of a healthy diet and lifestyle.
View details for DOI 10.1371/journal.pone.0255801
View details for PubMedID 34379647
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Genetic Loci Associated With COVID-19 Positivity and Hospitalization in White, Black, and Hispanic Veterans of the VA Million Veteran Program.
Frontiers in genetics
2021; 12: 777076
Abstract
SARS-CoV-2 has caused symptomatic COVID-19 and widespread death across the globe. We sought to determine genetic variants contributing to COVID-19 susceptibility and hospitalization in a large biobank linked to a national United States health system. We identified 19,168 (3.7%) lab-confirmed COVID-19 cases among Million Veteran Program participants between March 1, 2020, and February 2, 2021, including 11,778 Whites, 4,893 Blacks, and 2,497 Hispanics. A multi-population genome-wide association study (GWAS) for COVID-19 outcomes identified four independent genetic variants (rs8176719, rs73062389, rs60870724, and rs73910904) contributing to COVID-19 positivity, including one novel locus found exclusively among Hispanics. We replicated eight of nine previously reported genetic associations at an alpha of 0.05 in at least one population-specific or the multi-population meta-analysis for one of the four MVP COVID-19 outcomes. We used rs8176719 and three additional variants to accurately infer ABO blood types. We found that A, AB, and B blood types were associated with testing positive for COVID-19 compared with O blood type with the highest risk for the A blood group. We did not observe any genome-wide significant associations for COVID-19 severity outcomes among those testing positive. Our study replicates prior GWAS findings associated with testing positive for COVID-19 among mostly White samples and extends findings at three loci to Black and Hispanic individuals. We also report a new locus among Hispanics requiring further investigation. These findings may aid in the identification of novel therapeutic agents to decrease the morbidity and mortality of COVID-19 across all major ancestral populations.
View details for DOI 10.3389/fgene.2021.777076
View details for PubMedID 35222515
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Multi-Trait Genome-Wide Association Study of Atherosclerosis Detects Novel Pleiotropic Loci.
Frontiers in genetics
2021; 12: 787545
Abstract
Although affecting different arterial territories, the related atherosclerotic vascular diseases coronary artery disease (CAD) and peripheral artery disease (PAD) share similar risk factors and have shared pathobiology. To identify novel pleiotropic loci associated with atherosclerosis, we performed a joint analysis of their shared genetic architecture, along with that of common risk factors. Using summary statistics from genome-wide association studies of nine known atherosclerotic (CAD, PAD) and atherosclerosis risk factors (body mass index, smoking initiation, type 2 diabetes, low density lipoprotein, high density lipoprotein, total cholesterol, and triglycerides), we perform 15 separate multi-trait genetic association scans which resulted in 25 novel pleiotropic loci not yet reported as genome-wide significant for their respective traits. Colocalization with single-tissue eQTLs identified candidate causal genes at 14 of the detected signals. Notably, the signal between PAD and LDL-C at the PCSK6 locus affects PCSK6 splicing in human liver tissue and induced pluripotent derived hepatocyte-like cells. These results show that joint analysis of related atherosclerotic disease traits and their risk factors allowed identification of unified biology that may offer the opportunity for therapeutic manipulation. The signal at PCSK6 represent possible shared causal biology where existing inhibitors may be able to be leveraged for novel therapies.
View details for DOI 10.3389/fgene.2021.787545
View details for PubMedID 35186008
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Epigenome-wide association study of diet quality in the Women's Health Initiative and TwinsUK cohort.
International journal of epidemiology
2020
Abstract
BACKGROUND: Diet quality is a risk factor for chronic disease and mortality. Differential DNA methylation across the epigenome has been associated with chronic disease risk. Whether diet quality is associated with differential methylation is unknown. This study assessed whether diet quality was associated with differential DNA methylation measured across 445548 loci in the Women's Health Initiative (WHI) and the TwinsUK cohort.DESIGN: The discovery cohort consisted of 4355 women from the WHI. The replication cohort consisted of 571 mono- and dizygotic twins from the TwinsUK cohort. DNA methylation was measured in whole blood using the Illumina Infinium HumanMethylation450 Beadchip. Diet quality was assessed using the Alternative Healthy Eating Index 2010 (AHEI-2010). A meta-analysis, stratified by study cohort, was performed using generalized linear models that regressed methylation on AHEI-2010, adjusting for cell composition, chip number and location, study characteristics, principal components of genetic relatedness, age, smoking status, race/ethnicity and body mass index (BMI). Statistical significance was defined as a false discovery rate < 0.05. Significant sites were tested for replication in the TwinsUK cohort, with significant replication defined by P<0.05 and a consistent direction.RESULTS: Diet quality was significantly associated with differential DNA methylation at 428 cytosine-phosphate-guanine (CpG) sites in the discovery cohort. A total of 24 CpG sites were consistent with replication in the TwinsUK cohort, more than would be expected by chance (P=2.7x10-4), with one site replicated in both the blood and adipose tissue (cg16379999 located in the body of SEL1L).CONCLUSIONS: Diet quality was associated with methylation at 24 CpG sites, several of which have been associated with adiposity, inflammation and dysglycaemia. These findings may provide insight into pathways through which diet influences chronic disease.
View details for DOI 10.1093/ije/dyaa215
View details for PubMedID 33354722
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A genome-wide association study for a proxy nonalcoholic fatty liver phenotype identifies novel loci and trait-relevant candidate genes
SPRINGERNATURE. 2020: 59–60
View details for Web of Science ID 000598482600118
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CYP2C19 Polymorphisms and Clinical Outcomes Following Percutaneous Coronary Intervention (PCI) in the Million Veterans Program (MVP)
LIPPINCOTT WILLIAMS & WILKINS. 2020
View details for DOI 10.1161/circ.142.suppl_3.16710
View details for Web of Science ID 000607190405075
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LPA Variants Are Associated With Aortic Valve Stenosis, Heart Failure and Chronic Kidney Disease
LIPPINCOTT WILLIAMS & WILKINS. 2020
View details for Web of Science ID 000607190403040
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Risk of Coronary Artery Disease Associated With Familial Hypercholesterolemia Genetic Variants is Independent of Historical Low-density Lipoprotein Cholesterol Exposure
LIPPINCOTT WILLIAMS & WILKINS. 2020
View details for DOI 10.1161/circ.142.suppl_3.13601
View details for Web of Science ID 000607190401052
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Genome-wide association analysis on breastfeeding duration
SPRINGER. 2020: 448
View details for Web of Science ID 000581004100028
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The V122I Variant in Hereditary Transthyretin-Mediated Amyloidosis is Significantly Associated with Polyneuropathy
CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS. 2020: S96
View details for Web of Science ID 000579889600256
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Chromosome 1q21.2 and additional loci influence risk of spontaneous coronary artery dissection and myocardial infarction.
Nature communications
2020; 11 (1): 4432
Abstract
Spontaneous coronary artery dissection (SCAD) is a non-atherosclerotic cause of myocardial infarction (MI), typically in young women. We undertook a genome-wide association study of SCAD (Ncases=270/Ncontrols=5,263) and identified and replicated an association of rs12740679 at chromosome 1q21.2 (Pdiscovery+replication=2.19*10-12, OR=1.8) influencing ADAMTSL4 expression. Meta-analysis of discovery and replication samples identified associations with P<5*10-8 at chromosome 6p24.1 in PHACTR1, chromosome 12q13.3 in LRP1, and in females-only, at chromosome 21q22.11 near LINC00310. A polygenic risk score for SCAD was associated with (1) higher risk of SCAD in individuals with fibromuscular dysplasia (P=0.021, OR=1.82[95%CI:1.09-3.02]) and (2) lower risk of atherosclerotic coronary artery disease and MI in the UK Biobank (P=1.28*10-17, HR=0.91[95%CI:0.89-0.93], for MI) and Million Veteran Program (P=9.33*10-36, OR=0.95[95%CI:0.94-0.96], for CAD; P=3.35*10-6, OR=0.96[95%CI:0.95-0.98] for MI). Here we report that SCAD-related MI and atherosclerotic MI exist at opposite ends of a genetic risk spectrum, inciting MI with disparate underlying vascular biology.
View details for DOI 10.1038/s41467-020-17558-x
View details for PubMedID 32887874
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Mendelian Randomization Analysis of Hemostatic Factors and Their Contribution to Peripheral Artery Disease.
Arteriosclerosis, thrombosis, and vascular biology
2020: ATVBAHA119313847
Abstract
BACKGROUND: Peripheral artery disease (PAD) is the third most common form of atherosclerotic vascular disease and is characterized by significant functional disability and increased cardiovascular mortality. Recent genetic data support a role for a procoagulation protein variant, the factor V Leiden mutation, in PAD. The role of other hemostatic factors in PAD remains unknown.OBJECTIVE: To evaluate the role of hemostatic factors in PAD using Mendelian randomization. Approach and Results: Two-sample Mendelian randomization to evaluate the roles of FVII (factor VII), FVIII (factor VIII), FXI (factor XI), VWF (von Willebrand factor), and fibrinogen in PAD was performed using summary statistics from GWAS for hemostatic factors performed within the Cohorts for Heart and Aging Research in the Genome Epidemiology Consortium and from GWAS performed for PAD within the Million Veteran Program. Genetically determined FVIII and VWF, but not FVII, FXI, or fibrinogen, were associated with PAD in Mendelian randomization experiments (FVIII: odds ratio, 1.41 [95% CI, 1.23-1.62], P=6.0*10-7, VWF: odds ratio, 1.28 [95% CI, 1.07-1.52], P=0.0073). In single variant sensitivity analysis, the ABO locus was the strongest genetic instrument for both FVIII and VWF.CONCLUSIONS: Our results suggest a role for hemostasis, and by extension, thrombosis in PAD. Further study is warranted to determine whether VWF and FVIII independently affect the biology of PAD.
View details for DOI 10.1161/ATVBAHA.119.313847
View details for PubMedID 32847391
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Blood DNA methylation sites predict death risk in a longitudinal study of 12,300 individuals
AGING-US
2020; 12 (14): 14092–124
View details for Web of Science ID 000558669300018
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Blood DNA methylation sites predict death risk in a longitudinal study of 12, 300 individuals.
Aging
2020; 12
Abstract
DNA methylation has fundamental roles in gene programming and aging that may help predict mortality. However, no large-scale study has investigated whether site-specific DNA methylation predicts all-cause mortality. We used the Illumina-HumanMethylation450-BeadChip to identify blood DNA methylation sites associated with all-cause mortality for 12, 300 participants in 12 Cohorts of the Heart and Aging Research in Genetic Epidemiology (CHARGE) Consortium. Over an average 10-year follow-up, there were 2,561 deaths across the cohorts. Nine sites mapping to three intergenic and six gene-specific regions were associated with mortality (P < 9.3x10-7) independently of age and other mortality predictors. Six sites (cg14866069, cg23666362, cg20045320, cg07839457, cg07677157, cg09615688)-mapping respectively to BMPR1B, MIR1973, IFITM3, NLRC5, and two intergenic regions-were associated with reduced mortality risk. The remaining three sites (cg17086398, cg12619262, cg18424841)-mapping respectively to SERINC2, CHST12, and an intergenic region-were associated with increased mortality risk. DNA methylation at each site predicted 5%-15% of all deaths. We also assessed the causal association of those sites to age-related chronic diseases by using Mendelian randomization, identifying weak causal relationship between cg18424841 and cg09615688 with coronary heart disease. Of the nine sites, three (cg20045320, cg07839457, cg07677157) were associated with lower incidence of heart disease risk and two (cg20045320, cg07839457) with smoking and inflammation in prior CHARGE analyses. Methylation of cg20045320, cg07839457, and cg17086398 was associated with decreased expression of nearby genes (IFITM3, IRF, NLRC5, MT1, MT2, MARCKSL1) linked to immune responses and cardiometabolic diseases. These sites may serve as useful clinical tools for mortality risk assessment and preventative care.
View details for DOI 10.18632/aging.103408
View details for PubMedID 32697766
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The Project Baseline Health Study: a step towards a broader mission to map human health
NPJ DIGITAL MEDICINE
2020; 3 (1): 84
Abstract
The Project Baseline Health Study (PBHS) was launched to map human health through a comprehensive understanding of both the health of an individual and how it relates to the broader population. The study will contribute to the creation of a biomedical information system that accounts for the highly complex interplay of biological, behavioral, environmental, and social systems. The PBHS is a prospective, multicenter, longitudinal cohort study that aims to enroll thousands of participants with diverse backgrounds who are representative of the entire health spectrum. Enrolled participants will be evaluated serially using clinical, molecular, imaging, sensor, self-reported, behavioral, psychological, environmental, and other health-related measurements. An initial deeply phenotyped cohort will inform the development of a large, expanded virtual cohort. The PBHS will contribute to precision health and medicine by integrating state of the art testing, longitudinal monitoring and participant engagement, and by contributing to the development of an improved platform for data sharing and analysis.
View details for DOI 10.1038/s41746-020-0290-y
View details for Web of Science ID 000538242900001
View details for PubMedID 32550652
View details for PubMedCentralID PMC7275087
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The Project Baseline Health Study: a step towards a broader mission to map human health.
NPJ digital medicine
2020; 3 (1): 84
Abstract
The Project Baseline Health Study (PBHS) was launched to map human health through a comprehensive understanding of both the health of an individual and how it relates to the broader population. The study will contribute to the creation of a biomedical information system that accounts for the highly complex interplay of biological, behavioral, environmental, and social systems. The PBHS is a prospective, multicenter, longitudinal cohort study that aims to enroll thousands of participants with diverse backgrounds who are representative of the entire health spectrum. Enrolled participants will be evaluated serially using clinical, molecular, imaging, sensor, self-reported, behavioral, psychological, environmental, and other health-related measurements. An initial deeply phenotyped cohort will inform the development of a large, expanded virtual cohort. The PBHS will contribute to precision health and medicine by integrating state of the art testing, longitudinal monitoring and participant engagement, and by contributing to the development of an improved platform for data sharing and analysis.
View details for DOI 10.1038/s41746-020-0290-y
View details for PubMedID 33597683
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Horizontal and Vertical Pleiotropy Linking Coronary Artery Disease, Traumatic Experiences, and Post-traumatic Stress in > 650,000 Individuals
ELSEVIER SCIENCE INC. 2020: S52–S53
View details for Web of Science ID 000535308200125
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Polygenic Risk Score Identifies Patients at Increased Risk for Abdominal Aortic Aneurysm and May Benefit From Ultrasound Screening
LIPPINCOTT WILLIAMS & WILKINS. 2020
View details for Web of Science ID 000607042600069
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Association Between Genetic Variation in Blood Pressure and Lifetime Risk of Peripheral Artery Disease: A Mendelian Randomization Study
LIPPINCOTT WILLIAMS & WILKINS. 2020
View details for Web of Science ID 000607042600425
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Identification of Novel Loci Involved in Both Peripheral and Coronary Artery Disease Using a Bivariate Genome-wide Association Scan
LIPPINCOTT WILLIAMS & WILKINS. 2020
View details for Web of Science ID 000607042600326
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Methylome-Wide Association Of DNA Methylation And Aircraft Noise Exposure In The Women's Health Initiative
LIPPINCOTT WILLIAMS & WILKINS. 2020
View details for DOI 10.1161/circ.141.suppl_1.P143
View details for Web of Science ID 000589965800164
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Urinary Albumin, Sodium, and Potassium and Cardiovascular Outcomes in the UK Biobank: Observational and Mendelian Randomization Analyses.
Hypertension (Dallas, Tex. : 1979)
2020: HYPERTENSIONAHA11914028
Abstract
Urinary biomarkers are associated with cardiovascular disease, but the nature of these associations is not well understood. We performed multivariable-adjusted regression models to assess associations of random spot measurements of the urine sodium-potassium ratio (UNa/UK) and urine albumin adjusted for creatinine with cardiovascular risk factors, cardiovascular disease, and type 2 diabetes mellitus (T2D) in 478 311 participants of the UK Biobank. Further, we assessed the causal relationships of these kidney biomarkers, used as proxies for kidney function, with cardiovascular outcomes using the 2-sample Mendelian randomization approach. In observational analyses, UNa/UK showed significant inverse associations with atrial fibrillation, coronary artery disease, ischemic stroke, lipid-lowering medication, and T2D. In contrast, urine albumin adjusted for creatinine showed significant positive associations with atrial fibrillation, coronary artery disease, heart failure, hemorrhagic stroke, lipid-lowering medication, and T2D. We found a positive association between UNa/UK and albumin with blood pressure (BP), as well as with adiposity-related measures. After correcting for potential horizontal pleiotropy, we found evidence of causal associations of UNa/UK and albumin with BP (beta systolic BP ≥2.63; beta diastolic BP ≥0.85 SD increase in BP per SD change in UNa/UK and urine albumin adjusted for creatinine; P≤0.04), and of albumin with T2D (odds ratio=1.33 per SD change in albumin, P=0.02). Our comprehensive study of urinary biomarkers performed using state-of-the-art analyses of causality mirror and extend findings from randomized interventional trials which have established UNa/UK as a risk factor for hypertension. In addition, we detect a causal feedback loop between albumin and hypertension, and our finding of a bidirectional causal association between albumin and T2D reflects the well-known nephropathy in T2D.
View details for DOI 10.1161/HYPERTENSIONAHA.119.14028
View details for PubMedID 32008434
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Leukocyte Traits and Exposure to Ambient Particulate Matter Air Pollution in the Women's Health Initiative and Atherosclerosis Risk in Communities Study.
Environmental health perspectives
2020; 128 (1): 17004
Abstract
Inflammatory effects of ambient particulate matter (PM) air pollution exposures may underlie PM-related increases in cardiovascular disease risk and mortality, although evidence of PM-associated leukocytosis is inconsistent and largely based on small, cross-sectional, and/or unrepresentative study populations.Our objective was to estimate PM-leukocyte associations among U.S. women and men in the Women's Health Initiative and Atherosclerosis Risk in Communities study ( n = 165,675 ).We based the PM-leukocyte estimations on up to four study visits per participant, at which peripheral blood leukocytes and geocoded address-specific concentrations of PM ≤ 10 , ≤ 2.5 , and 2.5 - 10 μ m in diameter ( PM 10 , PM 2.5 , and PM 2.5 - 10 , respectively) were available. We multiply imputed missing data using chained equations and estimated PM-leukocyte count associations over daily to yearly PM exposure averaging periods using center-specific, linear, mixed, longitudinal models weighted for attrition and adjusted for sociodemographic, behavioral, meteorological, and geographic covariates. In a subset of participants with available data ( n = 8,457 ), we also estimated PM-leukocyte proportion associations in compositional data analyses.We found a 12 cells / μ L (95% confidence interval: - 9 , 33) higher leukocyte count, a 1.2% (0.6%, 1.8%) higher granulocyte proportion, and a - 1.1 % ( - 1.9 % , - 0.3 % ) lower CD 8 + T-cell proportion per 10 - μ g / m 3 increase in 1-month mean PM 2.5 . However, shorter-duration PM 10 exposures were inversely and only modestly associated with leukocyte count.The PM 2.5 -leukocyte estimates, albeit imprecise, suggest that among racially, ethnically, and environmentally diverse U.S. populations, sustained, ambient exposure to fine PM may induce subclinical, but epidemiologically important, inflammatory effects. https://doi.org/10.1289/EHP5360.
View details for DOI 10.1289/EHP5360
View details for PubMedID 31903802
View details for PubMedCentralID PMC7015624
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Validating a non-invasive, ALT-based non-alcoholic fatty liver phenotype in the million veteran program.
PloS one
2020; 15 (8): e0237430
Abstract
Given ongoing challenges in non-invasive non-alcoholic liver disease (NAFLD) diagnosis, we sought to validate an ALT-based NAFLD phenotype using measures readily available in electronic health records (EHRs) and population-based studies by leveraging the clinical and genetic data in the Million Veteran Program (MVP), a multi-ethnic mega-biobank of US Veterans.MVP participants with alanine aminotransferases (ALT) >40 units/L for men and >30 units/L for women without other causes of liver disease were compared to controls with normal ALT. Genetic variants spanning eight NAFLD risk or ALT-associated loci (LYPLAL1, GCKR, HSD17B13, TRIB1, PPP1R3B, ERLIN1, TM6SF2, PNPLA3) were tested for NAFLD associations with sensitivity analyses adjusting for metabolic risk factors and alcohol consumption. A manual EHR review assessed performance characteristics of the NAFLD phenotype with imaging and biopsy data as gold standards. Genetic associations with advanced fibrosis were explored using FIB4, NAFLD Fibrosis Score and platelet counts.Among 322,259 MVP participants, 19% met non-invasive criteria for NAFLD. Trans-ethnic meta-analysis replicated associations with previously reported genetic variants in all but LYPLAL1 and GCKR loci (P<6x10-3), without attenuation when adjusted for metabolic risk factors and alcohol consumption. At the previously reported LYPLAL1 locus, the established genetic variant did not appear to be associated with NAFLD, however the regional association plot showed a significant association with NAFLD 279kb downstream. In the EHR validation, the ALT-based NAFLD phenotype yielded a positive predictive value 0.89 and 0.84 for liver biopsy and abdominal imaging, respectively (inter-rater reliability (Cohen's kappa = 0.98)). HSD17B13 and PNPLA3 loci were associated with advanced fibrosis.We validate a simple, non-invasive ALT-based NAFLD phenotype using EHR data by leveraging previously established NAFLD risk-associated genetic polymorphisms.
View details for DOI 10.1371/journal.pone.0237430
View details for PubMedID 32841307
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Transcriptomic signatures across human tissues identify functional rare genetic variation.
Science (New York, N.Y.)
2020; 369 (6509)
Abstract
Rare genetic variants are abundant across the human genome, and identifying their function and phenotypic impact is a major challenge. Measuring aberrant gene expression has aided in identifying functional, large-effect rare variants (RVs). Here, we expanded detection of genetically driven transcriptome abnormalities by analyzing gene expression, allele-specific expression, and alternative splicing from multitissue RNA-sequencing data, and demonstrate that each signal informs unique classes of RVs. We developed Watershed, a probabilistic model that integrates multiple genomic and transcriptomic signals to predict variant function, validated these predictions in additional cohorts and through experimental assays, and used them to assess RVs in the UK Biobank, the Million Veterans Program, and the Jackson Heart Study. Our results link thousands of RVs to diverse molecular effects and provide evidence to associate RVs affecting the transcriptome with human traits.
View details for DOI 10.1126/science.aaz5900
View details for PubMedID 32913073
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The relationship between circulating lipids and breast cancer risk: A Mendelian randomization study.
PLoS medicine
2020; 17 (9): e1003302
Abstract
A number of epidemiological and genetic studies have attempted to determine whether levels of circulating lipids are associated with risks of various cancers, including breast cancer (BC). However, it remains unclear whether a causal relationship exists between lipids and BC. If alteration of lipid levels also reduced risk of BC, this could present a target for disease prevention. This study aimed to assess a potential causal relationship between genetic variants associated with plasma lipid traits (high-density lipoprotein, HDL; low-density lipoprotein, LDL; triglycerides, TGs) with risk for BC using Mendelian randomization (MR).Data from genome-wide association studies in up to 215,551 participants from the Million Veteran Program (MVP) were used to construct genetic instruments for plasma lipid traits. The effect of these instruments on BC risk was evaluated using genetic data from the BCAC (Breast Cancer Association Consortium) based on 122,977 BC cases and 105,974 controls. Using MR, we observed that a 1-standard-deviation genetically determined increase in HDL levels is associated with an increased risk for all BCs (HDL: OR [odds ratio] = 1.08, 95% confidence interval [CI] = 1.04-1.13, P < 0.001). Multivariable MR analysis, which adjusted for the effects of LDL, TGs, body mass index (BMI), and age at menarche, corroborated this observation for HDL (OR = 1.06, 95% CI = 1.03-1.10, P = 4.9 × 10-4) and also found a relationship between LDL and BC risk (OR = 1.03, 95% CI = 1.01-1.07, P = 0.02). We did not observe a difference in these relationships when stratified by breast tumor estrogen receptor (ER) status. We repeated this analysis using genetic variants independent of the leading association at core HDL pathway genes and found that these variants were also associated with risk for BCs (OR = 1.11, 95% CI = 1.06-1.16, P = 1.5 × 10-6), including locus-specific associations at ABCA1 (ATP Binding Cassette Subfamily A Member 1), APOE-APOC1-APOC4-APOC2 (Apolipoproteins E, C1, C4, and C2), and CETP (Cholesteryl Ester Transfer Protein). In addition, we found evidence that genetic variation at the ABO locus is associated with both lipid levels and BC. Through multiple statistical approaches, we minimized and tested for the confounding effects of pleiotropy and population stratification on our analysis; however, the possible existence of residual pleiotropy and stratification remains a limitation of this study.We observed that genetically elevated plasma HDL and LDL levels appear to be associated with increased BC risk. Future studies are required to understand the mechanism underlying this putative causal relationship, with the goal of developing potential therapeutic strategies aimed at altering the cholesterol-mediated effect on BC risk.
View details for DOI 10.1371/journal.pmed.1003302
View details for PubMedID 32915777
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Genetic determinants of increased body mass index mediate the effect of smoking on increased risk for type 2 diabetes risk but not coronary artery disease.
Human molecular genetics
2020
Abstract
Clinical observations have linked tobacco smoking with increased type 2 diabetes risk. Mendelian randomization analysis has recently suggested smoking may be a causal risk factor for type 2 diabetes. However, this association could be mediated by additional risk factors correlated with smoking behavior, which have not been investigated. We hypothesized that body mass index (BMI) could help to explain the association between smoking and diabetes risk. First, we confirmed that genetic determinants of smoking initiation increased risk for type 2 diabetes (OR = 1.21, 95% CI: 1.15-1.27, P = 1 × 10-12) and coronary artery disease (CAD; OR = 1.21, 95% CI: 1.16-1.26, P = 2 × 10-20). Additionally, 2-fold increased smoking risk was positively associated with increased BMI (~0.8 kg/m2, 95% CI: 0.54-0.98 kg/m2, P = 1.8 × 10-11). Multivariable Mendelian randomization analyses showed that BMI accounted for nearly all the risk smoking exerted on type 2 diabetes (OR 1.06, 95% CI: 1.01-1.11, P = 0.03). In contrast, the independent effect of smoking on increased CAD risk persisted (OR 1.12, 95% CI: 1.08-1.17, P = 3 × 10-8). Causal mediation analyses agreed with these estimates. Furthermore, analysis using individual-level data from the Million Veteran Program (MVP) independently replicated the association of smoking behavior with CAD (OR 1.24, 95% CI: 1.12-1.37, P = 2 × 10-5), but not type 2 diabetes (OR 0.98, 95% CI: 0.89-1.08, P = 0.69), after controlling for BMI. Our findings support a model whereby genetic determinants of smoking increase type 2 diabetes risk indirectly through their relationship with obesity. Smokers should be advised to stop smoking to limit type 2 diabetes and CAD risk. Therapeutic efforts should consider pathophysiology relating smoking and obesity.
View details for DOI 10.1093/hmg/ddaa193
View details for PubMedID 32833022
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Comprehensive Investigation of Circulating Biomarkers and their Causal Role in Atherosclerosis-related Risk Factors and Clinical Events.
Circulation. Genomic and precision medicine
2020
Abstract
Background - Circulating biomarkers have been previously associated with atherosclerosis related risk factors, but the nature of these associations is incompletely understood. Methods - We performed multivariable-adjusted regressions and two-sample Mendelian randomization (MR) analyses to assess observational and causal associations of 27 circulating biomarkers with 7 cardiovascular traits in up to 451,933 participants of the UK Biobank. Results - After multiple-testing correction (alpha=1.3*10-4), we found a total of 15, 9, 21, 22, 26, 24 and 26 biomarkers strongly associated with coronary artery disease (CAD), ischemic stroke, atrial fibrillation, type 2 diabetes (T2D), systolic blood pressure (SBP), body mass index (BMI) and waist-to-hip ratio (WHR); respectively. The MR analyses confirmed strong evidence of previously suggested causal associations for several glucose- and lipid-related biomarkers with T2D and CAD. Particularly interesting findings included a protective role of insulin-like growth factor 1 in SBP, and the strong causal association of lipoprotein(a) in CAD development (β, -0.13; per SD change in exposure and outcome and OR, 1.28; P=2.6*10-4 and P=7.4*10-35, respectively). In addition, our results indicated a causal role of increased alanine aminotransferase in the development of T2D and hypertension (OR, 1.59 and β,0.06, per SD change in exposure and outcome; P=4.8*10-11 and P=6.0*10-5). Our results suggest that it is unlikely that C-reactive protein and vitamin D play causal roles of any meaningful magnitude in development of cardiometabolic disease. Conclusions - We confirmed and extended known associations, and reported several novel causal associations providing important insights regarding the etiology of these diseases, which can help accelerate new prevention strategies.
View details for DOI 10.1161/CIRCGEN.120.002996
View details for PubMedID 33125266
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PCSK9 loss of function is protective against extra-coronary atherosclerotic cardiovascular disease in a large multi-ethnic cohort.
PloS one
2020; 15 (11): e0239752
Abstract
Therapeutic inhibition of PCSK9 protects against coronary artery disease (CAD) and ischemic stroke (IS). The impact on other diseases remains less well characterized.We created a genetic risk score (GRS) for PCSK9 using four single nucleotide polymorphisms (SNPs) at or near the PCSK9 locus known to impact lower LDL-Cholesterol (LDL-C): rs11583680, rs11591147, rs2479409, and rs11206510. We then used our GRS to calculate weighted odds ratios reflecting the impact of a genetically determined 10 mg/dL decrease in LDL-C on several pre-specified phenotypes including CAD, IS, peripheral artery disease (PAD), abdominal aortic aneurysm (AAA), type 2 diabetes, dementia, chronic obstructive pulmonary disease, and cancer. Finally, we used our weighted GRS to perform a phenome-wide association study.Genetic and electronic health record data that passed quality control was available in 312,097 individuals, (227,490 White participants, 58,907 Black participants, and 25,700 Hispanic participants). PCSK9 mediated reduction in LDL-C was associated with a reduced risk of CAD and AAA in trans-ethnic meta-analysis (CAD OR 0.83 [95% CI 0.80-0.87], p = 6.0 x 10-21; AAA OR 0.76 [95% CI 0.68-0.86], p = 2.9 x 10-06). Significant protective effects were noted for PAD in White individuals (OR 0.83 [95% CI 0.71-0.97], p = 2.3 x 10-04) but not in other genetic ancestries. Genetically reduced PCSK9 function associated with a reduced risk of dementia in trans-ethnic meta-analysis (OR 0.86 [95% CI 0.78-0.93], p = 5.0 x 10-04).Genetically reduced PCSK9 function results in a reduction in risk of several important extra-coronary atherosclerotic phenotypes in addition to known effects on CAD and IS, including PAD and AAA. We also highlight a novel reduction in risk of dementia, supporting a well-recognized vascular component to cognitive impairment and an opportunity for therapeutic repositioning.
View details for DOI 10.1371/journal.pone.0239752
View details for PubMedID 33166319
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Genetic Architecture of Abdominal Aortic Aneurysm in the Million Veteran Program.
Circulation
2020
View details for DOI 10.1161/CIRCULATIONAHA.120.047544
View details for PubMedID 32981348
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Discovery of 318 new risk loci for type 2 diabetes and related vascular outcomes among 1.4 million participants in a multi-ancestry meta-analysis.
Nature genetics
2020
Abstract
We investigated type 2 diabetes (T2D) genetic susceptibility via multi-ancestry meta-analysis of 228,499 cases and 1,178,783 controls in the Million Veteran Program (MVP), DIAMANTE, Biobank Japan and other studies. We report 568 associations, including 286 autosomal, 7 X-chromosomal and 25 identified in ancestry-specific analyses that were previously unreported. Transcriptome-wide association analysis detected 3,568 T2D associations with genetically predicted gene expression in 687 novel genes; of these, 54 are known to interact with FDA-approved drugs. A polygenic risk score (PRS) was strongly associated with increased risk of T2D-related retinopathy and modestly associated with chronic kidney disease (CKD), peripheral artery disease (PAD) and neuropathy. We investigated the genetic etiology of T2D-related vascular outcomes in the MVP and observed statistical SNP-T2D interactions at 13 variants, including coronary heart disease (CHD), CKD, PAD and neuropathy. These findings may help to identify potential therapeutic targets for T2D and genomic pathways that link T2D to vascular outcomes.
View details for DOI 10.1038/s41588-020-0637-y
View details for PubMedID 32541925
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Cross-trait analyses with migraine reveal widespread pleiotropy and suggest a vascular component to migraine headache.
International journal of epidemiology
2020
Abstract
Nearly a fifth of the world's population suffer from migraine headache, yet risk factors for this disease are poorly characterized.To further elucidate these factors, we conducted a genetic correlation analysis using cross-trait linkage disequilibrium (LD) score regression between migraine headache and 47 traits from the UK Biobank. We then tested for possible causality between these phenotypes and migraine, using Mendelian randomization. In addition, we attempted replication of our findings in an independent genome-wide association study (GWAS) when available.We report multiple phenotypes with genetic correlation (P < 1.06 × 10-3) with migraine, including heart disease, type 2 diabetes, lipid levels, blood pressure, autoimmune and psychiatric phenotypes. In particular, we find evidence that blood pressure directly contributes to migraine and explains a previously suggested causal relationship between calcium and migraine.This is the largest genetic correlation analysis of migraine headache to date, both in terms of migraine GWAS sample size and the number of phenotypes tested. We find that migraine has a shared genetic basis with a large number of traits, indicating pervasive pleiotropy at migraine-associated loci.
View details for DOI 10.1093/ije/dyaa050
View details for PubMedID 32306029
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Genotyping Array Design and Data Quality Control in the Million Veteran Program.
American journal of human genetics
2020; 106 (4): 535–48
Abstract
The Million Veteran Program (MVP), initiated by the Department of Veterans Affairs (VA), aims to collect biosamples with consent from at least one million veterans. Presently, blood samples have been collected from over 800,000 enrolled participants. The size and diversity of the MVP cohort, as well as the availability of extensive VA electronic health records, make it a promising resource for precision medicine. MVP is conducting array-based genotyping to provide a genome-wide scan of the entire cohort, in parallel with whole-genome sequencing, methylation, and other 'omics assays. Here, we present the design and performance of the MVP 1.0 custom Axiom array, which was designed and developed as a single assay to be used across the multi-ethnic MVP cohort. A unified genetic quality-control analysis was developed and conducted on an initial tranche of 485,856 individuals, leading to a high-quality dataset of 459,777 unique individuals. 668,418 genetic markers passed quality control and showed high-quality genotypes not only on common variants but also on rare variants. We confirmed that, with non-European individuals making up nearly 30%, MVP's substantial ancestral diversity surpasses that of other large biobanks. We also demonstrated the quality of the MVP dataset by replicating established genetic associations with height in European Americans and African Americans ancestries. This current dataset has been made available to approved MVP researchers for genome-wide association studies and other downstream analyses. Further data releases will be available for analysis as recruitment at the VA continues and the cohort expands both in size and diversity.
View details for DOI 10.1016/j.ajhg.2020.03.004
View details for PubMedID 32243820
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Minority-centric meta-analyses of blood lipid levels identify novel loci in the Population Architecture using Genomics and Epidemiology (PAGE) study.
PLoS genetics
2020; 16 (3): e1008684
Abstract
Lipid levels are important markers for the development of cardio-metabolic diseases. Although hundreds of associated loci have been identified through genetic association studies, the contribution of genetic factors to variation in lipids is not fully understood, particularly in U.S. minority groups. We performed genome-wide association analyses for four lipid traits in over 45,000 ancestrally diverse participants from the Population Architecture using Genomics and Epidemiology (PAGE) Study, followed by a meta-analysis with several European ancestry studies. We identified nine novel lipid loci, five of which showed evidence of replication in independent studies. Furthermore, we discovered one novel gene in a PrediXcan analysis, minority-specific independent signals at eight previously reported loci, and potential functional variants at two known loci through fine-mapping. Systematic examination of known lipid loci revealed smaller effect estimates in African American and Hispanic ancestry populations than those in Europeans, and better performance of polygenic risk scores based on minority-specific effect estimates. Our findings provide new insight into the genetic architecture of lipid traits and highlight the importance of conducting genetic studies in diverse populations in the era of precision medicine.
View details for DOI 10.1371/journal.pgen.1008684
View details for PubMedID 32226016
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Cardioinformatics: the nexus of bioinformatics and precision cardiology.
Briefings in bioinformatics
2019
Abstract
Cardiovascular disease (CVD) is the leading cause of death worldwide, causing over 17 million deaths per year, which outpaces global cancer mortality rates. Despite these sobering statistics, most bioinformatics and computational biology research and funding to date has been concentrated predominantly on cancer research, with a relatively modest footprint in CVD. In this paper, we review the existing literary landscape and critically assess the unmet need to further develop an emerging field at the multidisciplinary interface of bioinformatics and precision cardiovascular medicine, which we refer to as 'cardioinformatics'.
View details for DOI 10.1093/bib/bbz119
View details for PubMedID 31802103
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A Missense Variant in IL6R and Protection From Peripheral Artery Disease
LIPPINCOTT WILLIAMS & WILKINS. 2019
View details for Web of Science ID 000529998003189
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Genomic and transcriptomic association studies identify 16 novel susceptibility loci for venous thromboembolism
BLOOD
2019; 134 (19): 1645-1657
Abstract
Venous thromboembolism (VTE) is a significant contributor to morbidity and mortality. To advance our understanding of the biology contributing to VTE, we conducted a genome-wide association study (GWAS) of VTE and a transcriptome-wide association study (TWAS) based on imputed gene expression from whole blood and liver. We meta-analyzed GWAS data from 18 studies for 30 234 VTE cases and 172 122 controls and assessed the association between 12 923 718 genetic variants and VTE. We generated variant prediction scores of gene expression from whole blood and liver tissue and assessed them for association with VTE. Mendelian randomization analyses were conducted for traits genetically associated with novel VTE loci. We identified 34 independent genetic signals for VTE risk from GWAS meta-analysis, of which 14 are newly reported associations. This included 11 newly associated genetic loci (C1orf198, PLEK, OSMR-AS1, NUGGC/SCARA5, GRK5, MPHOSPH9, ARID4A, PLCG2, SMG6, EIF5A, and STX10) of which 6 replicated, and 3 new independent signals in 3 known genes. Further, TWAS identified 5 additional genetic loci with imputed gene expression levels differing between cases and controls in whole blood (SH2B3, SPSB1, RP11-747H7.3, RP4-737E23.2) and in liver (ERAP1). At some GWAS loci, we found suggestive evidence that the VTE association signal for novel and previously known regions colocalized with expression quantitative trait locus signals. Mendelian randomization analyses suggested that blood traits may contribute to the underlying risk of VTE. To conclude, we identified 16 novel susceptibility loci for VTE; for some loci, the association signals are likely mediated through gene expression of nearby genes.
View details for DOI 10.1182/blood.2019000435
View details for Web of Science ID 000495894200012
View details for PubMedID 31420334
View details for PubMedCentralID PMC6871304
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Genome-wide association analysis of venous thromboembolism identifies new risk loci and genetic overlap with arterial vascular disease.
Nature genetics
2019
Abstract
Venous thromboembolism is a significant cause of mortality1, yet its genetic determinants are incompletely defined. We performed a discovery genome-wide association study in the Million Veteran Program and UK Biobank, with testing of approximately 13 million DNA sequence variants for association with venous thromboembolism (26,066 cases and 624,053 controls) and meta-analyzed both studies, followed by independent replication with up to 17,672 venous thromboembolism cases and 167,295 controls. We identified 22 previously unknown loci, bringing the total number of venous thromboembolism-associated loci to 33, and subsequently fine-mapped these associations. We developed a genome-wide polygenic risk score for venous thromboembolism that identifies 5% of the population at an equivalent incident venous thromboembolism risk to carriers of the established factor V Leiden p.R506Q and prothrombin G20210A mutations. Our data provide mechanistic insights into the genetic epidemiology of venous thromboembolism and suggest a greater overlap among venous and arterial cardiovascular disease than previously thought.
View details for DOI 10.1038/s41588-019-0519-3
View details for PubMedID 31676865
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Association Between Heart Failure and Postoperative Mortality Among Patients Undergoing Ambulatory Noncardiac Surgery.
JAMA surgery
2019
Abstract
Importance: Heart failure is an established risk factor for postoperative mortality, but how heart failure is associated with operative outcomes specifically in the ambulatory surgical setting is not well characterized.Objective: To assess the risk of postoperative mortality and complications in patients with vs without heart failure at various levels of echocardiographic (left ventricular systolic dysfunction) and clinical (symptoms) severity who were undergoing ambulatory surgery.Design, Setting, and Participants: In this US multisite retrospective cohort study of all adult patients undergoing ambulatory, elective, noncardiac surgery in the Veterans Affairs Surgical Quality Improvement Project database during fiscal years 2009 to 2016, a total of 355 121 patient records were identified and analyzed with 1 year of follow-up after surgery (final date of follow-up September 1, 2017).Exposures: Heart failure, left ventricular ejection fraction, and presence of signs or symptoms of heart failure within 30 days of surgery.Main Outcomes and Measures: The primary outcomes were postoperative mortality at 90 days and any postoperative complication at 30 days.Results: Among 355 121 total patients, outcome data from 19 353 patients with heart failure (5.5%; mean [SD] age, 67.9 [10.1] years; 18 841 [96.9%] male) and 334 768 patients without heart failure (94.5%; mean [SD] age, 57.2 [14.0] years; 301 198 [90.0%] male) were analyzed. Compared with patients without heart failure, patients with heart failure had a higher risk of 90-day postoperative mortality (crude mortality risk, 2.00% vs 0.39%; adjusted odds ratio [aOR], 1.95; 95% CI, 1.69-2.44), and risk of mortality progressively increased with decreasing systolic function. Compared with patients without heart failure, symptomatic patients with heart failure had a greater risk of mortality (crude mortality risk, 3.57%; aOR, 2.76; 95% CI, 2.07-3.70), as did asymptomatic patients with heart failure (crude mortality risk, 1.85%; aOR, 1.85; 95% CI, 1.60-2.15). Patients with heart failure had a higher risk of experiencing a 30-day postoperative complication than did patients without heart failure (crude risk, 5.65% vs 2.65%; aOR, 1.10; 95% CI, 1.02-1.19).Conclusions and Relevance: In this study, among patients undergoing elective, ambulatory surgery, heart failure with or without symptoms was significantly associated with 90-day mortality and 30-day postoperative complications. These data may be helpful in preoperative discussions with patients with heart failure undergoing ambulatory surgery.
View details for DOI 10.1001/jamasurg.2019.2110
View details for PubMedID 31290953
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Genome-wide association study of peripheral artery disease in the Million Veteran Program.
Nature medicine
2019
Abstract
Peripheral artery disease (PAD) is a leading cause of cardiovascular morbidity and mortality; however, the extent to which genetic factors increase risk for PAD is largely unknown. Using electronic health record data, we performed a genome-wide association study in the Million Veteran Program testing ~32 million DNA sequence variants with PAD (31,307 cases and 211,753 controls) across veterans of European, African and Hispanic ancestry. The results were replicated in an independent sample of 5,117 PAD cases and 389,291 controls from the UK Biobank. We identified 19 PAD loci, 18 of which have not been previously reported. Eleven of the 19 loci were associated with disease in three vascular beds (coronary, cerebral, peripheral), including LDLR, LPL and LPA, suggesting that therapeutic modulation of low-density lipoprotein cholesterol, the lipoprotein lipase pathway or circulating lipoprotein(a) may be efficacious for multiple atherosclerotic disease phenotypes. Conversely, four of the variants appeared to be specific for PAD, including F5 p.R506Q, highlighting the pathogenic role of thrombosis in the peripheral vascular bed and providing genetic support for Factor Xa inhibition as a therapeutic strategy for PAD. Our results highlight mechanistic similarities and differences among coronary, cerebral and peripheral atherosclerosis and provide therapeutic insights.
View details for DOI 10.1038/s41591-019-0492-5
View details for PubMedID 31285632
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Epigenome-wide Association Study of Diet Quality in the Women's Health Initiative (OR31-06-19).
Current developments in nutrition
2019; 3 (Suppl 1)
Abstract
Objectives: This study examined the influence of diet on the methylome by analyzing 428,019 cytosine-guanine nucleotide pair (CpG) sites and assessing whether diet quality was associated with differential methylation patterns.Methods: The study population included 4529 women from the Women's Health Initiative (WHI) observation and clinical trial from three ancillary studies: EMPC, BAA23, and AS311. DNA methylation was measured from whole blood samples using the Illumina Infinium HumanMethylation450 Beadchip. Diet quality was assessed using the Alternative Healthy Eating Index 2010 (AHEI-2010). An epigenome-wide association study (EWAS) meta-analysis, stratified by study cohort, was done using generalized linear models by regressing methylation beta values (beta=Methylated probes/[Methylated+Unmethylated probes]) for each CpG site on the primary exposure, AHEI, adjusting for cell composition, chip number and location, study characteristics, principle components of genetic relatedness, age, ethnicity and BMI. Significance was set at Holm-Bonferroni P<0.05.Results: Demographic characteristics are described by quartile of AHEI with Quartile 4 equivalent to the healthiest diet (highest score) and Quartile 1 equivalent to the poorest diet (lowest score) in Table 1. We found diet quality was significantly associated with 340 CpG sites after false discovery correction (Figure 1). While statistically significant, effect sizes were small (0.0003). These findings suggest that, on average, as AHEI increases by one SD (10.1 units), methylation changes by only ±0.003 in associated CpG sites. When examining the top 20 CpG sites (Table 2), several sites were located in genes critical to metabolism, including cg26137868 in the FOXA2 gene and cg20006924 in the RORA gene, both related to the regulation of glucose and fat metabolism and 3 CpG sites in the SLC18A2, SLC2A14, and SLC16A3 genes related to nutrient transport.Conclusions: This is the first reported EWAS examining the relationship between diet quality and methylation in humans. While diet quality was statistically associated with many CpG sites, the effect sizes were small. Further investigation is required to understand the relationship between diet quality and the methylome.Funding Sources: NA.Supporting Tables Images and/or Graphs:
View details for DOI 10.1093/cdn/nzz037.OR31-06-19
View details for PubMedID 31224898
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Genetic Analysis Implicates LDL Cholesterol Reduction and Plasminogen Activator-inhibitor 1 Antagonism as Therapeutic Interventions for Venous Thromboembolism
LIPPINCOTT WILLIAMS & WILKINS. 2019
View details for Web of Science ID 000482037300012
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HeartBioPortal.
Circulation. Genomic and precision medicine
2019; 12 (4): e002426
View details for DOI 10.1161/CIRCGEN.118.002426
View details for PubMedID 31294639
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Identification of 22 novel loci associated withurinary biomarkers of albumin, sodium, andpotassium excretion.
Kidney international
2019
Abstract
Urine biomarkers reflecting kidney function and handling of dietary sodium and potassium are strongly associated with several common diseases including chronic kidney disease, cardiovascular disease, and diabetes mellitus. Knowledge about the genetic determinants of these biomarkers may shed light on pathophysiological mechanisms underlying the development of these diseases. We performed genome-wide association studies of urinary albumin: creatinine ratio (UACR), urinary potassium: creatinine ratio (UK/UCr), urinary sodium: creatinine ratio (UNa/UCr) and urinary sodium: potassium ratio (UNa/UK) in up to 218,450 (discovery) and 109,166 (replication) unrelated individuals of European ancestry from the UK Biobank. Further, we explored genetic correlations, tissue-specific gene expression, and possible genes implicated in the regulation of these biomarkers. After replication, we identified 19 genome-wide significant independent loci associated with UACR, 6 each with UK/UCr and UNa/UCr, and 4 with UNa/UK. In addition to 22 novel associations, we confirmed several established associations, including between the CUBN locus and microalbuminuria. We detected high pairwise genetic correlation across the urinary biomarkers, and between their levels and several physiological measurements. We highlight GIPR, a potential diabetes drug target, as possibly implicated in the genetic control of urinary potassium excretion, and NRBP1, a locus associated with gout, as plausibly involved in sodium and albumin excretion. Overall, we identified 22 novel genome-wide significant associations with urinary biomarkers and confirmed several previously established associations, providing new insights into the genetic basis of these traits and their connection to chronic diseases.
View details for PubMedID 30910378
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Association of Left Ventricular Ejection Fraction and Symptoms With Mortality After Elective Noncardiac Surgery Among Patients With Heart Failure.
JAMA
2019; 321 (6): 572-579
Abstract
Heart failure is an established risk factor for postoperative mortality, but how left ventricular ejection fraction and heart failure symptoms affect surgical outcomes is not fully described.To determine the risk of postoperative mortality among patients with heart failure at various levels of echocardiographic (left ventricular systolic dysfunction) and clinical (symptoms) severity compared with those without heart failure and to evaluate how risk varies across levels of surgical complexity.US multisite retrospective cohort study of all adult patients receiving elective, noncardiac surgery in the Veterans Affairs Surgical Quality Improvement Project database from 2009 through 2016. A total of 609 735 patient records were identified and analyzed with 1 year of follow-up after having surgery (final study follow-up: September 1, 2017).Heart failure, left ventricular ejection fraction, and presence of signs or symptoms of heart failure within 30 days of surgery.The primary outcome was postoperative mortality at 90 days.Outcome data from 47 997 patients with heart failure (7.9%; mean [SD] age, 68.6 [10.1] years; 1391 women [2.9%]) and 561 738 patients without heart failure (92.1%; mean [SD] age, 59.4 [13.4] years; 50 862 women [9.1%]) were analyzed. Compared with patients without heart failure, those with heart failure had a higher risk of 90-day postoperative mortality (2635 vs 6881 90-day deaths; crude mortality risk, 5.49% vs 1.22%; adjusted absolute risk difference [RD], 1.03% [95% CI, 0.91%-1.15%]; adjusted odds ratio [OR], 1.67 [95% CI, 1.57-1.76]). Compared with patients without heart failure, symptomatic patients with heart failure (n = 5906) had a higher risk (597 deaths [10.11%]; adjusted absolute RD, 2.37% [95% CI, 2.06%-2.57%]; adjusted OR, 2.37 [95% CI, 2.14-2.63]). Asymptomatic patients with heart failure (n = 42 091) (2038 deaths [crude risk, 4.84%]; adjusted absolute RD, 0.74% [95% CI, 0.63%-0.87%]; adjusted OR, 1.53 [95% CI, 1.44-1.63]), including the subset with preserved left ventricular systolic function (1144 deaths [4.42%]; adjusted absolute RD, 0.66% [95% CI, 0.54%-0.79%]; adjusted OR, 1.46 [95% CI, 1.35-1.57]), also experienced elevated risk.Among patients undergoing elective noncardiac surgery, heart failure with or without symptoms was significantly associated with 90-day postoperative mortality. These data may be helpful in preoperative discussions with patients with heart failure undergoing noncardiac surgery.
View details for DOI 10.1001/jama.2019.0156
View details for PubMedID 30747965
View details for PubMedCentralID PMC6439591
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Leveraging linkage evidence to identify low-frequency and rare variants on 16p13 associated with blood pressure using TOPMed whole genome sequencing data.
Human genetics
2019
Abstract
In this study, we investigated low-frequency and rare variants associated with blood pressure (BP) by focusing on a linkage region on chromosome 16p13. We used whole genome sequencing (WGS) data obtained through the NHLBI Trans-Omics for Precision Medicine (TOPMed) program on 395 Cleveland Family Study (CFS) European Americans (CFS-EA). By analyzing functional coding variants and non-coding rare variants with CADD score>10 residing within the chromosomal region in families with linkage evidence, we observed 25 genes with nominal statistical evidence (burden or SKAT p<0.05). One of the genes is RBFOX1, an evolutionarily conserved RNA-binding protein that regulates tissue-specific alternative splicing that we previously reported to be associated with BP using exome array data in CFS. After follow-up analysis of the 25 genes in ten independent TOPMed studies with individuals of European, African, and East Asian ancestry, and Hispanics (N=29,988), we identified variants in SLX4 (p=2.19*10-4) to be significantly associated with BP traits when accounting for multiple testing. We also replicated the associations previously reported for RBFOX1 (p=0.007). Follow-up analysis with GTEx eQTL data shows SLX4 variants are associated with gene expression in coronary artery, multiple brain tissues, and right atrial appendage of the heart. Our study demonstrates that linkage analysis of family data can provide an efficient approach for detecting rare variants associated with complex traits in WGS data.
View details for PubMedID 30671673
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DNA methylation GrimAge strongly predicts lifespan and healthspan.
Aging
2019; 11 (2): 303–27
Abstract
It was unknown whether plasma protein levels can be estimated based on DNA methylation (DNAm) levels, and if so, how the resulting surrogates can be consolidated into a powerful predictor of lifespan. We present here, seven DNAm-based estimators of plasma proteins including those of plasminogen activator inhibitor 1 (PAI-1) and growth differentiation factor 15. The resulting predictor of lifespan, DNAm GrimAge (in units of years), is a composite biomarker based on the seven DNAm surrogates and a DNAm-based estimator of smoking pack-years. Adjusting DNAm GrimAge for chronological age generated novel measure of epigenetic age acceleration, AgeAccelGrim.Using large scale validation data from thousands of individuals, we demonstrate that DNAm GrimAge stands out among existing epigenetic clocks in terms of its predictive ability for time-to-death (Cox regression P=2.0E-75), time-to-coronary heart disease (Cox P=6.2E-24), time-to-cancer (P= 1.3E-12), its strong relationship with computed tomography data for fatty liver/excess visceral fat, and age-at-menopause (P=1.6E-12). AgeAccelGrim is strongly associated with a host of age-related conditions including comorbidity count (P=3.45E-17). Similarly, age-adjusted DNAm PAI-1 levels are associated with lifespan (P=5.4E-28), comorbidity count (P= 7.3E-56) and type 2 diabetes (P=2.0E-26). These DNAm-based biomarkers show the expected relationship with lifestyle factors including healthy diet and educational attainment.Overall, these epigenetic biomarkers are expected to find many applications including human anti-aging studies.
View details for DOI 10.18632/aging.101684
View details for PubMedID 30669119
View details for PubMedCentralID PMC6366976
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Performance of Polygenic Risk Scores for Coronary Artery Disease in the Million Veteran Program
LIPPINCOTT WILLIAMS & WILKINS. 2019
View details for DOI 10.1161/circ.139.suppl_1.012
View details for Web of Science ID 000478079000013
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Predictors of High Intensity Statin Initiation for Primary Prevention in Veterans With Familial Hypercholesterolemia Phenotype
LIPPINCOTT WILLIAMS & WILKINS. 2019
View details for DOI 10.1161/circ.139.suppl_1.P336
View details for Web of Science ID 000478079000279
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Harmonizing Genetic Ancestry and Self-identified Race/Ethnicity in Genome-wide Association Studies.
American journal of human genetics
2019
Abstract
Large-scale multi-ethnic cohorts offer unprecedented opportunities to elucidate the genetic factors influencing complex traits related to health and disease among minority populations. At the same time, the genetic diversity in these cohorts presents new challenges for analysis and interpretation. We consider the utility of race and/or ethnicity categories in genome-wide association studies (GWASs) of multi-ethnic cohorts. We demonstrate that race/ethnicity information enhances the ability to understand population-specific genetic architecture. To address the practical issue that self-identified racial/ethnic information may be incomplete, we propose a machine learning algorithm that produces a surrogate variable, termed HARE. We use height as a model trait to demonstrate the utility of HARE and ethnicity-specific GWASs.
View details for DOI 10.1016/j.ajhg.2019.08.012
View details for PubMedID 31564439
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Blood Leukocyte DNA Methylation Predicts Risk of Future Myocardial Infarction and Coronary Heart Disease.
Circulation
2019; 140 (8): 645–57
Abstract
DNA methylation is implicated in coronary heart disease (CHD), but current evidence is based on small, cross-sectional studies. We examined blood DNA methylation in relation to incident CHD across multiple prospective cohorts.Nine population-based cohorts from the United States and Europe profiled epigenome-wide blood leukocyte DNA methylation using the Illumina Infinium 450k microarray, and prospectively ascertained CHD events including coronary insufficiency/unstable angina, recognized myocardial infarction, coronary revascularization, and coronary death. Cohorts conducted race-specific analyses adjusted for age, sex, smoking, education, body mass index, blood cell type proportions, and technical variables. We conducted fixed-effect meta-analyses across cohorts.Among 11 461 individuals (mean age 64 years, 67% women, 35% African American) free of CHD at baseline, 1895 developed CHD during a mean follow-up of 11.2 years. Methylation levels at 52 CpG (cytosine-phosphate-guanine) sites were associated with incident CHD or myocardial infarction (false discovery rate<0.05). These CpGs map to genes with key roles in calcium regulation (ATP2B2, CASR, GUCA1B, HPCAL1), and genes identified in genome- and epigenome-wide studies of serum calcium (CASR), serum calcium-related risk of CHD (CASR), coronary artery calcified plaque (PTPRN2), and kidney function (CDH23, HPCAL1), among others. Mendelian randomization analyses supported a causal effect of DNA methylation on incident CHD; these CpGs map to active regulatory regions proximal to long non-coding RNA transcripts.Methylation of blood-derived DNA is associated with risk of future CHD across diverse populations and may serve as an informative tool for gaining further insight on the development of CHD.
View details for DOI 10.1161/CIRCULATIONAHA.118.039357
View details for PubMedID 31424985
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DNA methylation-based estimator of telomere length.
Aging
2019
Abstract
Telomere length (TL) is associated with several aging-related diseases. Here, we present a DNA methylation estimator of TL (DNAmTL) based on 140 CpGs. Leukocyte DNAmTL is applicable across the entire age spectrum and is more strongly associated with age than measured leukocyte TL (LTL) (r ~-0.75 for DNAmTL versus r ~ -0.35 for LTL). Leukocyte DNAmTL outperforms LTL in predicting: i) time-to-death (p=2.5E-20), ii) time-to-coronary heart disease (p=6.6E-5), iii) time-to-congestive heart failure (p=3.5E-6), and iv) association with smoking history (p=1.21E-17). These associations are further validated in large scale methylation data (n=10k samples) from the Framingham Heart Study, Women's Health Initiative, Jackson Heart Study, InChianti, Lothian Birth Cohorts, Twins UK, and Bogalusa Heart Study. Leukocyte DNAmTL is also associated with measures of physical fitness/functioning (p=0.029), age-at-menopause (p=0.039), dietary variables (omega 3, fish, vegetable intake), educational attainment (p=3.3E-8) and income (p=3.1E-5). Experiments in cultured somatic cells show that DNAmTL dynamics reflect in part cell replication rather than TL per se. DNAmTL is not only an epigenetic biomarker of replicative history of cells, but a useful marker of age-related pathologies that are associated with it.
View details for DOI 10.18632/aging.102173
View details for PubMedID 31422385
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Association of APOL1 Risk Alleles with Cardiovascular Disease in African Americans in the Million Veteran Program.
Circulation
2019
Abstract
Approximately 13% of African-American individuals carry two copies of the APOL1 risk alleles G1 or G2, which are associated with 1.5-2.5 fold increased risk of chronic kidney disease (CKD). There have been conflicting reports as to whether an association exists between APOL1 risk alleles and cardiovascular disease, independent of the effects of APOL1 on kidney disease. We sought to test the association of APOL1 G1/G2 alleles with coronary artery disease (CAD), peripheral artery disease (PAD), and stroke among African American individuals in the Million Veteran Program (MVP).We performed a time-to-event analysis of retrospective electronic health record (EHR) data using Cox proportional hazard and competing risks Fine and Gray sub-distribution hazard models. The primary exposure was APOL1 risk allele status. The primary outcome was incident CAD amongst individuals without CKD during the 12.5 year follow up period. Separately we analyzed the cross-sectional association of APOL1 risk allele status with lipid traits and 115 cardiovascular diseases using phenome-wide association.Among 30,903 African American MVP participants, 3,941 (13%) carried the two APOL1 risk allele high-risk genotype. Individuals with normal kidney function at baseline with two risk alleles had slightly higher risk of developing CAD compared to those with no risk alleles (Hazard Ratio (HR): 1.11, 95% Confidence Interval (CI): 1.01-1.21, p=0.039). Similarly, modest associations were identified with incident stroke (HR: 1.20, 95% CI: 1.05-1.36, p=0.007) and PAD (HR: 1.15, 95% CI:1.01-1.29, p=0.031). When modeling both cardiovascular and renal outcomes, APOL1 was strongly associated with incident renal disease, while no significant association with the cardiovascular disease endpoints could be detected. Cardiovascular phenome-wide association analyses did not identify additional significant associations with cardiovascular disease subsets.APOL1 risk variants display a modest association with cardiovascular disease and this association is likely mediated by the known APOL1 association with CKD.
View details for DOI 10.1161/CIRCULATIONAHA.118.036589
View details for PubMedID 31337231
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Methylome-wide association study provides evidence of particulate matter air pollution-associated DNA methylation.
Environment international
2019; 132: 104723
Abstract
DNA methylation (DNAm) may contribute to processes that underlie associations between air pollution and poor health. Therefore, our objective was to evaluate associations between DNAm and ambient concentrations of particulate matter (PM) ≤2.5, ≤10, and 2.5-10 μm in diameter (PM2.5; PM10; PM2.5-10).We conducted a methylome-wide association study among twelve cohort- and race/ethnicity-stratified subpopulations from the Women's Health Initiative and the Atherosclerosis Risk in Communities study (n = 8397; mean age: 61.5 years; 83% female; 45% African American; 9% Hispanic/Latino American). We averaged geocoded address-specific estimates of daily and monthly mean PM concentrations over 2, 7, 28, and 365 days and 1 and 12 months before exams at which we measured leukocyte DNAm in whole blood. We estimated subpopulation-specific, DNAm-PM associations at approximately 485,000 Cytosine-phosphate-Guanine (CpG) sites in multi-level, linear, mixed-effects models. We combined subpopulation- and site-specific estimates in fixed-effects, inverse variance-weighted meta-analyses, then for associations that exceeded methylome-wide significance and were not heterogeneous across subpopulations (P < 1.0 × 10-7; PCochran's Q > 0.10), we characterized associations using publicly accessible genomic databases and attempted replication in the Cooperative Health Research in the Region of Augsburg (KORA) study.Analyses identified significant DNAm-PM associations at three CpG sites. Twenty-eight-day mean PM10 was positively associated with DNAm at cg19004594 (chromosome 20; MATN4; P = 3.33 × 10-8). One-month mean PM10 and PM2.5-10 were positively associated with DNAm at cg24102420 (chromosome 10; ARPP21; P = 5.84 × 10-8) and inversely associated with DNAm at cg12124767 (chromosome 7; CFTR; P = 9.86 × 10-8). The PM-sensitive CpG sites mapped to neurological, pulmonary, endocrine, and cardiovascular disease-related genes, but DNAm at those sites was not associated with gene expression in blood cells and did not replicate in KORA.Ambient PM concentrations were associated with DNAm at genomic regions potentially related to poor health among racially, ethnically and environmentally diverse populations of U.S. women and men. Further investigation is warranted to uncover mechanisms through which PM-induced epigenomic changes may cause disease.
View details for DOI 10.1016/j.envint.2019.03.071
View details for PubMedID 31208937
View details for PubMedCentralID PMC6754789
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An integrative cross-omics analysis of DNA methylation sites of glucose and insulin homeostasis.
Nature communications
2019; 10 (1): 2581
Abstract
Despite existing reports on differential DNA methylation in type 2 diabetes (T2D) and obesity, our understanding of its functional relevance remains limited. Here we show the effect of differential methylation in the early phases of T2D pathology by a blood-based epigenome-wide association study of 4808 non-diabetic Europeans in the discovery phase and 11,750 individuals in the replication. We identify CpGs in LETM1, RBM20, IRS2, MAN2A2 and the 1q25.3 region associated with fasting insulin, and in FCRL6, SLAMF1, APOBEC3H and the 15q26.1 region with fasting glucose. In silico cross-omics analyses highlight the role of differential methylation in the crosstalk between the adaptive immune system and glucose homeostasis. The differential methylation explains at least 16.9% of the association between obesity and insulin. Our study sheds light on the biological interactions between genetic variants driving differential methylation and gene expression in the early pathogenesis of T2D.
View details for DOI 10.1038/s41467-019-10487-4
View details for PubMedID 31197173
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The role of epigenetic aging in education and racial/ethnic mortality disparities among older U.S. Women.
Psychoneuroendocrinology
2019; 104: 18–24
Abstract
Higher mortality experienced by socially disadvantaged groups and/or racial/ethnic minorities is hypothesized to be, at least in part, due to an acceleration of the aging process. Using a new epigenetic aging measure, Levine DNAmAge, this study aimed to investigate whether epigenetic aging accounts for mortality disparities by race/ethnicity and education in a sample of U.S. postmenopausal women.1834 participants from an ancillary study (BA23) in the Women's Health Initiative, a national study that recruited postmenopausal women (50-79 years) were included. Over the 22 years of follow-up, 551 women died, and 31,946 person-years were observed. Levine DNAmAge (unit in years) was calculated based on an equation that we previously developed in an independent sample, which incorporates methylation levels at 513 CpG sites.As previously reported, non-Hispanic blacks and Hispanics were epigenetically older than non-Hispanic whites of the same chronological age. Similarly, those with less education had older epigenetic ages than expected in the full sample, as well as among non-Hispanic whites and Hispanics, but not among non-Hispanic blacks. Non-Hispanic blacks and those with low education exhibited the greatest risk of mortality. However, this association was partially attenuated when accounting for differences in DNAmAge. Furthermore, formal mediation analysis suggested that DNAmAge partially mediated the mortality increase among non-Hispanic blacks, compared to non-Hispanic whites (proportion mediated, 15.8%, P = 0.002), as well as the mortality increase for those with less than high school education, compared to college educated (proportion mediated, 11.6%, P < 2E-16).Among a group of postmenopausal women, non-Hispanic blacks and those with less education exhibit higher epigenetic aging, which partially accounts for their shorter life expectancies.
View details for DOI 10.1016/j.psyneuen.2019.01.028
View details for PubMedID 30784901
View details for PubMedCentralID PMC6555423
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Breastfeeding Duration and the Risk of Coronary Artery Disease.
Journal of women's health (2002)
2018
Abstract
BACKGROUND: Previous studies have suggested that prolonged breastfeeding has beneficial effects on the health of the mother including the reduction of long-term risk of coronary artery disease (CAD). The mechanism of this association remains unclear.METHODS: We surveyed 643 women aged 40-65 years receiving outpatient care at Stanford University Hospital on their reproductive/lactation history, including 137 women (cases) with clinically confirmed CAD. Survey data were supplemented with traditional risk factor data for CAD obtained from the participant's medical record. We then conducted logistic regression analyses to assess the relationship between breastfeeding duration and case-control status for each of the two separate definitions of duration. The first was based on the participant's single longest duration of breastfeeding considering all live births reported and the second was based on a participant's total duration of breastfeeding summed over all live births. For each of these two definitions, we ran three sequential models each with a different reference group-(1) nulliparous women, (2) parous women that never breastfed, and (3) parous women with a short duration of breastfeeding-successively excluding women in the reference group of the previous model(s).RESULTS: Just over one-half (51.6%) of the women surveyed reported a history of breastfeeding. We found nominally significant associations (p=0.04-0.12) for our multivariate analyses that modeled maximum duration of breastfeeding. When compared with nulliparous women, parous women who either never breastfed or always breastfed for <5 months had approximately double the risk of CAD. Among parous women, women who breastfeed for ≥5 months at least once in their lifetime had a 30% decrease risk of CAD compared with those who did not initiate breastfeeding. Among parous women who breastfed ≥1 month, women who breastfed ≥5 months had 50% decreased risk of CAD. We found similar point estimates of effect for analogous analyses modeling maximum breastfeeding duration but p-values for these analyses were not significant. Unadjusted analyses demonstrated higher valued odds ratios and lower p-values suggesting the presence of some confounding by traditional risk factors.CONCLUSIONS: Parous women who breastfeed ≥5 months in at least one pregnancy seem to be at decreased risk of CAD later in their life, whereas parous women who either never breastfed or discontinued breastfeeding early seem to be at increased risk. More research is needed to more reliably quantify and determine the nature of the relationship between parity, breastfeeding duration, and risk of CAD.
View details for PubMedID 30523760
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Effects of Genetic Variants Associated with Familial Hypercholesterolemia on Low-Density Lipoprotein-Cholesterol Levels and Cardiovascular Outcomes in the Million Veteran Program.
Circulation. Genomic and precision medicine
2018; 11 (12)
Abstract
Familial hypercholesterolemia (FH) is characterized by inherited high levels of low-density lipoprotein cholesterol (LDL-C) and premature coronary heart disease (CHD). Over a thousand low-frequency variants in LDLR, APOB and PCSK9 have been implicated in FH but few have been examined at the population level. We aim to estimate the phenotypic effects of a subset of FH variants on LDL-C and clinical outcomes among 331,107 multi-ethnic participants.We examined the individual and collective association between putatively pathogenic FH variants included on the MVP biobank array and the maximum LDL-C level over an interval of 15 years (maxLDL). We assessed the collective effect on clinical outcomes by leveraging data from 61.7 million clinical encounters.We found 8 out of 16 putatively pathogenic FH variants with ≥30 observed carriers to be significantly associated with elevated maxLDL (9.4-80.2 mg/dL). Phenotypic effects were similar for European and African Americans despite substantial differences in carrier frequencies. Based on observed effects on maxLDL, we identified a total of 748 carriers (1:443) who had elevated maxLDL (36.5±1.4 mg/dL, p=1.2×10-152), and higher prevalence of clinical diagnoses related to hypercholesterolemia and CHD in a phenome-wide scan. Adjusted for maxLDL, FH variants collectively associated with higher prevalence of CHD (odds ratio, 1.59 [95% CI 1.36-1.86], p=1.1×10-8) but not peripheral artery disease.The distribution and phenotypic effects of putatively pathogenic FH variants were heterogeneous within and across variants. More robust evidence of genotype-phenotype associations of FH variants in multi-ethnic populations is needed to accurately infer at-risk individuals from genetic screening.
View details for DOI 10.1161/CIRCGEN.118.002192
View details for PubMedID 31106297
View details for PubMedCentralID PMC6516478
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Genetics of blood lipids among ~300,000 multi-ethnic participants of the Million Veteran Program.
Nature genetics
2018
Abstract
The Million Veteran Program (MVP) was established in 2011 as a national research initiative to determine how genetic variation influences the health of US military veterans. Here we genotyped 312,571 MVP participants using a custom biobank array and linked the genetic data to laboratory and clinical phenotypes extracted from electronic health records covering a median of 10.0 years of follow-up. Among 297,626 veterans with at least one blood lipid measurement, including 57,332 black and 24,743 Hispanic participants, we tested up to around 32 million variants for association with lipid levels and identified 118 novel genome-wide significant loci after meta-analysis with data from the Global Lipids Genetics Consortium (total n>600,000). Through a focus on mutations predicted to result in a loss of gene function and a phenome-wide association study, we propose novel indications for pharmaceutical inhibitors targeting PCSK9 (abdominal aortic aneurysm), ANGPTL4 (type 2 diabetes) and PDE3B (triglycerides and coronary disease).
View details for PubMedID 30275531
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Genome-wide scan for circulating vascular adhesion protein-1 levels: MACROD2 as a potential transcriptional regulator of adipogenesis
JOURNAL OF DIABETES INVESTIGATION
2018; 9 (5): 1067–74
Abstract
Vascular adhesion protein-1 (VAP-1) is a membrane-bound amine oxidase highly expressed in mature adipocytes and released into the circulation. VAP-1 has been strongly implicated in several pathological processes, including diabetes, inflammation, hypertension, hepatic steatosis and renal diseases, and is an important disease marker and therapeutic target. Here, we aimed to identify the genetic loci for circulating VAP-1 levels.We carried out a genomic-wide linkage scan for the quantitative trait locus of circulating VAP-1 levels in 1,100 Han Chinese individuals from 398 families in the Stanford Asian Pacific Program for Hypertension and Insulin Resistance study. Regional association fine mapping was carried out using additional single-nucleotide polymorphisms.The estimated heritability of circulating VAP-1 levels is high (h2 = 69%). The most significant quantitative trait locus for circulating VAP-1 was located at 38 cM on chromosome 20, with a maximum empirical logarithm of odds score of 4.11 (P = 6.86 × 10-6 ) in females. Regional single-nucleotide polymorphism fine mapping within a 1-unit support region showed the strongest association signals in the MACRO domain containing 2 (MACROD2) gene in females (P = 5.38 × 10-6 ). Knockdown of MACROD2 significantly suppressed VAP-1 expression in human adipocytes, as well as the expression of key adipogenic genes. Furthermore, MACROD2 expression was found to be positively associated with VAP-1 in human visceral adipose tissue.MACROD2 is a potential genetic determinant of serum VAP-1 levels, probably through transcriptional regulation of adipogenesis.
View details for PubMedID 29364582
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Discovery, fine-mapping, and conditional analyses of genetic variants associated with C-reactive protein in multiethnic populations using the Metabochip in the Population Architecture using Genomics and Epidemiology (PAGE) study
HUMAN MOLECULAR GENETICS
2018; 27 (16): 2940–53
Abstract
C-reactive protein (CRP) is a circulating biomarker indicative of systemic inflammation. We aimed to evaluate genetic associations with CRP levels among non-European-ancestry populations through discovery, fine-mapping and conditional analyses. A total of 30 503 non-European-ancestry participants from 6 studies participating in the Population Architecture using Genomics and Epidemiology study had serum high-sensitivity CRP measurements and ∼200 000 single nucleotide polymorphisms (SNPs) genotyped on the Metabochip. We evaluated the association between each SNP and log-transformed CRP levels using multivariate linear regression, with additive genetic models adjusted for age, sex, the first four principal components of genetic ancestry, and study-specific factors. Differential linkage disequilibrium patterns between race/ethnicity groups were used to fine-map regions associated with CRP levels. Conditional analyses evaluated for multiple independent signals within genetic regions. One hundred and sixty-three unique variants in 12 loci in overall or race/ethnicity-stratified Metabochip-wide scans reached a Bonferroni-corrected P-value <2.5E-7. Three loci have no (HACL1, OLFML2B) or only limited (PLA2G6) previous associations with CRP levels. Six loci had different top hits in race/ethnicity-specific versus overall analyses. Fine-mapping refined the signal in six loci, particularly in HNF1A. Conditional analyses provided evidence for secondary signals in LEPR, IL1RN and HNF1A, and for multiple independent signals in CRP and APOE. We identified novel variants and loci associated with CRP levels, generalized known CRP associations to a multiethnic study population, refined association signals at several loci and found evidence for multiple independent signals at several well-known loci. This study demonstrates the benefit of conducting inclusive genetic association studies in large multiethnic populations.
View details for PubMedID 29878111
View details for PubMedCentralID PMC6077792
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Association of APOL1 Risk Alleles with Coronary Heart Disease in Million Veteran Program
LIPPINCOTT WILLIAMS & WILKINS. 2018
View details for DOI 10.1161/atvb.38.suppl_1.024
View details for Web of Science ID 000497511500023
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Genome Wide Association Study in the Million Veteran Program Identifies a Novel Role for Thrombosis in the Pathogenesis of Peripheral Artery Disease
LIPPINCOTT WILLIAMS & WILKINS. 2018
View details for DOI 10.1161/atvb.38.suppl_1.126
View details for Web of Science ID 000497511500087
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Methylome-wide Association Study Provides Evidence of Particulate Matter Air Pollution-associated Dna Methylation at Cardiovascular Disease-related Genes
LIPPINCOTT WILLIAMS & WILKINS. 2018
View details for Web of Science ID 000435770100227
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A Multi-pollutant, Multi-ethnic, and Methylome-wide Association Study Highlights Epigenetic Effects of Exposure to Ambient Air Pollution Mixtures
LIPPINCOTT WILLIAMS & WILKINS. 2018
View details for Web of Science ID 000435770100114
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Melanoma risk prediction using a multilocus genetic risk score in the Women's Health Initiative cohort.
Journal of the American Academy of Dermatology
2018
Abstract
BACKGROUND: Single-nucleotide polymorphisms (SNPs) associated with melanoma have been identified though genome-wide association studies. However, the combined impact of these SNPs on melanoma development remains unclear, particularly in postmenopausal women who carry a lower melanoma risk.OBJECTIVE: We examine the contribution of a combined polygenic risk score on melanoma development in postmenopausal women.METHODS: Genetic risk scores were calculated using 21 genome-wide association study-significant SNPs. Their combined effect on melanoma development was evaluated in 19,102 postmenopausal white women in the clinical trial and observational study arms of the Women's Health Initiative dataset.RESULTS: Compared to the tertile of weighted genetic risk score with the lowest genetic risk, the women in the tertile with the highest genetic risk were 1.9 times more likely to develop melanoma (95% confidence interval 1.50-2.42). The incremental change in c-index from adding genetic risk scores to age were 0.075 (95% confidence interval 0.041-0.109) for incident melanoma.LIMITATIONS: Limitations include a lack of information on nevi count, Fitzpatrick skin type, family history of melanoma, and potential reporting and selection bias in the Women's Health Initiative cohort.CONCLUSION: Higher genetic risk is associated with increased melanoma prevalence and incidence in postmenopausal women, but current genetic information may have a limited role in risk prediction when phenotypic information is available.
View details for PubMedID 29499294
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Hypermetabolic macrophages in rheumatoid arthritis and coronary artery disease due to glycogen synthase kinase 3b inactivation.
Annals of the rheumatic diseases
2018
Abstract
OBJECTIVES: Accelerated atherosclerotic disease typically complicates rheumatoid arthritis (RA), leading to premature cardiovascular death. Inflammatory macrophages are key effector cells in both rheumatoid synovitis and the plaques of coronary artery disease (CAD). Whether both diseases share macrophage-dependent pathogenic mechanisms is unknown.METHODS: Patients with RA or CAD (at least one myocardial infarction) and healthy age-matched controls were recruited into the study. Peripheral blood CD14+ monocytes were differentiated into macrophages. Metabolic profiles were assessed by Seahorse Analyzer, intracellular ATP concentrations were quantified and mitochondrial protein localisation was determined by confocal image analysis.RESULTS: In macrophages from patients with RA or CAD, mitochondria consumed more oxygen, generated more ATP and built tight interorganelle connections with the endoplasmic reticulum, forming mitochondria-associated membranes (MAM). Calcium transfer through MAM sites sustained mitochondrial hyperactivity and was dependent on inactivation of glycogen synthase kinase 3b (GSK3b), a serine/threonine kinase functioning as a metabolic switch. In patient-derived macrophages, inactivated pGSK3b-Ser9 co-precipitated with the mitochondrial fraction. Immunostaining of atherosclerotic plaques and synovial lesions confirmed that most macrophages had inactivated GSK3b. MAM formation and GSK3b inactivation sustained production of the collagenase cathepsin K, a macrophage effector function closely correlated with clinical disease activity in RA and CAD.CONCLUSIONS: Re-organisation of the macrophage metabolism in patients with RA and CAD drives unopposed oxygen consumption and ultimately, excessive production of tissue-destructive enzymes. The underlying molecular defect relates to the deactivation of GSK3b, which controls mitochondrial fuel influx and as such represents a potential therapeutic target for anti-inflammatory therapy.
View details for PubMedID 29431119
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GWAS of epigenetic aging rates in blood reveals a critical role for TERT
NATURE COMMUNICATIONS
2018; 9: 387
Abstract
DNA methylation age is an accurate biomarker of chronological age and predicts lifespan, but its underlying molecular mechanisms are unknown. In this genome-wide association study of 9907 individuals, we find gene variants mapping to five loci associated with intrinsic epigenetic age acceleration (IEAA) and gene variants in three loci associated with extrinsic epigenetic age acceleration (EEAA). Mendelian randomization analysis suggests causal influences of menarche and menopause on IEAA and lipoproteins on IEAA and EEAA. Variants associated with longer leukocyte telomere length (LTL) in the telomerase reverse transcriptase gene (TERT) paradoxically confer higher IEAA (P < 2.7 × 10-11). Causal modeling indicates TERT-specific and independent effects on LTL and IEAA. Experimental hTERT-expression in primary human fibroblasts engenders a linear increase in DNA methylation age with cell population doubling number. Together, these findings indicate a critical role for hTERT in regulating the epigenetic clock, in addition to its established role of compensating for cell replication-dependent telomere shortening.
View details for PubMedID 29374233
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An epigenetic biomarker of aging for lifespan and healthspan.
Aging
2018; 10 (4): 573–91
Abstract
Identifying reliable biomarkers of aging is a major goal in geroscience. While the first generation of epigenetic biomarkers of aging were developed using chronological age as a surrogate for biological age, we hypothesized that incorporation of composite clinical measures of phenotypic age that capture differences in lifespan and healthspan may identify novel CpGs and facilitate the development of a more powerful epigenetic biomarker of aging. Using an innovative two-step process, we develop a new epigenetic biomarker of aging, DNAm PhenoAge, that strongly outperforms previous measures in regards to predictions for a variety of aging outcomes, including all-cause mortality, cancers, healthspan, physical functioning, and Alzheimer's disease. While this biomarker was developed using data from whole blood, it correlates strongly with age in every tissue and cell tested. Based on an in-depth transcriptional analysis in sorted cells, we find that increased epigenetic, relative to chronological age, is associated with increased activation of pro-inflammatory and interferon pathways, and decreased activation of transcriptional/translational machinery, DNA damage response, and mitochondrial signatures. Overall, this single epigenetic biomarker of aging is able to capture risks for an array of diverse outcomes across multiple tissues and cells, and provide insight into important pathways in aging.
View details for DOI 10.18632/aging.101414
View details for PubMedID 29676998
View details for PubMedCentralID PMC5940111
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Genome-Wide Association Studies of Coronary Artery Disease: Recent Progress and Challenges Ahead.
Current atherosclerosis reports
2018; 20 (9): 47
Abstract
Genome-wide association studies (GWAS) have been the primary tool for unbiased assessment of the genetic basis of coronary artery disease (CAD) for more than a decade. We summarize successes as well as shortcomings of recent studies in this context.The number of CAD-associated loci has more than doubled in the past year to 161. This rapid progress has been in large part due to the release of genome-wide genotyping data for the largely European participants of the UK Biobank study which has been combined with existing GWAS from the CARDIoGRAMplusC4D consortium. Additional discoveries have been achieved through large-scale genotyping of participants using custom high-yield genotyping arrays including the Metabochip and the Exome chip. As a consequence, the ability of genetic risk scores in predicting incident CAD events has improved but that improvement has only been shown in European populations. GWAS have proven to be a fruitful approach for uncovering the genetic drivers of CAD. However, determining the mechanisms of association of GWAS findings remains a challenging endeavor requiring long-term investment. Genetic risk scores offer an opportunity for recent findings to have an immediate clinical impact. Going forward, CAD genetics will benefit greatly from the release of more genetic data produced by mega-biobanks. These new data will allow for the more comprehensive examination of underrepresented populations.
View details for DOI 10.1007/s11883-018-0748-4
View details for PubMedID 30022313
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Making the Most out of Mendel's Laws in Complex Coronary Artery Disease.
Journal of the American College of Cardiology
2018; 72 (3): 311–13
View details for PubMedID 30012325
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Genetic Risk Scores in Premature Coronary Artery Disease: Still Only One Piece of the Prevention Puzzle.
Circulation. Genomic and precision medicine
2018; 11 (1): e002006
View details for DOI 10.1161/CIRCGEN.117.002006
View details for PubMedID 29874182
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Evaluation of 71 Coronary Artery Disease Risk Variants in a Multiethnic Cohort.
Frontiers in cardiovascular medicine
2018; 5: 19
Abstract
Coronary heart disease (CHD) is the most common cause of death worldwide. Previous studies have identified numerous common CHD susceptibility loci, with the vast majority identified in populations of European ancestry. How well these findings transfer to other racial/ethnic populations remains unclear.We examined the generalizability of the associations with 71 known CHD loci in African American, Latino and Japanese men and women in the Multiethnic Cohort (6,035 cases and 11,251 controls). In the combined multiethnic sample, 78% of the loci demonstrated odds ratios that were directionally consistent with those previously reported (p = 2 × 10-6), with this fraction ranging from 59% in Japanese to 70% in Latinos. The number of nominally significant associations across all susceptibility regions ranged from only 1 in Japanese to 11 in African Americans with the most statistically significant association observed through locus fine-mapping noted for rs3832016 (OR = 1.16, p = 2.5×10-5) in the SORT1 region on chromosome 1p13. Lastly, we examined the cumulative predictive effect of CHD SNPs across populations with improved power by creating genetic risk scores (GRSs) that summarize an individual's aggregated exposure to risk variants. We found the GRSs to be significantly associated with risk in African Americans (OR = 1.03 per allele; p = 4.1×10-5) and Latinos (OR = 1.03; p = 2.2 × 10-8), but not in Japanese (OR = 1.01; p = 0.11).While a sizable fraction of the known CHD loci appear to generalize in these populations, larger fine-mapping studies will be needed to localize the functional alleles and better define their contribution to CHD risk in these populations.
View details for DOI 10.3389/fcvm.2018.00019
View details for PubMedID 29740590
View details for PubMedCentralID PMC5931137
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DNA Methylation Analysis Identifies Loci for Blood Pressure Regulation
AMERICAN JOURNAL OF HUMAN GENETICS
2017; 101 (6): 888–902
Abstract
Genome-wide association studies have identified hundreds of genetic variants associated with blood pressure (BP), but sequence variation accounts for a small fraction of the phenotypic variance. Epigenetic changes may alter the expression of genes involved in BP regulation and explain part of the missing heritability. We therefore conducted a two-stage meta-analysis of the cross-sectional associations of systolic and diastolic BP with blood-derived genome-wide DNA methylation measured on the Infinium HumanMethylation450 BeadChip in 17,010 individuals of European, African American, and Hispanic ancestry. Of 31 discovery-stage cytosine-phosphate-guanine (CpG) dinucleotides, 13 replicated after Bonferroni correction (discovery: N = 9,828, p < 1.0 × 10-7; replication: N = 7,182, p < 1.6 × 10-3). The replicated methylation sites are heritable (h2 > 30%) and independent of known BP genetic variants, explaining an additional 1.4% and 2.0% of the interindividual variation in systolic and diastolic BP, respectively. Bidirectional Mendelian randomization among up to 4,513 individuals of European ancestry from 4 cohorts suggested that methylation at cg08035323 (TAF1B-YWHAQ) influences BP, while BP influences methylation at cg00533891 (ZMIZ1), cg00574958 (CPT1A), and cg02711608 (SLC1A5). Gene expression analyses further identified six genes (TSPAN2, SLC7A11, UNC93B1, CPT1A, PTMS, and LPCAT3) with evidence of triangular associations between methylation, gene expression, and BP. Additional integrative Mendelian randomization analyses of gene expression and DNA methylation suggested that the expression of TSPAN2 is a putative mediator of association between DNA methylation at cg23999170 and BP. These findings suggest that heritable DNA methylation plays a role in regulating BP independently of previously known genetic variants.
View details for PubMedID 29198723
View details for PubMedCentralID PMC5812919
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Exome-wide association study of plasma lipids in > 300,000 individuals
NATURE GENETICS
2017; 49 (12): 1758-+
Abstract
We screened variants on an exome-focused genotyping array in >300,000 participants (replication in >280,000 participants) and identified 444 independent variants in 250 loci significantly associated with total cholesterol (TC), high-density-lipoprotein cholesterol (HDL-C), low-density-lipoprotein cholesterol (LDL-C), and/or triglycerides (TG). At two loci (JAK2 and A1CF), experimental analysis in mice showed lipid changes consistent with the human data. We also found that: (i) beta-thalassemia trait carriers displayed lower TC and were protected from coronary artery disease (CAD); (ii) excluding the CETP locus, there was not a predictable relationship between plasma HDL-C and risk for age-related macular degeneration; (iii) only some mechanisms of lowering LDL-C appeared to increase risk for type 2 diabetes (T2D); and (iv) TG-lowering alleles involved in hepatic production of TG-rich lipoproteins (TM6SF2 and PNPLA3) tracked with higher liver fat, higher risk for T2D, and lower risk for CAD, whereas TG-lowering alleles involved in peripheral lipolysis (LPL and ANGPTL4) had no effect on liver fat but decreased risks for both T2D and CAD.
View details for PubMedID 29083408
View details for PubMedCentralID PMC5709146
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Genetic Variation in PCSK9 and Protection From Peripheral Artery Disease
LIPPINCOTT WILLIAMS & WILKINS. 2017
View details for Web of Science ID 000437035903493
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A GWAS of EHR-Defined CAD Identifies Multiple Novel Loci Including the First 3 Loci on the X-Chromosome: The Million Veteran Program
LIPPINCOTT WILLIAMS & WILKINS. 2017
View details for Web of Science ID 000437035902445
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Trans-ethnic Genome-wide Association Study of Peripheral Artery Disease in the VA Million Veteran Program
LIPPINCOTT WILLIAMS & WILKINS. 2017
View details for Web of Science ID 000437035905104
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Genetic Variants Associated With Angiographic Burden of CAD in Europeans and African Americans: The Million Veteran Program
LIPPINCOTT WILLIAMS & WILKINS. 2017
View details for Web of Science ID 000437035901297
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Phenome-Wide Association Study of Familial Hypercholesterolemia Variants Among Multi-Ethnic Veterans
LIPPINCOTT WILLIAMS & WILKINS. 2017
View details for Web of Science ID 000437035904294
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Leveraging Multi-ethnic Evidence for Risk Assessment of Quantitative Traits in Minority Populations.
American journal of human genetics
2017; 101 (4): 638
View details for DOI 10.1016/j.ajhg.2017.09.005
View details for PubMedID 28985498
View details for PubMedCentralID PMC5630193
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Trans-ethnic fine-mapping of genetic loci for body mass index in the diverse ancestral populations of the Population Architecture using Genomics and Epidemiology (PAGE) Study reveals evidence for multiple signals at established loci
HUMAN GENETICS
2017; 136 (6): 771-800
Abstract
Most body mass index (BMI) genetic loci have been identified in studies of primarily European ancestries. The effect of these loci in other racial/ethnic groups is less clear. Thus, we aimed to characterize the generalizability of 170 established BMI variants, or their proxies, to diverse US populations and trans-ethnically fine-map 36 BMI loci using a sample of >102,000 adults of African, Hispanic/Latino, Asian, European and American Indian/Alaskan Native descent from the Population Architecture using Genomics and Epidemiology Study. We performed linear regression of the natural log of BMI (18.5-70 kg/m(2)) on the additive single nucleotide polymorphisms (SNPs) at BMI loci on the MetaboChip (Illumina, Inc.), adjusting for age, sex, population stratification, study site, or relatedness. We then performed fixed-effect meta-analyses and a Bayesian trans-ethnic meta-analysis to empirically cluster by allele frequency differences. Finally, we approximated conditional and joint associations to test for the presence of secondary signals. We noted directional consistency with the previously reported risk alleles beyond what would have been expected by chance (binomial p < 0.05). Nearly, a quarter of the previously described BMI index SNPs and 29 of 36 densely-genotyped BMI loci on the MetaboChip replicated/generalized in trans-ethnic analyses. We observed multiple signals at nine loci, including the description of seven loci with novel multiple signals. This study supports the generalization of most common genetic loci to diverse ancestral populations and emphasizes the importance of dense multiethnic genomic data in refining the functional variation at genetic loci of interest and describing several loci with multiple underlying genetic variants.
View details for DOI 10.1007/s00439-017-1787-6
View details for PubMedID 28391526
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Fifteen new risk loci for coronary artery disease highlight arterial-wall-specific mechanisms.
Nature genetics
2017
Abstract
Coronary artery disease (CAD) is a leading cause of morbidity and mortality worldwide. Although 58 genomic regions have been associated with CAD thus far, most of the heritability is unexplained, indicating that additional susceptibility loci await identification. An efficient discovery strategy may be larger-scale evaluation of promising associations suggested by genome-wide association studies (GWAS). Hence, we genotyped 56,309 participants using a targeted gene array derived from earlier GWAS results and performed meta-analysis of results with 194,427 participants previously genotyped, totaling 88,192 CAD cases and 162,544 controls. We identified 25 new SNP-CAD associations (P < 5 × 10(-8), in fixed-effects meta-analysis) from 15 genomic regions, including SNPs in or near genes involved in cellular adhesion, leukocyte migration and atherosclerosis (PECAM1, rs1867624), coagulation and inflammation (PROCR, rs867186 (p.Ser219Gly)) and vascular smooth muscle cell differentiation (LMOD1, rs2820315). Correlation of these regions with cell-type-specific gene expression and plasma protein levels sheds light on potential disease mechanisms.
View details for DOI 10.1038/ng.3874
View details for PubMedID 28530674
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Association analyses of East Asian individuals and trans-ancestry analyses with European individuals reveal new loci associated with cholesterol and triglyceride levels
HUMAN MOLECULAR GENETICS
2017; 26 (9): 1770-1784
Abstract
Large-scale meta-analyses of genome-wide association studies (GWAS) have identified >175 loci associated with fasting cholesterol levels, including total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG). With differences in linkage disequilibrium (LD) structure and allele frequencies between ancestry groups, studies in additional large samples may detect new associations. We conducted staged GWAS meta-analyses in up to 69,414 East Asian individuals from 24 studies with participants from Japan, the Philippines, Korea, China, Singapore, and Taiwan. These meta-analyses identified (P < 5 × 10-8) three novel loci associated with HDL-C near CD163-APOBEC1 (P = 7.4 × 10-9), NCOA2 (P = 1.6 × 10-8), and NID2-PTGDR (P = 4.2 × 10-8), and one novel locus associated with TG near WDR11-FGFR2 (P = 2.7 × 10-10). Conditional analyses identified a second signal near CD163-APOBEC1. We then combined results from the East Asian meta-analysis with association results from up to 187,365 European individuals from the Global Lipids Genetics Consortium in a trans-ancestry meta-analysis. This analysis identified (log10Bayes Factor ≥6.1) eight additional novel lipid loci. Among the twelve total loci identified, the index variants at eight loci have demonstrated at least nominal significance with other metabolic traits in prior studies, and two loci exhibited coincident eQTLs (P < 1 × 10-5) in subcutaneous adipose tissue for BPTF and PDGFC. Taken together, these analyses identified multiple novel lipid loci, providing new potential therapeutic targets.
View details for DOI 10.1093/hmg/ddx062
View details for PubMedID 28334899
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Coffee consumption is associated with DNA methylation levels of human blood
EUROPEAN JOURNAL OF HUMAN GENETICS
2017; 25 (5): 608-616
Abstract
Beneficial health effects have been attributed to coffee consumption, but it is not yet known whether epigenetics may have a role in this process. Here we associate epigenome-wide DNA methylation levels to habitual coffee consumption from two studies with blood (2100 and 215 participants), and one with saliva samples (256 participants). Adjusting for age, gender, and blood cell composition, one CpG (cg21566642 near ALPPL2) surpassed genome-wide significance (P=3.7 × 10(-10)) and from among 10 additional CpGs significant at P≤5.0 × 10(-6), six were located within 1500 bps of a transcriptional start site. Results for these 11 top-ranked CpGs remained significant after further adjusting for smoking. Also, methylation levels of another 135 CpGs were influenced by both coffee drinking and smoking (P≤1.0 × 10(-7)). Functional enrichment analysis suggested that coffee-associated CpGs were located near transcription factor binding (P=1.2 × 10(-6)) and protein kinase activity genes (P=2.9 × 10(-5)). Interestingly, when we stratified by menopausal hormone therapy (MHT), methylation differences with coffee consumption were observed only in women who never used MHT. We did not replicate any of the associations found in blood in our saliva samples, suggesting that coffee may affect DNA methylation levels in immune cells of the blood but not in saliva.
View details for DOI 10.1038/ejhg.2016.175
View details for Web of Science ID 000399406200014
View details for PubMedID 28198392
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Leveraging information from genetic risk scores of coronary atherosclerosis.
Current opinion in lipidology
2017; 28 (2): 104-112
Abstract
Genome-wide association studies (GWAS) have identified ∼60 loci for coronary artery disease (CAD). Through genetic risk scores (GRSs), investigators are leveraging this genomic information to gain insights on both the fundamental mechanisms driving these associations as well as their utility in improving risk prediction.GRSs of CAD track with the earliest atherosclerosis lesions in the coronary including fatty streaks and uncomplicated raised lesions. In multiple cohort studies, they predict incident CAD events independent of all traditional and lifestyle risk factors. The incorporation of SNPs with suggestive but not genome-wide association in GWAS into GRSs often increases the strength of these associations. GRS may also predict recurrent events and identify patients most likely to respond to statins. The effect of the GRS on discrimination metrics remains modest but the minimal degree of improvement needed for clinical utility is unknown.Most novel loci for CAD identified through GWAS facilitate the formation of coronary atherosclerosis and stratify individuals based on their underlying burden of coronary atherosclerosis. GRSs may one day be routinely used in clinical practice to not only assess the risk of incident events but also to predict who will respond best to established prevention strategies.
View details for DOI 10.1097/MOL.0000000000000400
View details for PubMedID 28207434
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Genetic Risk, Incident Coronary Heart Disease Events, and the Benefits of a Healthy Lifestyle: Joint and Interacting Effects Across Four US Cohorts
LIPPINCOTT WILLIAMS & WILKINS. 2017
View details for Web of Science ID 000396461300225
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Epigenetic clock analysis of diet, exercise, education, and lifestyle factors.
Aging
2017; 9 (2): 419-446
Abstract
Behavioral and lifestyle factors have been shown to relate to a number of health-related outcomes, yet there is a need for studies that examine their relationship to molecular aging rates. Toward this end, we use recent epigenetic biomarkers of age that have previously been shown to predict all-cause mortality, chronic conditions, and age-related functional decline. We analyze cross-sectional data from 4,173 postmenopausal female participants from the Women's Health Initiative, as well as 402 male and female participants from the Italian cohort study, Invecchiare nel Chianti.Extrinsic epigenetic age acceleration (EEAA) exhibits significant associations with fish intake (p=0.02), moderate alcohol consumption (p=0.01), education (p=3x10(-5)), BMI (p=0.01), and blood carotenoid levels (p=1x10(-5))-an indicator of fruit and vegetable consumption, whereas intrinsic epigenetic age acceleration (IEAA) is associated with poultry intake (p=0.03) and BMI (p=0.05). Both EEAA and IEAA were also found to relate to indicators of metabolic syndrome, which appear to mediate their associations with BMI. Metformin-the first-line medication for the treatment of type 2 diabetes-does not delay epigenetic aging in this observational study. Finally, longitudinal data suggests that an increase in BMI is associated with increase in both EEAA and IEAA.Overall, the epigenetic age analysis of blood confirms the conventional wisdom regarding the benefits of eating a high plant diet with lean meats, moderate alcohol consumption, physical activity, and education, as well as the health risks of obesity and metabolic syndrome.
View details for DOI 10.18632/aging.101168
View details for PubMedID 28198702
View details for PubMedCentralID PMC5361673
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Coronary Artery Disease and Myocardial Infarction
Genomic and Precision Medicine - Primary Care
Academic Press. 2017; 3rd: 127–163
View details for DOI 10.1016/B978-0-12-800685-6.00008-4
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Association analyses based on false discovery rate implicate new loci for coronary artery disease.
Nature genetics
2017; 49 (9): 1385–91
Abstract
Genome-wide association studies (GWAS) in coronary artery disease (CAD) had identified 66 loci at 'genome-wide significance' (P < 5 × 10(-8)) at the time of this analysis, but a much larger number of putative loci at a false discovery rate (FDR) of 5% (refs. 1,2,3,4). Here we leverage an interim release of UK Biobank (UKBB) data to evaluate the validity of the FDR approach. We tested a CAD phenotype inclusive of angina (SOFT; ncases = 10,801) as well as a stricter definition without angina (HARD; ncases = 6,482) and selected cases with the former phenotype to conduct a meta-analysis using the two most recent CAD GWAS. This approach identified 13 new loci at genome-wide significance, 12 of which were on our previous list of loci meeting the 5% FDR threshold, thus providing strong support that the remaining loci identified by FDR represent genuine signals. The 304 independent variants associated at 5% FDR in this study explain 21.2% of CAD heritability and identify 243 loci that implicate pathways in blood vessel morphogenesis as well as lipid metabolism, nitric oxide signaling and inflammation.
View details for PubMedID 28714975
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Identification of new susceptibility loci for type 2 diabetes and shared etiological pathways with coronary heart disease.
Nature genetics
2017
Abstract
To evaluate the shared genetic etiology of type 2 diabetes (T2D) and coronary heart disease (CHD), we conducted a genome-wide, multi-ancestry study of genetic variation for both diseases in up to 265,678 subjects for T2D and 260,365 subjects for CHD. We identify 16 previously unreported loci for T2D and 1 locus for CHD, including a new T2D association at a missense variant in HLA-DRB5 (odds ratio (OR) = 1.29). We show that genetically mediated increase in T2D risk also confers higher CHD risk. Joint T2D-CHD analysis identified eight variants-two of which are coding-where T2D and CHD associations appear to colocalize, including a new joint T2D-CHD association at the CCDC92 locus that also replicated for T2D. The variants associated with both outcomes implicate new pathways as well as targets of existing drugs, including icosapent ethyl and adipocyte fatty-acid-binding protein.
View details for PubMedID 28869590
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Leveraging Multi-ethnic Evidence for Risk Assessment of Quantitative Traits in Minority Populations.
American journal of human genetics
2017; 101 (2): 218–26
Abstract
An essential component of precision medicine is the ability to predict an individual's risk of disease based on genetic and non-genetic factors. For complex traits and diseases, assessing the risk due to genetic factors is challenging because it requires knowledge of both the identity of variants that influence the trait and their corresponding allelic effects. Although the set of risk variants and their allelic effects may vary between populations, a large proportion of these variants were identified based on studies in populations of European descent. Heterogeneity in genetic architecture underlying complex traits and diseases, while broadly acknowledged, remains poorly characterized. Ignoring such heterogeneity likely reduces predictive accuracy for minority individuals. In this study, we propose an approach, called XP-BLUP, which ameliorates this ethnic disparity by combining trans-ethnic and ethnic-specific information. We build a polygenic model for complex traits that distinguishes candidate trait-relevant variants from the rest of the genome. The set of candidate variants are selected based on studies in any human population, yet the allelic effects are evaluated in a population-specific fashion. Simulation studies and real data analyses demonstrate that XP-BLUP adaptively utilizes trans-ethnic information and can substantially improve predictive accuracy in minority populations. At the same time, our study highlights the importance of the continued expansion of minority cohorts.
View details for PubMedID 28757202
View details for PubMedCentralID PMC5544393
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Leukocyte telomere length, T cell composition and DNA methylation age.
Aging
2017
Abstract
Both leukocyte telomere length (LTL) and DNA methylation age are strongly associated with chronological age. One measure of DNA methylation age─ the extrinsic epigenetic age acceleration (EEAA)─ is highly predictive of all-cause mortality. We examined the relation between LTL and EEAA. LTL was measured by Southern blots and leukocyte DNA methylation was determined using Illumina Infinium HumanMethylation450 BeadChip in participants in the Women's Health Initiative (WHI; n=804), the Framingham Heart Study (FHS; n=909) and the Bogalusa Heart study (BHS; n=826). EEAA was computed using 71 DNA methylation sites, further weighted by proportions of naïve CD8(+) T cells, memory CD8(+) T cells, and plasmablasts. Shorter LTL was associated with increased EEAA in participants from the WHI (r=-0.16, p=3.1x10(-6)). This finding was replicated in the FHS (r=-0.09, p=6.5x10(-3)) and the BHS (r=-0.07, p=3.8x 10(-2)). LTL was also inversely related to proportions of memory CD8(+) T cells (p=4.04x10(-16)) and positively related to proportions of naive CD8(+) T cells (p=3.57x10(-14)). These findings suggest that for a given age, an individual whose blood contains comparatively more memory CD8(+) T cells and less naive CD8(+) T cells would display a relatively shorter LTL and an older DNA methylation age, which jointly explain the striking ability of EEAA to predict mortality.
View details for PubMedID 28930701
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Impact of a Genetic Risk Score for Coronary Artery Disease on Reducing Cardiovascular Risk: A Pilot Randomized Controlled Study.
Frontiers in cardiovascular medicine
2017; 4: 53
Abstract
We tested whether providing a genetic risk score (GRS) for coronary artery disease (CAD) would serve as a motivator to improve adherence to risk-reducing strategies.We randomized 94 participants with at least moderate risk of CAD to receive standard-of-care with (N = 49) or without (N = 45) their GRS at a subsequent 3-month follow-up visit. Our primary outcome was change in low density lipoprotein cholesterol (LDL-C) between the 3- and 6-month follow-up visits (ΔLDL-C). Secondary outcomes included other CAD risk factors, weight loss, diet, physical activity, risk perceptions, and psychological outcomes. In pre-specified analyses, we examined whether there was a greater motivational effect in participants with a higher GRS.Sixty-five participants completed the protocol including 30 participants in the GRS arm. We found no change in the primary outcome between participants receiving their GRS and standard-of-care participants (ΔLDL-C: -13 vs. -9 mg/dl). Among participants with a higher GRS, we observed modest effects on weight loss and physical activity. All other secondary outcomes were not significantly different, including anxiety and worry.Adding GRS to standard-of-care did not change lipids, adherence, or psychological outcomes. Potential modest benefits in weight loss and physical activity for participants with high GRS need to be validated in larger trials.
View details for PubMedID 28856136
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Genetics: Implications for Prevention and Management of Coronary Artery Disease
JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
2016; 68 (25): 2797-2818
Abstract
An exciting new era has dawned for the prevention and management of coronary artery disease (CAD) utilizing genetic risk variants. The recent identification of over 60 susceptibility loci for CAD confirms not only the importance of established risk factors, but also the existence of many novel causal pathways that are expected to improve our understanding of the genetic basis of CAD and facilitate the development of new therapeutic agents over time. Concurrently, Mendelian randomization studies have provided intriguing insights on the causal relationship between CAD-related traits, and highlight the potential benefits of long-term modifications of risk factors. Last, genetic risk scores of CAD may serve not only as prognostic, but also as predictive markers, and carry the potential to considerably improve the delivery of established prevention strategies. This review will summarize the evolution and discovery of genetic risk variants for CAD and their current and future clinical applications.
View details for DOI 10.1016/j.jacc.2016.10.039
View details for Web of Science ID 000392990600011
View details for PubMedID 28007143
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Fine-mapping of lipid regions in global populations discovers ethnic-specific signals and refines previously identified lipid loci
HUMAN MOLECULAR GENETICS
2016; 25 (24): 5500-5512
Abstract
Genome-wide association studies have identified over 150 loci associated with lipid traits, however, no large-scale studies exist for Hispanics and other minority populations. Additionally, the genetic architecture of lipid-influencing loci remains largely unknown. We performed one of the most racially/ethnically diverse fine-mapping genetic studies of HDL-C, LDL-C, and triglycerides to-date using SNPs on the MetaboChip array on 54,119 individuals: 21,304 African Americans, 19,829 Hispanic Americans, 12,456 Asians, and 530 American Indians. The majority of signals found in these groups generalize to European Americans. While we uncovered signals unique to racial/ethnic populations, we also observed systematically consistent lipid associations across these groups. In African Americans, we identified three novel signals associated with HDL-C (LPL, APOA5, LCAT) and two associated with LDL-C (ABCG8, DHODH). In addition, using this population, we refined the location for 16 out of the 58 known MetaboChip lipid loci. These results can guide tailored screening efforts, reveal population-specific responses to lipid-lowering medications, and aid in the development of new targeted drug therapies.
View details for DOI 10.1093/hmg/ddw358
View details for PubMedID 28426890
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DNA methylation signatures of chronic low-grade inflammation are associated with complex diseases
GENOME BIOLOGY
2016; 17
Abstract
Chronic low-grade inflammation reflects a subclinical immune response implicated in the pathogenesis of complex diseases. Identifying genetic loci where DNA methylation is associated with chronic low-grade inflammation may reveal novel pathways or therapeutic targets for inflammation.We performed a meta-analysis of epigenome-wide association studies (EWAS) of serum C-reactive protein (CRP), which is a sensitive marker of low-grade inflammation, in a large European population (n = 8863) and trans-ethnic replication in African Americans (n = 4111). We found differential methylation at 218 CpG sites to be associated with CRP (P < 1.15 × 10(-7)) in the discovery panel of European ancestry and replicated (P < 2.29 × 10(-4)) 58 CpG sites (45 unique loci) among African Americans. To further characterize the molecular and clinical relevance of the findings, we examined the association with gene expression, genetic sequence variants, and clinical outcomes. DNA methylation at nine (16%) CpG sites was associated with whole blood gene expression in cis (P < 8.47 × 10(-5)), ten (17%) CpG sites were associated with a nearby genetic variant (P < 2.50 × 10(-3)), and 51 (88%) were also associated with at least one related cardiometabolic entity (P < 9.58 × 10(-5)). An additive weighted score of replicated CpG sites accounted for up to 6% inter-individual variation (R2) of age-adjusted and sex-adjusted CRP, independent of known CRP-related genetic variants.We have completed an EWAS of chronic low-grade inflammation and identified many novel genetic loci underlying inflammation that may serve as targets for the development of novel therapeutic interventions for inflammation.
View details for DOI 10.1186/s13059-016-1119-5
View details for PubMedID 27955697
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Associations between a Genetic Risk Score for Clinical CAD and Early Stage Lesions in the Coronary Artery and the Aorta
PLOS ONE
2016; 11 (11)
Abstract
The correlation between the extent of fatty streaks, more advanced atherosclerotic lesions, and community rates of coronary artery disease (CAD) is substantially higher for the coronary artery compared to the aorta. We sought to determine whether a genetic basis contributes to these differences.We conducted a cluster analysis of 6 subclinical atherosclerosis phenotypes documented in 564 white participants of the Pathobiological Determinants of Atherosclerosis in Youth study including the extent of fatty streaks and raised lesions in the coronary artery (CF and CR), thoracic aorta (TF and TR), and abdominal aorta (AF and AR) followed by a genetic association analysis of the same phenotypes. Our cluster analysis grouped all raised lesions and fatty streaks in the coronary into one cluster (CF, CR, TR, and AR) and the fatty streaks in the aorta into a second cluster (TF and AF). We found a genetic risk score of high-risk alleles at 57 susceptibility loci for CAD to be variably associated with the phenotypes in the first cluster (OR: 1.30 p = 0.009 for being in top quartile of degree of involvement of CF, 1.34 p = 0.005 for CR, 1.25: p = 0.11 for TR, and 1.19 p = 0.08 for AR) but not at all with the phenotypes in the second cluster (OR: 1.01, p = 0.95 for TF and 0.98, p = 0.82 for AF).The genetic determinants of fatty streaks in the aorta do not appear to overlap substantially with the genetic determinants of fatty streaks in the coronary as well as raised lesions in both the coronary and the aorta. These findings may explain why a larger fraction of fatty streaks in the aorta are less likely to progress to raised lesions compared to the coronary artery.
View details for DOI 10.1371/journal.pone.0166994
View details for Web of Science ID 000388350300141
View details for PubMedID 27861582
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Unbiased Estimate of Heritability of CAD Before and After Adjustment for Traditional Risk Factors in Five NHLBI Cohorts
LIPPINCOTT WILLIAMS & WILKINS. 2016
View details for Web of Science ID 000396815601030
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Unbiased Estimate of Heritability of CAD Before and After Adjustment for Traditional Risk Factors in Five NHLBI Cohorts
LIPPINCOTT WILLIAMS & WILKINS. 2016
View details for Web of Science ID 000396815303075
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Genome-wide linkage analysis and regional fine mapping identified variants in the RYR3 gene as a novel quantitative trait locus for circulating adiponectin in Chinese population
MEDICINE
2016; 95 (44)
Abstract
Adiponectin is adipocyte-secreted cytokine with potent insulin-sensitizing action in peripheral tissues. The heritability of plasma adiponectin is high in Han Chinese population.To identify genetic loci influencing plasma adiponectin levels in Chinese population, we performed a genome-wide linkage scan in 1949 Chinese participants of the Stanford Asia-Pacific Program for Hypertension and Insulin Resistance family study and mapped a quantitative trail locus located on chromosome 15 at 31 cM (logarithm of odds = 3.04) with 1-logarithm of odds support interval at 24 to 34 cM. Within this mapped region, we further genotyped a total of 68 single-nucleotide polymorphisms in 12 genes. Association analysis revealed that haplotypes composed of single-nucleotide polymorphisms in the ryanodine receptor 3 (RYR3) gene had strongest association with plasma adiponectin. RYR3 haplotypes were also associated with systolic (P = 0.001) and diastolic (P = 7.1 × 10) blood pressure and high-density lipoprotein cholesterol (P = 1.4 × 10). Furthermore, an inverse relationship between expression of RYR3 and adiponectin was observed in human abdominal adipose tissue. In conclusion, a genome-wide linkage scan and regional association fine-mapping identified variants in the RYR3 gene as a quantitative trail locus for plasma adiponectin levels in Chinese population.
View details for DOI 10.1097/MD.0000000000005174
View details for Web of Science ID 000388566200018
View details for PubMedID 27858853
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No Association of Coronary Artery Disease with X-Chromosomal Variants in Comprehensive International Meta-Analysis
SCIENTIFIC REPORTS
2016; 6
Abstract
In recent years, genome-wide association studies have identified 58 independent risk loci for coronary artery disease (CAD) on the autosome. However, due to the sex-specific data structure of the X chromosome, it has been excluded from most of these analyses. While females have 2 copies of chromosome X, males have only one. Also, one of the female X chromosomes may be inactivated. Therefore, special test statistics and quality control procedures are required. Thus, little is known about the role of X-chromosomal variants in CAD. To fill this gap, we conducted a comprehensive X-chromosome-wide meta-analysis including more than 43,000 CAD cases and 58,000 controls from 35 international study cohorts. For quality control, sex-specific filters were used to adequately take the special structure of X-chromosomal data into account. For single study analyses, several logistic regression models were calculated allowing for inactivation of one female X-chromosome, adjusting for sex and investigating interactions between sex and genetic variants. Then, meta-analyses including all 35 studies were conducted using random effects models. None of the investigated models revealed genome-wide significant associations for any variant. Although we analyzed the largest-to-date sample, currently available methods were not able to detect any associations of X-chromosomal variants with CAD.
View details for DOI 10.1038/srep35278
View details for PubMedID 27731410
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The genetics of blood pressure regulation and its target organs from association studies in 342,415 individuals.
Nature genetics
2016; 48 (10): 1171-1184
Abstract
To dissect the genetic architecture of blood pressure and assess effects on target organ damage, we analyzed 128,272 SNPs from targeted and genome-wide arrays in 201,529 individuals of European ancestry, and genotypes from an additional 140,886 individuals were used for validation. We identified 66 blood pressure-associated loci, of which 17 were new; 15 harbored multiple distinct association signals. The 66 index SNPs were enriched for cis-regulatory elements, particularly in vascular endothelial cells, consistent with a primary role in blood pressure control through modulation of vascular tone across multiple tissues. The 66 index SNPs combined in a risk score showed comparable effects in 64,421 individuals of non-European descent. The 66-SNP blood pressure risk score was significantly associated with target organ damage in multiple tissues but with minor effects in the kidney. Our findings expand current knowledge of blood pressure-related pathways and highlight tissues beyond the classical renal system in blood pressure regulation.
View details for DOI 10.1038/ng.3667
View details for PubMedID 27618452
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DNA methylation-based measures of biological age: meta-analysis predicting time to death.
Aging
2016; 8 (9): 1844-1865
Abstract
Estimates of biological age based on DNA methylation patterns, often referred to as "epigenetic age", "DNAm age", have been shown to be robust biomarkers of age in humans. We previously demonstrated that independent of chronological age, epigenetic age assessed in blood predicted all-cause mortality in four human cohorts. Here, we expanded our original observation to 13 different cohorts for a total sample size of 13,089 individuals, including three racial/ethnic groups. In addition, we examined whether incorporating information on blood cell composition into the epigenetic age metrics improves their predictive power for mortality. All considered measures of epigenetic age acceleration were predictive of mortality (p≤8.2x10(-9)), independent of chronological age, even after adjusting for additional risk factors (p<5.4x10(-4)), and within the racial/ethnic groups that we examined (non-Hispanic whites, Hispanics, African Americans). Epigenetic age estimates that incorporated information on blood cell composition led to the smallest p-values for time to death (p=7.5x10(-43)). Overall, this study a) strengthens the evidence that epigenetic age predicts all-cause mortality above and beyond chronological age and traditional risk factors, and b) demonstrates that epigenetic age estimates that incorporate information on blood cell counts lead to highly significant associations with all-cause mortality.
View details for DOI 10.18632/aging.101020
View details for PubMedID 27690265
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The associations of leptin, adiponectin and resistin with incident atrial fibrillation in women.
Heart
2016; 102 (17): 1354-1362
Abstract
Higher body mass index (BMI) is an important risk factor for atrial fibrillation (AF). The adipokines leptin, adiponectin and resistin are correlates of BMI, but their association with incident AF is not well known. We explored this relationship in a large cohort of postmenopausal women.We studied an ethnically diverse cohort of community-dwelling postmenopausal women aged 50-79 who were nationally recruited at 40 clinical centres as part of the Women's Health Initiative investigation. Participants underwent measurements of baseline serum leptin, adiponectin and resistin levels and were followed for incident AF. Adipokine levels were log transformed and normalised using inverse probability weighting. Cox proportional hazard regression models were used to estimate associations with adjustment for known AF risk factors.Of the 4937 participants included, 892 developed AF over a follow-up of 11.1 years. Those with AF had higher mean leptin (14.9 pg/mL vs 13.9 pg/mL), adiponectin (26.3 ug/mL vs 24.5 ug/mL) and resistin (12.9 ng/mL vs 12.1 ng/mL) levels. After multivariable adjustment, neither log leptin nor log adiponectin levels were significantly associated with incident AF. However, log resistin levels remained significantly associated with incident AF (HR=1.57 per 1 log (ng/mL) increase, p=0.006). Additional adjustment for inflammatory cytokines only partially attenuated the association between resistin and incident AF (HR=1.43, p=0.06 adjusting for C-reactive protein (CRP); HR=1.39, p=0.08 adjusting for IL-6). Adjusting for resistin partially attenuated the association between BMI and incident AF (HR=1.14 per 5 kg/m(2), p=0.006 without resistin; HR=1.12, p=0.02 with resistin).In women, elevated levels of serum resistin are significantly associated with higher rates of incident AF and partially mediate the association between BMI and AF. In the same population, leptin and adiponectin levels are not significantly associated with AF.
View details for DOI 10.1136/heartjnl-2015-308927
View details for PubMedID 27146694
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Menopause accelerates biological aging.
Proceedings of the National Academy of Sciences of the United States of America
2016; 113 (33): 9327-9332
Abstract
Although epigenetic processes have been linked to aging and disease in other systems, it is not yet known whether they relate to reproductive aging. Recently, we developed a highly accurate epigenetic biomarker of age (known as the "epigenetic clock"), which is based on DNA methylation levels. Here we carry out an epigenetic clock analysis of blood, saliva, and buccal epithelium using data from four large studies: the Women's Health Initiative (n = 1,864); Invecchiare nel Chianti (n = 200); Parkinson's disease, Environment, and Genes (n = 256); and the United Kingdom Medical Research Council National Survey of Health and Development (n = 790). We find that increased epigenetic age acceleration in blood is significantly associated with earlier menopause (P = 0.00091), bilateral oophorectomy (P = 0.0018), and a longer time since menopause (P = 0.017). Conversely, epigenetic age acceleration in buccal epithelium and saliva do not relate to age at menopause; however, a higher epigenetic age in saliva is exhibited in women who undergo bilateral oophorectomy (P = 0.0079), while a lower epigenetic age in buccal epithelium was found for women who underwent menopausal hormone therapy (P = 0.00078). Using genetic data, we find evidence of coheritability between age at menopause and epigenetic age acceleration in blood. Using Mendelian randomization analysis, we find that two SNPs that are highly associated with age at menopause exhibit a significant association with epigenetic age acceleration. Overall, our Mendelian randomization approach and other lines of evidence suggest that menopause accelerates epigenetic aging of blood, but mechanistic studies will be needed to dissect cause-and-effect relationships further.
View details for DOI 10.1073/pnas.1604558113
View details for PubMedID 27457926
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Epigenetic Aging and Immune Senescence in Women With Insomnia Symptoms: Findings From the Women's Health Initiative Study.
Biological psychiatry
2016
Abstract
Insomnia symptoms are associated with vulnerability to age-related morbidity and mortality. Cross-sectional data suggest that accelerated biological aging may be a mechanism through which sleep influences risk. A novel method for determining age acceleration using epigenetic methylation to DNA has demonstrated predictive utility as an epigenetic clock and prognostic of age-related morbidity and mortality.We examined the association of epigenetic age and immune cell aging with sleep in the Women's Health Initiative study (N = 2078; mean 64.5 ± 7.1 years of age) with assessment of insomnia symptoms (restlessness, difficulty falling asleep, waking at night, trouble getting back to sleep, and early awakenings), sleep duration (short sleep 5 hours or less; long sleep greater than 8 hours), epigenetic age, naive T cell (CD8+CD45RA+CCR7+), and late differentiated T cells (CD8+CD28-CD45RA-).Insomnia symptoms were related to advanced epigenetic age (β ± SE = 1.02 ± 0.37, p = .005) after adjustments for covariates. Insomnia symptoms were also associated with more late differentiated T cells (β ± SE = 0.59 ± 0.21, p = .006), but not with naive T cells. Self-reported short and long sleep duration were unrelated to epigenetic age. Short sleep, but not long sleep, was associated with fewer naive T cells (p < .005) and neither was related to late differentiated T cells.Symptoms of insomnia were associated with increased epigenetic age of blood tissue and were associated with higher counts of late differentiated CD8+ T cells. Short sleep was unrelated to epigenetic age and late differentiated cell counts, but was related to a decline in naive T cells. In this large population-based study of women in the United States, insomnia symptoms are implicated in accelerated aging.
View details for DOI 10.1016/j.biopsych.2016.07.008
View details for PubMedID 27702440
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Lean body mass and risk of incident atrial fibrillation in post-menopausal women
EUROPEAN HEART JOURNAL
2016; 37 (20): 1606-1613
Abstract
High body mass index (BMI) is a risk factor for atrial fibrillation (AF). The aim of this study was to determine whether lean body mass (LBM) predicts AF.The Women's Health Initiative is a study of post-menopausal women aged 50-79 enrolled at 40 US centres from 1994 to 1998. A subset of 11 393 participants at three centres underwent dual-energy X-ray absorptiometry. Baseline demographics and clinical histories were recorded. Incident AF was identified using hospitalization records and diagnostic codes from Medicare claims. A multivariable Cox hazard regression model adjusted for demographic and clinical risk factors was used to evaluate associations between components of body composition and AF risk. After exclusion for prevalent AF or incomplete data, 8832 participants with an average age of 63.3 years remained for analysis. Over the 11.6 years of average follow-up time, 1035 women developed incident AF. After covariate adjustment, all measures of LBM were independently associated with higher rates of AF: total LBM [hazard ratio (HR) 1.24 per 5 kg increase, 95% confidence intervals (CI) 1.14-1.34], central LBM (HR 1.51 per 5 kg increase, 95% CI 1.31-1.74), and peripheral LBM (HR 1.39 per 5 kg increase, 95% CI 1.19-1.63). The association between total LBM and AF remained significant after adjustment for total fat mass (HR 1.22 per 5 kg increase, 95% CI 1.13-1.31).Greater LBM is a strong independent risk factor for AF. After adjusting for obesity-related risk factors, the risk of AF conferred by higher BMI is primarily driven by the association between LBM and AF.
View details for DOI 10.1093/eurheartj/ehv423
View details for Web of Science ID 000376168100013
View details for PubMedID 26371115
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The glycolytic enzyme PKM2 bridges metabolic and inflammatory dysfunction in coronary artery disease
JOURNAL OF EXPERIMENTAL MEDICINE
2016; 213 (3): 337-354
Abstract
Abnormal glucose metabolism and enhanced oxidative stress accelerate cardiovascular disease, a chronic inflammatory condition causing high morbidity and mortality. Here, we report that in monocytes and macrophages of patients with atherosclerotic coronary artery disease (CAD), overutilization of glucose promotes excessive and prolonged production of the cytokines IL-6 and IL-1β, driving systemic and tissue inflammation. In patient-derived monocytes and macrophages, increased glucose uptake and glycolytic flux fuel the generation of mitochondrial reactive oxygen species, which in turn promote dimerization of the glycolytic enzyme pyruvate kinase M2 (PKM2) and enable its nuclear translocation. Nuclear PKM2 functions as a protein kinase that phosphorylates the transcription factor STAT3, thus boosting IL-6 and IL-1β production. Reducing glycolysis, scavenging superoxide and enforcing PKM2 tetramerization correct the proinflammatory phenotype of CAD macrophages. In essence, PKM2 serves a previously unidentified role as a molecular integrator of metabolic dysfunction, oxidative stress and tissue inflammation and represents a novel therapeutic target in cardiovascular disease.
View details for DOI 10.1084/jem.20150900
View details for PubMedID 26926996
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A Multi-ethnic Mendelian Randomization Study of Moderate Alcohol Use and the Risk of Atherosclerotic Cardiovascular Disease in the Women's Health Initiative
LIPPINCOTT WILLIAMS & WILKINS. 2016
View details for Web of Science ID 000381415500054
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Gene by Environment Investigation of Incident Lung Cancer Risk in African-Americans.
EBioMedicine
2016; 4: 153-161
Abstract
Genome-wide association studies have identified polymorphisms linked to both smoking exposure and risk of lung cancer. The degree to which lung cancer risk is driven by increased smoking, genetics, or gene-environment interactions is not well understood.We analyzed associations between 28 single nucleotide polymorphisms (SNPs) previously associated with smoking quantity and lung cancer in 7156 African-American females in the Women's Health Initiative (WHI), then analyzed main effects of top nominally significant SNPs and interactions between SNPs, cigarettes per day (CPD) and pack-years for lung cancer in an independent, multi-center case-control study of African-American females and males (1078 lung cancer cases and 822 controls).Nine nominally significant SNPs for CPD in WHI were associated with incident lung cancer (corrected p-values from 0.027 to 6.09 × 10(- 5)). CPD was found to be a nominally significant effect modifier between SNP and lung cancer for six SNPs, including CHRNA5 rs2036527[A](betaSNP*CPD = - 0.017, p = 0.0061, corrected p = 0.054), which was associated with CPD in a previous genome-wide meta-analysis of African-Americans.These results suggest that chromosome 15q25.1 variants are robustly associated with CPD and lung cancer in African-Americans and that the allelic dose effect of these polymorphisms on lung cancer risk is most pronounced in lighter smokers.
View details for DOI 10.1016/j.ebiom.2016.01.002
View details for PubMedID 26981579
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Genetics of Coronary Artery Disease in Taiwan: A Cardiometabochip Study by the Taichi Consortium.
PloS one
2016; 11 (3)
Abstract
By means of a combination of genome-wide and follow-up studies, recent large-scale association studies of populations of European descent have now identified over 46 loci associated with coronary artery disease (CAD). As part of the TAICHI Consortium, we have collected and genotyped 8556 subjects from Taiwan, comprising 5423 controls and 3133 cases with coronary artery disease, for 9087 CAD SNPs using the CardioMetaboChip. We applied penalized logistic regression to ascertain the top SNPs that contribute together to CAD susceptibility in Taiwan. We observed that the 9p21 locus contributes to CAD at the level of genome-wide significance (rs1537372, with the presence of C, the major allele, the effect estimate is -0.216, standard error 0.033, p value 5.8x10-10). In contrast to a previous report, we propose that the 9p21 locus is a single genetic contribution to CAD in Taiwan because: 1) the penalized logistic regression and the follow-up conditional analysis suggested that rs1537372 accounts for all of the CAD association in 9p21, and 2) the high linkage disequilibrium observed for all associated SNPs in 9p21. We also observed evidence for the following loci at a false discovery rate >5%: SH2B3, ADAMTS7, PHACTR1, GGCX, HTRA1, COL4A1, and LARP6-LRRC49. We also took advantage of the fact that penalized methods are an efficient approach to search for gene-by-gene interactions, and observed that two-way interactions between the PHACTR1 and ADAMTS7 loci and between the SH2B3 and COL4A1 loci contribute to CAD risk. Both the similarities and differences between the significance of these loci when compared with significance of loci in studies of populations of European descent underscore the fact that further genetic association of studies in additional populations will provide clues to identify the genetic architecture of CAD across all populations worldwide.
View details for DOI 10.1371/journal.pone.0138014
View details for PubMedID 26982883
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Genetic cardiovascular risk prediction: are we already there?
European heart journal
2016; 37 (43): 3279–81
View details for DOI 10.1093/eurheartj/ehw498
View details for PubMedID 27940815
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An epigenetic clock analysis of race/ethnicity, sex, and coronary heart disease.
Genome biology
2016; 17 (1): 171-?
Abstract
Epigenetic biomarkers of aging (the "epigenetic clock") have the potential to address puzzling findings surrounding mortality rates and incidence of cardio-metabolic disease such as: (1) women consistently exhibiting lower mortality than men despite having higher levels of morbidity; (2) racial/ethnic groups having different mortality rates even after adjusting for socioeconomic differences; (3) the black/white mortality cross-over effect in late adulthood; and (4) Hispanics in the United States having a longer life expectancy than Caucasians despite having a higher burden of traditional cardio-metabolic risk factors.We analyzed blood, saliva, and brain samples from seven different racial/ethnic groups. We assessed the intrinsic epigenetic age acceleration of blood (independent of blood cell counts) and the extrinsic epigenetic aging rates of blood (dependent on blood cell counts and tracks the age of the immune system). In blood, Hispanics and Tsimane Amerindians have lower intrinsic but higher extrinsic epigenetic aging rates than Caucasians. African-Americans have lower extrinsic epigenetic aging rates than Caucasians and Hispanics but no differences were found for the intrinsic measure. Men have higher epigenetic aging rates than women in blood, saliva, and brain tissue.Epigenetic aging rates are significantly associated with sex, race/ethnicity, and to a lesser extent with CHD risk factors, but not with incident CHD outcomes. These results may help elucidate lower than expected mortality rates observed in Hispanics, older African-Americans, and women.
View details for DOI 10.1186/s13059-016-1030-0
View details for PubMedID 27511193
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Integrative functional genomics identifies regulatory mechanisms at coronary artery disease loci.
Nature communications
2016; 7: 12092-?
Abstract
Coronary artery disease (CAD) is the leading cause of mortality and morbidity, driven by both genetic and environmental risk factors. Meta-analyses of genome-wide association studies have identified >150 loci associated with CAD and myocardial infarction susceptibility in humans. A majority of these variants reside in non-coding regions and are co-inherited with hundreds of candidate regulatory variants, presenting a challenge to elucidate their functions. Herein, we use integrative genomic, epigenomic and transcriptomic profiling of perturbed human coronary artery smooth muscle cells and tissues to begin to identify causal regulatory variation and mechanisms responsible for CAD associations. Using these genome-wide maps, we prioritize 64 candidate variants and perform allele-specific binding and expression analyses at seven top candidate loci: 9p21.3, SMAD3, PDGFD, IL6R, BMP1, CCDC97/TGFB1 and LMOD1. We validate our findings in expression quantitative trait loci cohorts, which together reveal new links between CAD associations and regulatory function in the appropriate disease context.
View details for DOI 10.1038/ncomms12092
View details for PubMedID 27386823
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Susceptibility Loci for Clinical Coronary Artery Disease and Subclinical Coronary Atherosclerosis Throughout the Life-Course.
Circulation. Cardiovascular genetics
2015; 8 (6): 803-811
Abstract
-Recent genome wide association studies (GWAS) have identified 49 single nucleotide polymorphisms (SNPs) associated with clinical CAD. The mechanism by which these loci influence risk remains largely unclear.-We examined the association between a genetic risk score (GRS) composed of high-risk alleles at the 49 SNPs and the degree of subclinical coronary atherosclerosis in 7,798 participants from six studies stratified into four age groups at the time of assessment (15-34, 35-54, 55-74, >75 years). Atherosclerosis was quantified by staining and direct visual inspection of the right coronary artery in the youngest group, and by scanning for coronary artery calcification in the remaining groups. We defined cases as subjects within the top quartile of degree of atherosclerosis in three groups and as subjects with a CAC>0 in the fourth (35-54 years) where less than one quarter had any CAC. In our meta-analysis of all strata, we found one SD increase in the GRS increased the risk of advanced subclinical coronary atherosclerosis by 36% (p=8.3×10(-25)). This increase in risk was significant in all four age groups including the youngest group where atherosclerosis consisted primarily of raised lesions without macroscopic evidence of plaque rupture or thrombosis. Results were similar when we restricted the GRS to 32 SNPs not associated with traditional risk factors (TRFs) and/or when we adjusted for TRFs.-A GRS for clinical CAD is associated with advanced subclinical coronary atherosclerosis throughout the life-course. This association is apparent even at the earliest, uncomplicated stages of atherosclerosis.
View details for DOI 10.1161/CIRCGENETICS.114.001071
View details for PubMedID 26417035
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Association Between a Genetic Risk Score for Clinical CAD and Early Stage Lesions in the Coronary and Aorta Provides Insights Into the Pathophysiology of Atherosclerosis
LIPPINCOTT WILLIAMS & WILKINS. 2015
View details for Web of Science ID 000381010607119
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A comprehensive 1000 Genomes-based genome-wide association meta-analysis of coronary artery disease
NATURE GENETICS
2015; 47 (10): 1121-?
Abstract
Existing knowledge of genetic variants affecting risk of coronary artery disease (CAD) is largely based on genome-wide association study (GWAS) analysis of common SNPs. Leveraging phased haplotypes from the 1000 Genomes Project, we report a GWAS meta-analysis of ∼185,000 CAD cases and controls, interrogating 6.7 million common (minor allele frequency (MAF) > 0.05) and 2.7 million low-frequency (0.005 < MAF < 0.05) variants. In addition to confirming most known CAD-associated loci, we identified ten new loci (eight additive and two recessive) that contain candidate causal genes newly implicating biological processes in vessel walls. We observed intralocus allelic heterogeneity but little evidence of low-frequency variants with larger effects and no evidence of synthetic association. Our analysis provides a comprehensive survey of the fine genetic architecture of CAD, showing that genetic susceptibility to this common disease is largely determined by common SNPs of small effect size.
View details for DOI 10.1038/ng.3396
View details for PubMedID 26343387
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The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape: A Large-Scale Genome-Wide Interaction Study.
PLoS genetics
2015; 11 (10)
Abstract
Genome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ substantially between men and women. To systematically screen for age- and/or sex-specific effects of genetic variants on BMI and WHRadjBMI, we performed meta-analyses of 114 studies (up to 320,485 individuals of European descent) with genome-wide chip and/or Metabochip data by the Genetic Investigation of Anthropometric Traits (GIANT) Consortium. Each study tested the association of up to ~2.8M SNPs with BMI and WHRadjBMI in four strata (men ≤50y, men >50y, women ≤50y, women >50y) and summary statistics were combined in stratum-specific meta-analyses. We then screened for variants that showed age-specific effects (G x AGE), sex-specific effects (G x SEX) or age-specific effects that differed between men and women (G x AGE x SEX). For BMI, we identified 15 loci (11 previously established for main effects, four novel) that showed significant (FDR<5%) age-specific effects, of which 11 had larger effects in younger (<50y) than in older adults (≥50y). No sex-dependent effects were identified for BMI. For WHRadjBMI, we identified 44 loci (27 previously established for main effects, 17 novel) with sex-specific effects, of which 28 showed larger effects in women than in men, five showed larger effects in men than in women, and 11 showed opposite effects between sexes. No age-dependent effects were identified for WHRadjBMI. This is the first genome-wide interaction meta-analysis to report convincing evidence of age-dependent genetic effects on BMI. In addition, we confirm the sex-specificity of genetic effects on WHRadjBMI. These results may provide further insights into the biology that underlies weight change with age or the sexually dimorphism of body shape.
View details for DOI 10.1371/journal.pgen.1005378
View details for PubMedID 26426971
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Leukocyte Telomere Length and Risks of Incident Coronary Heart Disease and Mortality in a Racially Diverse Population of Postmenopausal Women
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
2015; 35 (10): 2225-2231
Abstract
Telomeres are regions at the ends of chromosomes that maintain chromosomal structural integrity and genomic stability. In studies of mainly older, white populations, shorter leukocyte telomere length (LTL) is associated with cardiometabolic risk factors and increased risks of mortality and coronary heart disease (CHD). On average, blacks have longer LTL than whites, but the LTL-CHD relationship in blacks is unknown. We investigated the relationship of LTL with CHD and mortality among blacks.Using a case-cohort design, 1525 postmenopausal women (667 blacks and 858 whites) from the Women's Health Initiative had LTL measured in baseline blood samples by Southern blotting. CHD or mortality hazards ratios were estimated using race-stratified and risk factor-adjusted Cox proportional hazards models. There were 367 incident CHD (226 mortality) events in whites, whereas blacks experienced 269 incident CHD (216 mortality) events during median follow-up of 13 years. Shorter LTL was associated with older age, current smoking, and white race/ethnicity. In whites, each 1 kilobase decrease in LTL was associated with 50% increased hazard of CHD, hazard ratio=1.50 (95% confidence interval, 1.08-2.10), P=0.017. There was no association between CHD and LTL in blacks. White women with shorter LTL had higher risks of mortality. In contrast, shorter LTL was weakly associated with decreased mortality hazard in blacks.As one of the largest prospective studies of LTL associations with incident CHD and mortality in a racially diverse sample, our study suggests differences in LTL associations with CHD and mortality between white and black postmenopausal women.
View details for DOI 10.1161/ATVBAHA.115.305838
View details for Web of Science ID 000361610700019
View details for PubMedID 26249011
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DNA methylation age of blood predicts future onset of lung cancer in the women's health initiative.
Aging
2015
Abstract
Lung cancer is considered an age-associated disease, whose progression is in part due to accumulation of genomic instability as well as age-related decline in system integrity and function. Thus even among individuals exposed to high levels of genotoxic carcinogens, such as those found in cigarette smoke, lung cancer susceptibility may vary as a function of individual differences in the rate of biological aging. We recently developed a highly accurate candidate biomarker of aging based on DNA methylation (DNAm) levels, which may prove useful in assessing risk of aging-related diseases, such as lung cancer. Using data on 2,029 females from the Women's Health Initiative, we examined whether baseline measures of "intrinsic epigenetic age acceleration" (IEAA) predicted subsequent lung cancer incidence. We observed 43 lung cancer cases over the nearly twenty years of follow-up. Results showed that standardized measures of IEAA were significantly associated with lung cancer incidence (HR: 1.50, P=3.4x10-3). Furthermore, stratified Cox proportional hazard models suggested that the association may be even stronger among older individuals (70 years or above) or those who are current smokers. Overall, our results suggest that IEAA may be a useful biomarker for evaluating lung cancer susceptibility from a biological aging perspective.
View details for PubMedID 26411804
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Contemporary Considerations for Constructing a Genetic Risk Score: An Empirical Approach.
Genetic epidemiology
2015; 39 (6): 439-445
Abstract
Genetic risk scores are an increasingly popular tool for summarizing the cumulative risk of a set of Single Nucleotide Polymorphisms (SNPs) with disease. Typically only the set of the SNPs that have reached genome-wide significance compose these scores. However recent work suggests that including additional SNPs may aid risk assessment. In this paper, we used the Atherosclerosis Risk in Communities (ARIC) Study cohort to illustrate how one can choose the optimal set of SNPs for a genetic risk score (GRS). In addition to P-value threshold, we also examined linkage disequilibrium, imputation quality, and imputation type. We provide a variety of evaluation metrics. Results suggest that P-value threshold had the greatest impact on GRS quality for the outcome of coronary heart disease, with an optimal threshold around 0.001. However, GRSs are relatively robust to both linkage disequilibrium and imputation quality. We also show that the optimal GRS partially depends on the evaluation metric and consequently the way one intends to use the GRS. Overall the implications highlight both the robustness of GRS and a means to empirically choose the best set of GRSs.
View details for DOI 10.1002/gepi.21912
View details for PubMedID 26198599
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Effect of Common Genetic Variants of Growth Arrest-Specific 6 Gene on Insulin Resistance, Obesity and Type 2 Diabetes in an Asian Population.
PloS one
2015; 10 (8): e0135681
Abstract
Growth arrest-specific 6 (Gas6), a vitamin K-dependent protein, has been implicated in systemic inflammation, obesity, and insulin resistance (IR). Data from recent studies suggest that polymorphisms in the Gas6 gene are associated with cardiovascular disorders and type 2 diabetes (T2D). However, the association of Gas6 gene variants with obesity, IR, and T2D development has not been explored.Four common single nucleotide polymorphisms (SNPs) in the Gas6 gene were genotyped in 984 participants from the Stanford Asia-Pacific Program for Hypertension and Insulin Resistance (SAPPHIRe) family cohort. An insulin suppression test was performed to determine IR based on steady-state plasma glucose (SSPG). Associations between IR indices and obesity, and SNP genotypes, based on previously-reported data for this cohort (Phase I), were analyzed. In the present follow-up study (Phase II), the effects of gene variants of Gas6 on the progression to T2D were explored in individuals who were free of T2D in Phase I. The mean follow-up period for Phase II was 5.7 years.The mean age of the study population in Phase I was 49.5 years and 16.7% of individuals developed T2D during follow-up. After adjusting for covariates, three SNPs (rs8191973, rs8197974, and rs7323932) were found to be associated with SSPG levels (p = 0.007, p = 0.03, and p = 0.011, respectively). This association remained significant after multiple testing and showed a significant interaction with physical activity for SNP rs8191973. However, no other significant correlations were observed between Gas6 polymorphisms and other indices of IR or obesity. A specific haplotype, AACG (from rs8191974, rs7323932, rs7331124, and rs8191973), was positively associated with SSPG levels (p = 0.0098). None of the polymorphisms were associated with an increased risk of T2D development.Our results suggest that Gas6 gene variants are associated with IR, although their effects on subsequent progression to T2D were minimal in this prospective Asian cohort.
View details for DOI 10.1371/journal.pone.0135681
View details for PubMedID 26284522
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Genetic variants primarily associated with type 2 diabetes are related to coronary artery disease risk.
Atherosclerosis
2015; 241 (2): 419-426
Abstract
The mechanisms underlying the association between diabetes and coronary artery disease (CAD) risk are unclear. We aimed to assess this association by studying genetic variants that have been shown to associate with type 2 diabetes (T2DM). If the association between diabetes and CAD is causal, we expected to observe an association of these variants with CAD as well.We studied all genetic variants currently known to be associated with T2DM at a genome-wide significant level (p < 5*10(-8)) in CARDIoGRAM, a genome-wide data-set of CAD including 22,233 CAD cases and 64,762 controls. Out of the 44 published T2DM SNPs 10 were significantly associated with CAD in CARDIoGRAM (OR>1, p < 0.05), more than expected by chance (p = 5.0*10(-5)). Considering all 44 SNPs, the average CAD risk observed per individual T2DM risk allele was 1.0076 (95% confidence interval (CI), 0.9973-1.0180). Such average risk increase was significantly lower than the increase expected based on i) the published effects of the SNPs on T2DM risk and ii) the effect of T2DM on CAD risk as observed in the Framingham Heart Study, which suggested a risk of 1.067 per allele (p = 7.2*10(-10) vs. the observed effect). Studying two risk scores based on risk alleles of the diabetes SNPs, one score using individual level data in 9856 subjects, and the second score on average effects of reported beta-coefficients from the entire CARDIoGRAM data-set, we again observed a significant - yet smaller than expected - association with CAD.Our data indicate that an association between type 2 diabetes related SNPs and CAD exists. However, the effects on CAD risk appear to be by far lower than what would be expected based on the effects of risk alleles on T2DM and the effect of T2DM on CAD in the epidemiological setting.
View details for DOI 10.1016/j.atherosclerosis.2015.05.033
View details for PubMedID 26074316
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Systems Genetics Analysis of Genome-Wide Association Study Reveals Novel Associations Between Key Biological Processes and Coronary Artery Disease
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
2015; 35 (7): 1712-1722
Abstract
Genome-wide association studies have identified multiple genetic variants affecting the risk of coronary artery disease (CAD). However, individually these explain only a small fraction of the heritability of CAD and for most, the causal biological mechanisms remain unclear. We sought to obtain further insights into potential causal processes of CAD by integrating large-scale GWA data with expertly curated databases of core human pathways and functional networks.Using pathways (gene sets) from Reactome, we carried out a 2-stage gene set enrichment analysis strategy. From a meta-analyzed discovery cohort of 7 CAD genome-wide association study data sets (9889 cases/11 089 controls), nominally significant gene sets were tested for replication in a meta-analysis of 9 additional studies (15 502 cases/55 730 controls) from the Coronary ARtery DIsease Genome wide Replication and Meta-analysis (CARDIoGRAM) Consortium. A total of 32 of 639 Reactome pathways tested showed convincing association with CAD (replication P<0.05). These pathways resided in 9 of 21 core biological processes represented in Reactome, and included pathways relevant to extracellular matrix (ECM) integrity, innate immunity, axon guidance, and signaling by PDRF, NOTCH, and the transforming growth factor-β/SMAD receptor complex. Many of these pathways had strengths of association comparable to those observed in lipid transport pathways. Network analysis of unique genes within the replicated pathways further revealed several interconnected functional and topologically interacting modules representing novel associations (eg, semaphoring-regulated axonal guidance pathway) besides confirming known processes (lipid metabolism). The connectivity in the observed networks was statistically significant compared with random networks (P<0.001). Network centrality analysis (degree and betweenness) further identified genes (eg, NCAM1, FYN, FURIN, etc.) likely to play critical roles in the maintenance and functioning of several of the replicated pathways.These findings provide novel insights into how genetic variation, interpreted in the context of biological processes and functional interactions among genes, may help define the genetic architecture of CAD.
View details for DOI 10.1161/ATVBAHA.115.305513
View details for Web of Science ID 000356867300021
View details for PubMedID 25977570
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MOLECULAR BASIS OF REGULATORY VARIATION AT CORONARY HEART DISEASE ASSOCIATED LOCI
ELSEVIER IRELAND LTD. 2015: E17
View details for DOI 10.1016/j.atherosclerosis.2015.04.077
View details for Web of Science ID 000360100600058
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Detecting clinically meaningful biomarkers with repeated measurements: An illustration with electronic health records
BIOMETRICS
2015; 71 (2): 478-486
Abstract
Data sources with repeated measurements are an appealing resource to understand the relationship between changes in biological markers and risk of a clinical event. While longitudinal data present opportunities to observe changing risk over time, these analyses can be complicated if the measurement of clinical metrics is sparse and/or irregular, making typical statistical methods unsuitable. In this article, we use electronic health record (EHR) data as an example to present an analytic procedure to both create an analytic sample and analyze the data to detect clinically meaningful markers of acute myocardial infarction (MI). Using an EHR from a large national dialysis organization we abstracted the records of 64,318 individuals and identified 4769 people that had an MI during the study period. We describe a nested case-control design to sample appropriate controls and an analytic approach using regression splines. Fitting a mixed-model with truncated power splines we perform a series of goodness-of-fit tests to determine whether any of 11 regularly collected laboratory markers are useful clinical predictors. We test the clinical utility of each marker using an independent test set. The results suggest that EHR data can be easily used to detect markers of clinically acute events. Special software or analytic tools are not needed, even with irregular EHR data.
View details for DOI 10.1111/biom.12283
View details for Web of Science ID 000356810000024
View details for PubMedID 25652566
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Genetic analysis for a shared biological basis between migraine and coronary artery disease.
Neurology. Genetics
2015; 1 (1)
Abstract
To apply genetic analysis of genome-wide association data to study the extent and nature of a shared biological basis between migraine and coronary artery disease (CAD).Four separate methods for cross-phenotype genetic analysis were applied on data from 2 large-scale genome-wide association studies of migraine (19,981 cases, 56,667 controls) and CAD (21,076 cases, 63,014 controls). The first 2 methods quantified the extent of overlapping risk variants and assessed the load of CAD risk loci in migraineurs. Genomic regions of shared risk were then identified by analysis of covariance patterns between the 2 phenotypes and by querying known genome-wide significant loci.We found a significant overlap of genetic risk loci for migraine and CAD. When stratified by migraine subtype, this was limited to migraine without aura, and the overlap was protective in that patients with migraine had a lower load of CAD risk alleles than controls. Genes indicated by 16 shared risk loci point to mechanisms with potential roles in migraine pathogenesis and CAD, including endothelial dysfunction (PHACTR1) and insulin homeostasis (GIP).The results suggest that shared biological processes contribute to risk of migraine and CAD, but surprisingly this commonality is restricted to migraine without aura and the impact is in opposite directions. Understanding the mechanisms underlying these processes and their opposite relationship to migraine and CAD may improve our understanding of both disorders.
View details for DOI 10.1212/NXG.0000000000000010
View details for PubMedID 27066539
View details for PubMedCentralID PMC4821079
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Characterization of TCF21 Downstream Target Regions Identifies a Transcriptional Network Linking Multiple Independent Coronary Artery Disease Loci.
PLoS genetics
2015; 11 (5)
Abstract
To functionally link coronary artery disease (CAD) causal genes identified by genome wide association studies (GWAS), and to investigate the cellular and molecular mechanisms of atherosclerosis, we have used chromatin immunoprecipitation sequencing (ChIP-Seq) with the CAD associated transcription factor TCF21 in human coronary artery smooth muscle cells (HCASMC). Analysis of identified TCF21 target genes for enrichment of molecular and cellular annotation terms identified processes relevant to CAD pathophysiology, including "growth factor binding," "matrix interaction," and "smooth muscle contraction." We characterized the canonical binding sequence for TCF21 as CAGCTG, identified AP-1 binding sites in TCF21 peaks, and by conducting ChIP-Seq for JUN and JUND in HCASMC confirmed that there is significant overlap between TCF21 and AP-1 binding loci in this cell type. Expression quantitative trait variation mapped to target genes of TCF21 was significantly enriched among variants with low P-values in the GWAS analyses, suggesting a possible functional interaction between TCF21 binding and causal variants in other CAD disease loci. Separate enrichment analyses found over-representation of TCF21 target genes among CAD associated genes, and linkage disequilibrium between TCF21 peak variation and that found in GWAS loci, consistent with the hypothesis that TCF21 may affect disease risk through interaction with other disease associated loci. Interestingly, enrichment for TCF21 target genes was also found among other genome wide association phenotypes, including height and inflammatory bowel disease, suggesting a functional profile important for basic cellular processes in non-vascular tissues. Thus, data and analyses presented here suggest that study of GWAS transcription factors may be a highly useful approach to identifying disease gene interactions and thus pathways that may be relevant to complex disease etiology.
View details for DOI 10.1371/journal.pgen.1005202
View details for PubMedID 26020271
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Genetically Determined Height and Coronary Artery Disease
NEW ENGLAND JOURNAL OF MEDICINE
2015; 372 (17): 1608-1618
Abstract
The nature and underlying mechanisms of an inverse association between adult height and the risk of coronary artery disease (CAD) are unclear.We used a genetic approach to investigate the association between height and CAD, using 180 height-associated genetic variants. We tested the association between a change in genetically determined height of 1 SD (6.5 cm) with the risk of CAD in 65,066 cases and 128,383 controls. Using individual-level genotype data from 18,249 persons, we also examined the risk of CAD associated with the presence of various numbers of height-associated alleles. To identify putative mechanisms, we analyzed whether genetically determined height was associated with known cardiovascular risk factors and performed a pathway analysis of the height-associated genes.We observed a relative increase of 13.5% (95% confidence interval [CI], 5.4 to 22.1; P<0.001) in the risk of CAD per 1-SD decrease in genetically determined height. There was a graded relationship between the presence of an increased number of height-raising variants and a reduced risk of CAD (odds ratio for height quartile 4 versus quartile 1, 0.74; 95% CI, 0.68 to 0.84; P<0.001). Of the 12 risk factors that we studied, we observed significant associations only with levels of low-density lipoprotein cholesterol and triglycerides (accounting for approximately 30% of the association). We identified several overlapping pathways involving genes associated with both development and atherosclerosis.There is a primary association between a genetically determined shorter height and an increased risk of CAD, a link that is partly explained by the association between shorter height and an adverse lipid profile. Shared biologic processes that determine achieved height and the development of atherosclerosis may explain some of the association. (Funded by the British Heart Foundation and others.).
View details for DOI 10.1056/NEJMoa1404881
View details for Web of Science ID 000353294000006
View details for PubMedID 25853659
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Dissecting the Roles of MicroRNAs in Coronary Heart Disease via Integrative Genomic Analyses
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
2015; 35 (4): 1011-1021
Abstract
The roles of microRNAs (miRNAs) in coronary heart disease (CHD) have not been well characterized. This study sought to systematically characterize the complex genomic architecture of CHD by integrating whole blood miRNA and mRNA expression with genetic variation in 186 CHD cases and 186 controls.At false discovery rate <0.2, 15 miRNAs were differentially expressed between CHD cases and controls. To explore regulatory mechanisms, we integrated miRNA and mRNA expression with genome-wide genotype data to investigate miRNA and mRNA associations and relationships of genetic variation with miRNAs. We identified a large number of correlated miRNA-mRNA pairs and genetic loci that seem to regulate miRNA levels. Subsequently, we explored the relationships of these complex molecular associations with CHD status. We identified a large difference in miRNA-mRNA associations between CHD cases and controls, as demonstrated by a significantly higher proportion of inversely correlated miRNA-mRNA pairs in cases versus controls (80% versus 30%; P<1×10(-16)), suggesting a genome-wide shift in the regulatory structure of the transcriptome in CHD. The differentially coexpressed miRNA-mRNA pairs showed enrichment for CHD risk genetic variants affecting both miRNA and mRNA expression levels, implicating a putatively causal role in CHD. Furthermore, 3 miRNAs (miR-1275, miR-365a-3p, and miR-150-5p) were associated with an mRNA coexpression module that was causally linked to CHD and reflected the dysregulation of B-cell centered immune function.Our results provide novel evidence that miRNAs are important regulators of biological processes involved in CHD via genetic control and via their tight coexpression with mRNAs.
View details for DOI 10.1161/ATVBAHA.114.305176
View details for Web of Science ID 000351709200034
View details for PubMedID 25657313
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Cardiometabolic effects of genetic upregulation of the interleukin 1 receptor antagonist: a Mendelian randomisation analysis
LANCET DIABETES & ENDOCRINOLOGY
2015; 3 (4): 243-253
Abstract
To investigate potential cardiovascular and other effects of long-term pharmacological interleukin 1 (IL-1) inhibition, we studied genetic variants that produce inhibition of IL-1, a master regulator of inflammation.We created a genetic score combining the effects of alleles of two common variants (rs6743376 and rs1542176) that are located upstream of IL1RN, the gene encoding the IL-1 receptor antagonist (IL-1Ra; an endogenous inhibitor of both IL-1α and IL-1β); both alleles increase soluble IL-1Ra protein concentration. We compared effects on inflammation biomarkers of this genetic score with those of anakinra, the recombinant form of IL-1Ra, which has previously been studied in randomised trials of rheumatoid arthritis and other inflammatory disorders. In primary analyses, we investigated the score in relation to rheumatoid arthritis and four cardiometabolic diseases (type 2 diabetes, coronary heart disease, ischaemic stroke, and abdominal aortic aneurysm; 453,411 total participants). In exploratory analyses, we studied the relation of the score to many disease traits and to 24 other disorders of proposed relevance to IL-1 signalling (746,171 total participants).For each IL1RN minor allele inherited, serum concentrations of IL-1Ra increased by 0.22 SD (95% CI 0.18-0.25; 12.5%; p = 9.3 × 10(-33)), concentrations of interleukin 6 decreased by 0.02 SD (-0.04 to -0.01; -1.7%; p = 3.5 × 10(-3)), and concentrations of C-reactive protein decreased by 0.03 SD (-0.04 to -0.02; -3.4%; p = 7.7 × 10(-14)). We noted the effects of the genetic score on these inflammation biomarkers to be directionally concordant with those of anakinra. The allele count of the genetic score had roughly log-linear, dose-dependent associations with both IL-1Ra concentration and risk of coronary heart disease. For people who carried four IL-1Ra-raising alleles, the odds ratio for coronary heart disease was 1.15 (1.08-1.22; p = 1.8 × 10(-6)) compared with people who carried no IL-1Ra-raising alleles; the per-allele odds ratio for coronary heart disease was 1.03 (1.02-1.04; p = 3.9 × 10(-10)). Per-allele odds ratios were 0.97 (0.95-0.99; p = 9.9 × 10(-4)) for rheumatoid arthritis, 0.99 (0.97-1.01; p = 0.47) for type 2 diabetes, 1.00 (0.98-1.02; p = 0.92) for ischaemic stroke, and 1.08 (1.04-1.12; p = 1.8 × 10(-5)) for abdominal aortic aneurysm. In exploratory analyses, we observed per-allele increases in concentrations of proatherogenic lipids, including LDL-cholesterol, but no clear evidence of association for blood pressure, glycaemic traits, or any of the 24 other disorders studied. Modelling suggested that the observed increase in LDL-cholesterol could account for about a third of the association observed between the genetic score and increased coronary risk.Human genetic data suggest that long-term dual IL-1α/β inhibition could increase cardiovascular risk and, conversely, reduce the risk of development of rheumatoid arthritis. The cardiovascular risk might, in part, be mediated through an increase in proatherogenic lipid concentrations.
View details for DOI 10.1016/S2213-8587(15)00034-0
View details for Web of Science ID 000353032600020
View details for PubMedCentralID PMC4648058
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Identification and validation of N-acetyltransferase 2 as an insulin sensitivity gene
JOURNAL OF CLINICAL INVESTIGATION
2015; 125 (4): 1739-1751
Abstract
Decreased insulin sensitivity, also referred to as insulin resistance (IR), is a fundamental abnormality in patients with type 2 diabetes and a risk factor for cardiovascular disease. While IR predisposition is heritable, the genetic basis remains largely unknown. The GENEticS of Insulin Sensitivity consortium conducted a genome-wide association study (GWAS) for direct measures of insulin sensitivity, such as euglycemic clamp or insulin suppression test, in 2,764 European individuals, with replication in an additional 2,860 individuals. The presence of a nonsynonymous variant of N-acetyltransferase 2 (NAT2) [rs1208 (803A>G, K268R)] was strongly associated with decreased insulin sensitivity that was independent of BMI. The rs1208 "A" allele was nominally associated with IR-related traits, including increased fasting glucose, hemoglobin A1C, total and LDL cholesterol, triglycerides, and coronary artery disease. NAT2 acetylates arylamine and hydrazine drugs and carcinogens, but predicted acetylator NAT2 phenotypes were not associated with insulin sensitivity. In a murine adipocyte cell line, silencing of NAT2 ortholog Nat1 decreased insulin-mediated glucose uptake, increased basal and isoproterenol-stimulated lipolysis, and decreased adipocyte differentiation, while Nat1 overexpression produced opposite effects. Nat1-deficient mice had elevations in fasting blood glucose, insulin, and triglycerides and decreased insulin sensitivity, as measured by glucose and insulin tolerance tests, with intermediate effects in Nat1 heterozygote mice. Our results support a role for NAT2 in insulin sensitivity.
View details for DOI 10.1172/JCI74592
View details for Web of Science ID 000352248600037
View details for PubMedID 25798622
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New genetic loci link adipose and insulin biology to body fat distribution.
Nature
2015; 518 (7538): 187-196
Abstract
Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.
View details for DOI 10.1038/nature14132
View details for PubMedID 25673412
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Genetic studies of body mass index yield new insights for obesity biology.
Nature
2015; 518 (7538): 197-206
Abstract
Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.
View details for DOI 10.1038/nature14177
View details for PubMedID 25673413
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Exome sequencing identifies rare LDLR and APOA5 alleles conferring risk for myocardial infarction.
Nature
2015; 518 (7537): 102-106
Abstract
Myocardial infarction (MI), a leading cause of death around the world, displays a complex pattern of inheritance. When MI occurs early in life, genetic inheritance is a major component to risk. Previously, rare mutations in low-density lipoprotein (LDL) genes have been shown to contribute to MI risk in individual families, whereas common variants at more than 45 loci have been associated with MI risk in the population. Here we evaluate how rare mutations contribute to early-onset MI risk in the population. We sequenced the protein-coding regions of 9,793 genomes from patients with MI at an early age (≤50 years in males and ≤60 years in females) along with MI-free controls. We identified two genes in which rare coding-sequence mutations were more frequent in MI cases versus controls at exome-wide significance. At low-density lipoprotein receptor (LDLR), carriers of rare non-synonymous mutations were at 4.2-fold increased risk for MI; carriers of null alleles at LDLR were at even higher risk (13-fold difference). Approximately 2% of early MI cases harbour a rare, damaging mutation in LDLR; this estimate is similar to one made more than 40 years ago using an analysis of total cholesterol. Among controls, about 1 in 217 carried an LDLR coding-sequence mutation and had plasma LDL cholesterol > 190 mg dl(-1). At apolipoprotein A-V (APOA5), carriers of rare non-synonymous mutations were at 2.2-fold increased risk for MI. When compared with non-carriers, LDLR mutation carriers had higher plasma LDL cholesterol, whereas APOA5 mutation carriers had higher plasma triglycerides. Recent evidence has connected MI risk with coding-sequence mutations at two genes functionally related to APOA5, namely lipoprotein lipase and apolipoprotein C-III (refs 18, 19). Combined, these observations suggest that, as well as LDL cholesterol, disordered metabolism of triglyceride-rich lipoproteins contributes to MI risk.
View details for DOI 10.1038/nature13917
View details for PubMedID 25487149
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Leveraging population admixture to characterize the heritability of complex traits.
Nature genetics
2014; 46 (12): 1356-1362
Abstract
Despite recent progress on estimating the heritability explained by genotyped SNPs (h(2)g), a large gap between h(2)g and estimates of total narrow-sense heritability (h(2)) remains. Explanations for this gap include rare variants or upward bias in family-based estimates of h(2) due to shared environment or epistasis. We estimate h(2) from unrelated individuals in admixed populations by first estimating the heritability explained by local ancestry (h(2)γ). We show that h(2)γ = 2FSTCθ(1 - θ)h(2), where FSTC measures frequency differences between populations at causal loci and θ is the genome-wide ancestry proportion. Our approach is not susceptible to biases caused by epistasis or shared environment. We applied this approach to the analysis of 13 phenotypes in 21,497 African-American individuals from 3 cohorts. For height and body mass index (BMI), we obtained h(2) estimates of 0.55 ± 0.09 and 0.23 ± 0.06, respectively, which are larger than estimates of h(2)g in these and other data but smaller than family-based estimates of h(2).
View details for DOI 10.1038/ng.3139
View details for PubMedID 25383972
View details for PubMedCentralID PMC4244251
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Inactivating mutations in NPC1L1 and protection from coronary heart disease.
New England journal of medicine
2014; 371 (22): 2072-2082
Abstract
Ezetimibe lowers plasma levels of low-density lipoprotein (LDL) cholesterol by inhibiting the activity of the Niemann-Pick C1-like 1 (NPC1L1) protein. However, whether such inhibition reduces the risk of coronary heart disease is not known. Human mutations that inactivate a gene encoding a drug target can mimic the action of an inhibitory drug and thus can be used to infer potential effects of that drug.We sequenced the exons of NPC1L1 in 7364 patients with coronary heart disease and in 14,728 controls without such disease who were of European, African, or South Asian ancestry. We identified carriers of inactivating mutations (nonsense, splice-site, or frameshift mutations). In addition, we genotyped a specific inactivating mutation (p.Arg406X) in 22,590 patients with coronary heart disease and in 68,412 controls. We tested the association between the presence of an inactivating mutation and both plasma lipid levels and the risk of coronary heart disease.With sequencing, we identified 15 distinct NPC1L1 inactivating mutations; approximately 1 in every 650 persons was a heterozygous carrier for 1 of these mutations. Heterozygous carriers of NPC1L1 inactivating mutations had a mean LDL cholesterol level that was 12 mg per deciliter (0.31 mmol per liter) lower than that in noncarriers (P=0.04). Carrier status was associated with a relative reduction of 53% in the risk of coronary heart disease (odds ratio for carriers, 0.47; 95% confidence interval, 0.25 to 0.87; P=0.008). In total, only 11 of 29,954 patients with coronary heart disease had an inactivating mutation (carrier frequency, 0.04%) in contrast to 71 of 83,140 controls (carrier frequency, 0.09%).Naturally occurring mutations that disrupt NPC1L1 function were found to be associated with reduced plasma LDL cholesterol levels and a reduced risk of coronary heart disease. (Funded by the National Institutes of Health and others.).
View details for DOI 10.1056/NEJMoa1405386
View details for PubMedID 25390462
View details for PubMedCentralID PMC4335708
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Susceptibility Loci for Clinical CAD Predispose to Subclinical Coronary Atherosclerosis Throughout the Life Course
LIPPINCOTT WILLIAMS & WILKINS. 2014
View details for Web of Science ID 000209790205120
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Genetic Variants Primarily Associated With Inflammatory Bowel Disease Do Not Associate With Coronary Artery Disease
LIPPINCOTT WILLIAMS & WILKINS. 2014
View details for Web of Science ID 000209790204230
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Defining the role of common variation in the genomic and biological architecture of adult human height
NATURE GENETICS
2014; 46 (11): 1173-1186
Abstract
Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explained one-fifth of the heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated ∼2,000, ∼3,700 and ∼9,500 SNPs explained ∼21%, ∼24% and ∼29% of phenotypic variance. Furthermore, all common variants together captured 60% of heritability. The 697 variants clustered in 423 loci were enriched for genes, pathways and tissue types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/β-catenin and chondroitin sulfate-related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants.
View details for DOI 10.1038/ng.3097
View details for Web of Science ID 000344131900008
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Meta-analysis of genome-wide association studies in East Asian-ancestry populations identifies four new loci for body mass index
HUMAN MOLECULAR GENETICS
2014; 23 (20): 5492-5504
Abstract
Recent genetic association studies have identified 55 genetic loci associated with obesity or body mass index (BMI). The vast majority, 51 loci, however, were identified in European-ancestry populations. We conducted a meta-analysis of associations between BMI and approximately 2.5 million genotyped or imputed SNPs among 86 757 individuals of Asian ancestry, followed by in silico and de novo replication among 7488 to 47 352 additional Asian-ancestry individuals. We identified four novel BMI-associated loci near the KCNQ1 (rs2237892, P=9.29×10(-13)), ALDH2/MYL2 (rs671, P=3.40×10(-11); rs12229654, P=4.56×10(-9)), ITIH4 (rs2535633, P=1.77×10(-10)), and NT5C2 (rs11191580, P=3.83×10(-8)) genes. The association of BMI with rs2237892, rs671, and rs12229654 was significantly stronger among men than among women. Of the 51 BMI-associated loci initially identified in European-ancestry populations, we confirmed 8 loci at the genome-wide significance level (P<5.0×10(-8)) and an additional 14 at P<1.0×10(-3) with the same direction of effect as reported previously. Findings from this analysis expand our knowledge of the genetic basis of obesity.
View details for DOI 10.1093/hmg/ddu248
View details for Web of Science ID 000343202400016
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Study of exonic variation identifies incremental information regarding lipid-related and coronary heart disease genes.
Circulation research
2014; 115 (5): 478-480
View details for DOI 10.1161/CIRCRESAHA.114.304693
View details for PubMedID 25124323
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Obesity, physical activity, and their interaction in incident atrial fibrillation in postmenopausal women.
Journal of the American Heart Association
2014; 3 (4)
Abstract
Atrial fibrillation (AF) is the most common cardiac arrhythmia and is associated with increased risk of stroke and death. Obesity is an independent risk factor for AF, but modifiers of this risk are not well known. We studied the roles of obesity, physical activity, and their interaction in conferring risk of incident AF.The Women's Health Initiative (WHI) Observational Study was a prospective observational study of 93 676 postmenopausal women followed for an average of 11.5 years. Incident AF was identified using WHI-ascertained hospitalization records and diagnostic codes from Medicare claims. A multivariate Cox's hazard regression model adjusted for demographic and clinical risk factors was used to evaluate the interaction between obesity and physical activity and its association with incident AF. After exclusion of women with prevalent AF, incomplete data, or underweight body mass index (BMI), 9792 of the remaining 81 317 women developed AF. Women were, on average, 63.4 years old, 7.8% were African American, and 3.6% were Hispanic. Increased BMI (hazard ratio [HR], 1.12 per 5-kg/m(2) increase; 95% confidence interval [CI], 1.10 to 1.14) and reduced physical activity (>9 vs. 0 metabolic equivalent task hours per week; HR, 0.90; 95% CI, 0.85 to 0.96) were independently associated with higher rates of AF after multivariate adjustment. Higher levels of physical activity reduced the AF risk conferred by obesity (interaction P=0.033).Greater physical activity is associated with lower rates of incident AF and modifies the association between obesity and incident AF.
View details for DOI 10.1161/JAHA.114.001127
View details for PubMedID 25142057
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Loss-of-Function Mutations in APOC3, Triglycerides, and Coronary Disease
NEW ENGLAND JOURNAL OF MEDICINE
2014; 371 (1): 22-31
Abstract
Background Plasma triglyceride levels are heritable and are correlated with the risk of coronary heart disease. Sequencing of the protein-coding regions of the human genome (the exome) has the potential to identify rare mutations that have a large effect on phenotype. Methods We sequenced the protein-coding regions of 18,666 genes in each of 3734 participants of European or African ancestry in the Exome Sequencing Project. We conducted tests to determine whether rare mutations in coding sequence, individually or in aggregate within a gene, were associated with plasma triglyceride levels. For mutations associated with triglyceride levels, we subsequently evaluated their association with the risk of coronary heart disease in 110,970 persons. Results An aggregate of rare mutations in the gene encoding apolipoprotein C3 (APOC3) was associated with lower plasma triglyceride levels. Among the four mutations that drove this result, three were loss-of-function mutations: a nonsense mutation (R19X) and two splice-site mutations (IVS2+1G→A and IVS3+1G→T). The fourth was a missense mutation (A43T). Approximately 1 in 150 persons in the study was a heterozygous carrier of at least one of these four mutations. Triglyceride levels in the carriers were 39% lower than levels in noncarriers (P<1×10(-20)), and circulating levels of APOC3 in carriers were 46% lower than levels in noncarriers (P=8×10(-10)). The risk of coronary heart disease among 498 carriers of any rare APOC3 mutation was 40% lower than the risk among 110,472 noncarriers (odds ratio, 0.60; 95% confidence interval, 0.47 to 0.75; P=4×10(-6)). Conclusions Rare mutations that disrupt APOC3 function were associated with lower levels of plasma triglycerides and APOC3. Carriers of these mutations were found to have a reduced risk of coronary heart disease. (Funded by the National Heart, Lung, and Blood Institute and others.).
View details for DOI 10.1056/NEJMoa1307095
View details for Web of Science ID 000338265700006
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Multiple nonglycemic genomic Loci are newly associated with blood level of glycated hemoglobin in East asians.
Diabetes
2014; 63 (7): 2551-2562
Abstract
Glycated hemoglobin (HbA1C) is used as a measure of glycemic control and also as a diagnostic criterion for diabetes mellitus. To discover novel loci harbouring common variants associated with HbA1C in East Asians, we conducted a meta-analysis of 13 genome wide association studies (N=21,026). We replicated our findings in 3 additional studies comprising 11,576 individuals of East Asian ancestry. 10 variants showed associations that reached genome wide significance in the discovery dataset of which 9 [4 novel variants at TMEM79 (P-value 1.3 × 10(-23)), HBS1L/MYB (8.5 × 10(-15)), MYO9B (9.0 × 10(-12)) and CYBA (1.1 × 10(-8)) as well as 5 variants at loci that had been previously identified (CDKAL1, G6PC2/ABCB11, GCK, ANK1, and FN3K)] showed consistent evidence of association in replication datasets. These variants explained 1.76% of the variance in HbA1C. Several of these variants (TMEM79, HBS1L/MYB, CYBA, MYO9B, ANK1, and FN3K) showed no association with either blood glucose or type 2 diabetes. Amongst individuals with non-diabetic levels of fasting glucose (<7.0 mmol/l) but elevated (>=6.5%) HbA1c, 36.1% had HbA1C<6.5% after adjustment for these 6 variants. . Our East Asian GWAS meta-analysis has identified novel variants associated with HbA1C as well as demonstrating that the effects of known variants are largely transferable across ethnic groups. Variants affecting erythrocyte parameters rather than glucose metabolism may be relevant to the use of HbA1C for diagnosing diabetes in these populations.
View details for DOI 10.2337/db13-1815
View details for PubMedID 24647736
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Integrative genomics reveals novel molecular pathways and gene networks for coronary artery disease.
PLoS genetics
2014; 10 (7)
Abstract
The majority of the heritability of coronary artery disease (CAD) remains unexplained, despite recent successes of genome-wide association studies (GWAS) in identifying novel susceptibility loci. Integrating functional genomic data from a variety of sources with a large-scale meta-analysis of CAD GWAS may facilitate the identification of novel biological processes and genes involved in CAD, as well as clarify the causal relationships of established processes. Towards this end, we integrated 14 GWAS from the CARDIoGRAM Consortium and two additional GWAS from the Ottawa Heart Institute (25,491 cases and 66,819 controls) with 1) genetics of gene expression studies of CAD-relevant tissues in humans, 2) metabolic and signaling pathways from public databases, and 3) data-driven, tissue-specific gene networks from a multitude of human and mouse experiments. We not only detected CAD-associated gene networks of lipid metabolism, coagulation, immunity, and additional networks with no clear functional annotation, but also revealed key driver genes for each CAD network based on the topology of the gene regulatory networks. In particular, we found a gene network involved in antigen processing to be strongly associated with CAD. The key driver genes of this network included glyoxalase I (GLO1) and peptidylprolyl isomerase I (PPIL1), which we verified as regulatory by siRNA experiments in human aortic endothelial cells. Our results suggest genetic influences on a diverse set of both known and novel biological processes that contribute to CAD risk. The key driver genes for these networks highlight potential novel targets for further mechanistic studies and therapeutic interventions.
View details for DOI 10.1371/journal.pgen.1004502
View details for PubMedID 25033284
View details for PubMedCentralID PMC4102418
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Impact of type 2 diabetes susceptibility variants on quantitative glycemic traits reveals mechanistic heterogeneity.
Diabetes
2014; 63 (6): 2158-2171
Abstract
Patients with established type 2 diabetes display both beta-cell dysfunction and insulin resistance. To define fundamental processes leading to the diabetic state, we examined the relationship between type 2 diabetes risk variants at 37 established susceptibility loci and indices of proinsulin processing, insulin secretion and insulin sensitivity. We included data from up to 58,614 non-diabetic subjects with basal measures, and 17,327 with dynamic measures. We employed additive genetic models with adjustment for sex, age and BMI, followed by fixed-effects inverse variance meta-analyses. Cluster analyses grouped risk loci into five major categories based on their relationship to these continuous glycemic phenotypes. The first cluster (PPARG, KLF14, IRS1, GCKR) was characterized by primary effects on insulin sensitivity. The second (MTNR1B, GCK) featured risk alleles associated with reduced insulin secretion and fasting hyperglycemia. ARAP1 constituted a third cluster characterized by defects in insulin processing. A fourth cluster (including TCF7L2, SLC30A8, HHEX/IDE, CDKAL1, CDKN2A/2B) was defined by loci influencing insulin processing and secretion without detectable change in fasting glucose. The final group contained twenty risk loci with no clear-cut associations to continuous glycemic traits. By assembling extensive data on continuous glycemic traits, we have exposed the diverse mechanisms whereby type 2 diabetes risk variants impact disease predisposition.
View details for DOI 10.2337/db13-0949
View details for PubMedID 24296717
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Dissecting the causal genetic mechanisms of coronary heart disease.
Current atherosclerosis reports
2014; 16 (5): 406-?
Abstract
Large-scale genome-wide association studies (GWAS) have identified 46 loci that are associated with coronary heart disease (CHD). Additionally, 104 independent candidate variants (false discovery rate of 5 %) have been identified (Schunkert H, Konig IR, Kathiresan S, Reilly MP, Assimes TL, Holm H et al. Nat Genet 43:333-8, 2011; Deloukas P, Kanoni S, Willenborg C, Farrall M, Assimes TL, Thompson JR et al. Nat Genet 45:25-33, 2012; C4D Genetics Consortium. Nat Genet 43:339-44, 2011). The majority of the causal genes in these loci function independently of conventional risk factors. It is postulated that a number of the CHD-associated genes regulate basic processes in the vascular cells involved in atherosclerosis, and that study of the signaling pathways that are modulated in this cell type by causal regulatory variation will provide critical new insights for targeting the initiation and progression of disease. In this review, we will discuss the types of experimental approaches and data that are critical to understanding the molecular processes that underlie the disease risk at 9p21.3, TCF21, SORT1, and other CHD-associated loci.
View details for DOI 10.1007/s11883-014-0406-4
View details for PubMedID 24623178
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Coronary Heart Disease-Associated Variation in TCF21 Disrupts a MicroRNA-224 Binding Site and miRNA-Mediated Regulation
LIPPINCOTT WILLIAMS & WILKINS. 2014
View details for Web of Science ID 000606994400126
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Quantifying rare, deleterious variation in 12 human cytochrome P450 drug-metabolism genes in a large-scale exome dataset.
Human molecular genetics
2014; 23 (8): 1957-1963
Abstract
The study of genetic influences on drug response and efficacy ('pharmacogenetics') has existed for over 50 years. Yet, we still lack a complete picture of how genetic variation, both common and rare, affects each individual's responses to medications. Exome sequencing is a promising alternative method for pharmacogenetic discovery as it provides information on both common and rare variation in large numbers of individuals. Using exome data from 2203 AA and 4300 Caucasian individuals through the NHLBI Exome Sequencing Project, we conducted a survey of coding variation within 12 Cytochrome P450 (CYP) genes that are collectively responsible for catalyzing nearly 75% of all known Phase I drug oxidation reactions. In addition to identifying many polymorphisms with known pharmacogenetic effects, we discovered over 730 novel nonsynonymous alleles across the 12 CYP genes of interest. These alleles include many with diverse functional effects such as premature stop codons, aberrant splicesites and mutations at conserved active site residues. Our analysis considering both novel, predicted functional alleles as well as known, actionable CYP alleles reveals that rare, deleterious variation contributes markedly to the overall burden of pharmacogenetic alleles within the populations considered, and that the contribution of rare variation to this burden is over three times greater in AA individuals as compared with Caucasians. While most of these impactful alleles are individually rare, 7.6-11.7% of individuals interrogated in the study carry at least one newly described potentially deleterious alleles in a major drug-metabolizing CYP.
View details for DOI 10.1093/hmg/ddt588
View details for PubMedID 24282029
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Clinical interpretation and implications of whole-genome sequencing.
JAMA
2014; 311 (10): 1035-1045
Abstract
Whole-genome sequencing (WGS) is increasingly applied in clinical medicine and is expected to uncover clinically significant findings regardless of sequencing indication.To examine coverage and concordance of clinically relevant genetic variation provided by WGS technologies; to quantitate inherited disease risk and pharmacogenomic findings in WGS data and resources required for their discovery and interpretation; and to evaluate clinical action prompted by WGS findings.An exploratory study of 12 adult participants recruited at Stanford University Medical Center who underwent WGS between November 2011 and March 2012. A multidisciplinary team reviewed all potentially reportable genetic findings. Five physicians proposed initial clinical follow-up based on the genetic findings.Genome coverage and sequencing platform concordance in different categories of genetic disease risk, person-hours spent curating candidate disease-risk variants, interpretation agreement between trained curators and disease genetics databases, burden of inherited disease risk and pharmacogenomic findings, and burden and interrater agreement of proposed clinical follow-up.Depending on sequencing platform, 10% to 19% of inherited disease genes were not covered to accepted standards for single nucleotide variant discovery. Genotype concordance was high for previously described single nucleotide genetic variants (99%-100%) but low for small insertion/deletion variants (53%-59%). Curation of 90 to 127 genetic variants in each participant required a median of 54 minutes (range, 5-223 minutes) per genetic variant, resulted in moderate classification agreement between professionals (Gross κ, 0.52; 95% CI, 0.40-0.64), and reclassified 69% of genetic variants cataloged as disease causing in mutation databases to variants of uncertain or lesser significance. Two to 6 personal disease-risk findings were discovered in each participant, including 1 frameshift deletion in the BRCA1 gene implicated in hereditary breast and ovarian cancer. Physician review of sequencing findings prompted consideration of a median of 1 to 3 initial diagnostic tests and referrals per participant, with fair interrater agreement about the suitability of WGS findings for clinical follow-up (Fleiss κ, 0.24; P < 001).In this exploratory study of 12 volunteer adults, the use of WGS was associated with incomplete coverage of inherited disease genes, low reproducibility of detection of genetic variation with the highest potential clinical effects, and uncertainty about clinically reportable findings. In certain cases, WGS will identify clinically actionable genetic variants warranting early medical intervention. These issues should be considered when determining the role of WGS in clinical medicine.
View details for DOI 10.1001/jama.2014.1717
View details for PubMedID 24618965
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Coronary heart disease-associated variation in TCF21 disrupts a miR-224 binding site and miRNA-mediated regulation.
PLoS genetics
2014; 10 (3)
Abstract
Genome-wide association studies (GWAS) have identified chromosomal loci that affect risk of coronary heart disease (CHD) independent of classical risk factors. One such association signal has been identified at 6q23.2 in both Caucasians and East Asians. The lead CHD-associated polymorphism in this region, rs12190287, resides in the 3' untranslated region (3'-UTR) of TCF21, a basic-helix-loop-helix transcription factor, and is predicted to alter the seed binding sequence for miR-224. Allelic imbalance studies in circulating leukocytes and human coronary artery smooth muscle cells (HCASMC) showed significant imbalance of the TCF21 transcript that correlated with genotype at rs12190287, consistent with this variant contributing to allele-specific expression differences. 3' UTR reporter gene transfection studies in HCASMC showed that the disease-associated C allele has reduced expression compared to the protective G allele. Kinetic analyses in vitro revealed faster RNA-RNA complex formation and greater binding of miR-224 with the TCF21 C allelic transcript. In addition, in vitro probing with Pb2+ and RNase T1 revealed structural differences between the TCF21 variants in proximity of the rs12190287 variant, which are predicted to provide greater access to the C allele for miR-224 binding. miR-224 and TCF21 expression levels were anti-correlated in HCASMC, and miR-224 modulates the transcriptional response of TCF21 to transforming growth factor-β (TGF-β) and platelet derived growth factor (PDGF) signaling in an allele-specific manner. Lastly, miR-224 and TCF21 were localized in human coronary artery lesions and anti-correlated during atherosclerosis. Together, these data suggest that miR-224 interaction with the TCF21 transcript contributes to allelic imbalance of this gene, thus partly explaining the genetic risk for coronary heart disease associated at 6q23.2. These studies implicating rs12190287 in the miRNA-dependent regulation of TCF21, in conjunction with previous studies showing that this variant modulates transcriptional regulation through activator protein 1 (AP-1), suggests a unique bimodal level of complexity previously unreported for disease-associated variants.
View details for DOI 10.1371/journal.pgen.1004263
View details for PubMedID 24676100
View details for PubMedCentralID PMC3967965
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Whole-Exome Sequencing Identifies Rare and Low-Frequency Coding Variants Associated with LDL Cholesterol.
American journal of human genetics
2014; 94 (2): 233-245
Abstract
Elevated low-density lipoprotein cholesterol (LDL-C) is a treatable, heritable risk factor for cardiovascular disease. Genome-wide association studies (GWASs) have identified 157 variants associated with lipid levels but are not well suited to assess the impact of rare and low-frequency variants. To determine whether rare or low-frequency coding variants are associated with LDL-C, we exome sequenced 2,005 individuals, including 554 individuals selected for extreme LDL-C (>98(th) or <2(nd) percentile). Follow-up analyses included sequencing of 1,302 additional individuals and genotype-based analysis of 52,221 individuals. We observed significant evidence of association between LDL-C and the burden of rare or low-frequency variants in PNPLA5, encoding a phospholipase-domain-containing protein, and both known and previously unidentified variants in PCSK9, LDLR and APOB, three known lipid-related genes. The effect sizes for the burden of rare variants for each associated gene were substantially higher than those observed for individual SNPs identified from GWASs. We replicated the PNPLA5 signal in an independent large-scale sequencing study of 2,084 individuals. In conclusion, this large whole-exome-sequencing study for LDL-C identified a gene not known to be implicated in LDL-C and provides unique insight into the design and analysis of similar experiments.
View details for DOI 10.1016/j.ajhg.2014.01.010
View details for PubMedID 24507775
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The combination of 9p21.3 genotype and biomarker profile improves a peripheral artery disease risk prediction model.
Vascular medicine
2014; 19 (1): 3-8
Abstract
Peripheral artery disease (PAD) is a highly morbid condition affecting more than 8 million Americans. Frequently, PAD patients are unrecognized and therefore do not receive appropriate therapies. Therefore, new methods to identify PAD have been pursued, but have thus far had only modest success. Here we describe a new approach combining genomic and metabolic information to enhance the diagnosis of PAD. We measured the genotype of the chromosome 9p21 cardiovascular-risk polymorphism rs10757269 as well as the biomarkers C-reactive protein, cystatin C, β2-microglobulin, and plasma glucose in a study population of 393 patients undergoing coronary angiography. The rs10757269 allele was associated with PAD status (ankle-brachial index < 0.9) independent of biomarkers and traditional cardiovascular risk factors (odds ratio=1.92; 95% confidence interval, 1.29-2.85). Importantly, compared to a previously validated risk factor-based PAD prediction model, the addition of biomarkers and rs10757269 significantly and incrementally improved PAD risk prediction as assessed by the net reclassification index (NRI=33.5%; p=0.001) and integrated discrimination improvement (IDI=0.016; p=0.017). In conclusion, a model including a panel of biomarkers, which includes both genomic information (which is reflective of heritable risk) and metabolic information (which integrates environmental exposures), predicts the presence or absence of PAD better than established risk models, suggesting clinical utility for the diagnosis of PAD.
View details for DOI 10.1177/1358863X13514791
View details for PubMedID 24323119
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Near-Term Prediction of Sudden Cardiac Death in Older Hemodialysis Patients Using Electronic Health Records
CLINICAL JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY
2014; 9 (1): 82-91
Abstract
Sudden cardiac death is the most common cause of death among individuals undergoing hemodialysis. The epidemiology of sudden cardiac death has been well studied, and efforts are shifting to risk assessment. This study aimed to test whether assessment of acute changes during hemodialysis that are captured in electronic health records improved risk assessment.Data were collected from all hemodialysis sessions of patients 66 years and older receiving hemodialysis from a large national dialysis provider between 2004 and 2008. The primary outcome of interest was sudden cardiac death the day of or day after a dialysis session. This study used data from 2004 to 2006 as the training set and data from 2007 to 2008 as the validation set. The machine learning algorithm, Random Forests, was used to derive the prediction model.In 22 million sessions, 898 people between 2004 and 2006 and 826 people between 2007 and 2008 died on the day of or day after a dialysis session that was serving as a training or test data session, respectively. A reasonably strong predictor was derived using just predialysis information (concordance statistic=0.782), which showed modest but significant improvement after inclusion of postdialysis information (concordance statistic=0.799, P<0.001). However, risk prediction decreased the farther out that it was forecasted (up to 1 year), and postdialytic information became less important.Subtle changes in the experience of hemodialysis aid in the assessment of sudden cardiac death and are captured by modern electronic health records. The collected data are better for the assessment of near-term risk as opposed to longer-term risk.
View details for DOI 10.2215/CJN.03050313
View details for Web of Science ID 000329364700013
View details for PubMedID 24178968
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Shared Genetic Susceptibility to Ischemic Stroke and Coronary Artery Disease A Genome-Wide Analysis of Common Variants
STROKE
2014; 45 (1): 24-36
Abstract
Ischemic stroke (IS) and coronary artery disease (CAD) share several risk factors and each has a substantial heritability. We conducted a genome-wide analysis to evaluate the extent of shared genetic determination of the two diseases.Genome-wide association data were obtained from the METASTROKE, Coronary Artery Disease Genome-wide Replication and Meta-analysis (CARDIoGRAM), and Coronary Artery Disease (C4D) Genetics consortia. We first analyzed common variants reaching a nominal threshold of significance (P<0.01) for CAD for their association with IS and vice versa. We then examined specific overlap across phenotypes for variants that reached a high threshold of significance. Finally, we conducted a joint meta-analysis on the combined phenotype of IS or CAD. Corresponding analyses were performed restricted to the 2167 individuals with the ischemic large artery stroke (LAS) subtype.Common variants associated with CAD at P<0.01 were associated with a significant excess risk for IS and for LAS and vice versa. Among the 42 known genome-wide significant loci for CAD, 3 and 5 loci were significantly associated with IS and LAS, respectively. In the joint meta-analyses, 15 loci passed genome-wide significance (P<5×10(-8)) for the combined phenotype of IS or CAD and 17 loci passed genome-wide significance for LAS or CAD. Because these loci had prior evidence for genome-wide significance for CAD, we specifically analyzed the respective signals for IS and LAS and found evidence for association at chr12q24/SH2B3 (PIS=1.62×10(-7)) and ABO (PIS=2.6×10(-4)), as well as at HDAC9 (PLAS=2.32×10(-12)), 9p21 (PLAS=3.70×10(-6)), RAI1-PEMT-RASD1 (PLAS=2.69×10(-5)), EDNRA (PLAS=7.29×10(-4)), and CYP17A1-CNNM2-NT5C2 (PLAS=4.9×10(-4)).Our results demonstrate substantial overlap in the genetic risk of IS and particularly the LAS subtype with CAD.
View details for DOI 10.1161/STROKEAHA.113.002707
View details for Web of Science ID 000328823400015
View details for PubMedID 24262325
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Use of Medicare Data to Identify Coronary Heart Disease Outcomes in the Women's Health Initiative.
Circulation. Cardiovascular quality and outcomes
2014; 7 (1): 157-162
View details for DOI 10.1161/CIRCOUTCOMES.113.000373
View details for PubMedID 24399330
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Simple, standardized incorporation of genetic risk into non-genetic risk prediction tools for complex traits: coronary heart disease as an example.
Frontiers in genetics
2014; 5: 254-?
Abstract
Genetic risk assessment is becoming an important component of clinical decision-making. Genetic Risk Scores (GRSs) allow the composite assessment of genetic risk in complex traits. A technically and clinically pertinent question is how to most easily and effectively combine a GRS with an assessment of clinical risk derived from established non-genetic risk factors as well as to clearly present this information to patient and health care providers.We illustrate a means to combine a GRS with an independent assessment of clinical risk using a log-link function. We apply the method to the prediction of coronary heart disease (CHD) in the Atherosclerosis Risk in Communities (ARIC) cohort. We evaluate different constructions based on metrics of effect change, discrimination, and calibration.The addition of a GRS to a clinical risk score (CRS) improves both discrimination and calibration for CHD in ARIC. RESULTS are similar regardless of whether external vs. internal coefficients are used for the CRS, risk factor single nucleotide polymorphisms (SNPs) are included in the GRS, or subjects with diabetes at baseline are excluded. We outline how to report the construction and the performance of a GRS using our method and illustrate a means to present genetic risk information to subjects and/or their health care provider.The proposed method facilitates the standardized incorporation of a GRS in risk assessment.
View details for DOI 10.3389/fgene.2014.00254
View details for PubMedID 25136350
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Insulin resistance: regression and clustering.
PloS one
2014; 9 (6)
Abstract
In this paper we try to define insulin resistance (IR) precisely for a group of Chinese women. Our definition deliberately does not depend upon body mass index (BMI) or age, although in other studies, with particular random effects models quite different from models used here, BMI accounts for a large part of the variability in IR. We accomplish our goal through application of Gauss mixture vector quantization (GMVQ), a technique for clustering that was developed for application to lossy data compression. Defining data come from measurements that play major roles in medical practice. A precise statement of what the data are is in Section 1. Their family structures are described in detail. They concern levels of lipids and the results of an oral glucose tolerance test (OGTT). We apply GMVQ to residuals obtained from regressions of outcomes of an OGTT and lipids on functions of age and BMI that are inferred from the data. A bootstrap procedure developed for our family data supplemented by insights from other approaches leads us to believe that two clusters are appropriate for defining IR precisely. One cluster consists of women who are IR, and the other of women who seem not to be. Genes and other features are used to predict cluster membership. We argue that prediction with "main effects" is not satisfactory, but prediction that includes interactions may be.
View details for DOI 10.1371/journal.pone.0094129
View details for PubMedID 24887437
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Genetics and Genomics for the Prevention and Treatment of Cardiovascular Disease: Update A Scientific Statement From the American Heart Association
CIRCULATION
2013; 128 (25): 2813-2851
View details for DOI 10.1161/01.cir.0000437913.98912.1d
View details for Web of Science ID 000330348100020
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Trans-ethnic fine mapping identifies a novel independent locus at the 3 ' end of CDKAL1 and novel variants of several susceptibility loci for type 2 diabetes in a Han Chinese population
DIABETOLOGIA
2013; 56 (12): 2619-2628
Abstract
Candidate gene and genome-wide association studies have identified ∼60 susceptibility loci for type 2 diabetes. A majority of these loci have been discovered and tested only in European populations. The aim of this study was to assess the presence and extent of trans-ethnic effects of these loci in an East Asian population.A total of 9,335 unrelated Chinese Han individuals, including 4,535 with type 2 diabetes and 4,800 non-diabetic ethnically matched controls, were genotyped using the Illumina 200K Metabochip. We tested 50 established loci for type 2 diabetes and related traits (fasting glucose, fasting insulin, 2 h glucose). Disease association with the additive model of inheritance was analysed with logistic regression.We found that 14 loci significantly transferred to the Chinese population, with two loci (p = 5.7 × 10(-12) for KCNQ1; p = 5.0 × 10(-8) for CDKN2A/B-CDKN2BAS) reaching independent genome-wide statistical significance. Five of these 14 loci had similar lead single-nucleotide polymorphisms (SNPs) as were found in the European studies while the other nine were different. Further stepwise conditional analysis identified a total of seven secondary signals and an independent novel locus at the 3' end of CDKAL1.These results suggest that many loci associated with type 2 diabetes are commonly shared between European and Chinese populations. Identification of population-specific SNPs may increase our understanding of the genetic architecture underlying type 2 diabetes in different ethnic populations.
View details for DOI 10.1007/s00125-013-3047-1
View details for Web of Science ID 000326599300010
View details for PubMedID 24013783
View details for PubMedCentralID PMC3825282
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Discovery and refinement of loci associated with lipid levels.
Nature genetics
2013; 45 (11): 1274-1283
Abstract
Levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides and total cholesterol are heritable, modifiable risk factors for coronary artery disease. To identify new loci and refine known loci influencing these lipids, we examined 188,577 individuals using genome-wide and custom genotyping arrays. We identify and annotate 157 loci associated with lipid levels at P < 5 × 10(-8), including 62 loci not previously associated with lipid levels in humans. Using dense genotyping in individuals of European, East Asian, South Asian and African ancestry, we narrow association signals in 12 loci. We find that loci associated with blood lipid levels are often associated with cardiovascular and metabolic traits, including coronary artery disease, type 2 diabetes, blood pressure, waist-hip ratio and body mass index. Our results demonstrate the value of using genetic data from individuals of diverse ancestry and provide insights into the biological mechanisms regulating blood lipids to guide future genetic, biological and therapeutic research.
View details for DOI 10.1038/ng.2797
View details for PubMedID 24097068
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Imputation of coding variants in African Americans: better performance using data from the exome sequencing project
BIOINFORMATICS
2013; 29 (21): 2744-2749
Abstract
Although the 1000 Genomes haplotypes are the most commonly used reference panel for imputation, medical sequencing projects are generating large alternate sets of sequenced samples. Imputation in African Americans using 3384 haplotypes from the Exome Sequencing Project, compared with 2184 haplotypes from 1000 Genomes Project, increased effective sample size by 8.3-11.4% for coding variants with minor allele frequency <1%. No loss of imputation quality was observed using a panel built from phenotypic extremes. We recommend using haplotypes from Exome Sequencing Project alone or concatenation of the two panels over quality score-based post-imputation selection or IMPUTE2's two-panel combination.yunli@med.unc.edu.Supplementary data are available at Bioinformatics online.
View details for DOI 10.1093/bioinformatics/btt477
View details for Web of Science ID 000325997500011
View details for PubMedID 23956302
View details for PubMedCentralID PMC3799474
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Common variants associated with plasma triglycerides and risk for coronary artery disease.
Nature genetics
2013; 45 (11): 1345-1352
Abstract
Triglycerides are transported in plasma by specific triglyceride-rich lipoproteins; in epidemiological studies, increased triglyceride levels correlate with higher risk for coronary artery disease (CAD). However, it is unclear whether this association reflects causal processes. We used 185 common variants recently mapped for plasma lipids (P < 5 × 10(-8) for each) to examine the role of triglycerides in risk for CAD. First, we highlight loci associated with both low-density lipoprotein cholesterol (LDL-C) and triglyceride levels, and we show that the direction and magnitude of the associations with both traits are factors in determining CAD risk. Second, we consider loci with only a strong association with triglycerides and show that these loci are also associated with CAD. Finally, in a model accounting for effects on LDL-C and/or high-density lipoprotein cholesterol (HDL-C) levels, the strength of a polymorphism's effect on triglyceride levels is correlated with the magnitude of its effect on CAD risk. These results suggest that triglyceride-rich lipoproteins causally influence risk for CAD.
View details for DOI 10.1038/ng.2795
View details for PubMedID 24097064
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Mendelian randomization studies do not support a causal role for reduced circulating adiponectin levels in insulin resistance and type 2 diabetes.
Diabetes
2013; 62 (10): 3589-3598
Abstract
Adiponectin is strongly inversely associated with insulin resistance and type 2 diabetes, but its causal role remains controversial. We used a Mendelian randomization approach to test the hypothesis that adiponectin causally influences insulin resistance and type 2 diabetes. We used genetic variants at the ADIPOQ gene as instruments to calculate a regression slope between adiponectin levels and metabolic traits (up to 31,000 individuals) and a combination of instrumental variables and summary statistics-based genetic risk scores to test the associations with gold-standard measures of insulin sensitivity (2,969 individuals) and type 2 diabetes (15,960 case subjects and 64,731 control subjects). In conventional regression analyses, a 1-SD decrease in adiponectin levels was correlated with a 0.31-SD (95% CI 0.26-0.35) increase in fasting insulin, a 0.34-SD (0.30-0.38) decrease in insulin sensitivity, and a type 2 diabetes odds ratio (OR) of 1.75 (1.47-2.13). The instrumental variable analysis revealed no evidence of a causal association between genetically lower circulating adiponectin and higher fasting insulin (0.02 SD; 95% CI -0.07 to 0.11; N = 29,771), nominal evidence of a causal relationship with lower insulin sensitivity (-0.20 SD; 95% CI -0.38 to -0.02; N = 1,860), and no evidence of a relationship with type 2 diabetes (OR 0.94; 95% CI 0.75-1.19; N = 2,777 case subjects and 13,011 control subjects). Using the ADIPOQ summary statistics genetic risk scores, we found no evidence of an association between adiponectin-lowering alleles and insulin sensitivity (effect per weighted adiponectin-lowering allele: -0.03 SD; 95% CI -0.07 to 0.01; N = 2,969) or type 2 diabetes (OR per weighted adiponectin-lowering allele: 0.99; 95% CI 0.95-1.04; 15,960 case subjects vs. 64,731 control subjects). These results do not provide any consistent evidence that interventions aimed at increasing adiponectin levels will improve insulin sensitivity or risk of type 2 diabetes.
View details for DOI 10.2337/db13-0128
View details for PubMedID 23835345
View details for PubMedCentralID PMC3781444
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The shared allelic architecture of adiponectin levels and coronary artery disease.
Atherosclerosis
2013; 229 (1): 145-148
Abstract
OBJECTIVE: A large body of epidemiologic data strongly suggests an association between excess adiposity and coronary artery disease (CAD). Low adiponectin levels, a hormone secreted only from adipocytes, have been associated with an increased risk of CAD in observational studies. However, these associations cannot clarify whether this relationship is causal or due to a shared set of causal factors or even confounding. Genome-wide association studies have identified common variants that influence adiponectin levels, providing valuable tools to examine the genetic relationship between adiponectin and CAD. METHODS: Using 145 genome wide significant SNPs for adiponectin from the ADIPOGen consortium (n = 49,891), we tested whether adiponectin-decreasing alleles influenced risk of CAD in the CARDIoGRAM consortium (n = 85,274). RESULTS: In single-SNP analysis, 5 variants among 145 SNPs were associated with increased risk of CAD after correcting for multiple testing (P < 4.4 × 10(-4)). Using a multi-SNP genotypic risk score to test whether adiponectin levels and CAD have a shared genetic etiology, we found that adiponectin-decreasing alleles increased risk of CAD (P = 5.4 × 10(-7)). CONCLUSION: These findings demonstrate that adiponectin levels and CAD have a shared allelic architecture and provide rationale to undertake a Mendelian randomization studies to understand if this relationship is causal.
View details for DOI 10.1016/j.atherosclerosis.2013.03.034
View details for PubMedID 23664276
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Disease-Related Growth Factor and Embryonic Signaling Pathways Modulate an Enhancer of TCF21 Expression at the 6q23.2 Coronary Heart Disease Locus
PLOS GENETICS
2013; 9 (7)
Abstract
Coronary heart disease (CHD) is the leading cause of mortality in both developed and developing countries worldwide. Genome-wide association studies (GWAS) have now identified 46 independent susceptibility loci for CHD, however, the biological and disease-relevant mechanisms for these associations remain elusive. The large-scale meta-analysis of GWAS recently identified in Caucasians a CHD-associated locus at chromosome 6q23.2, a region containing the transcription factor TCF21 gene. TCF21 (Capsulin/Pod1/Epicardin) is a member of the basic-helix-loop-helix (bHLH) transcription factor family, and regulates cell fate decisions and differentiation in the developing coronary vasculature. Herein, we characterize a cis-regulatory mechanism by which the lead polymorphism rs12190287 disrupts an atypical activator protein 1 (AP-1) element, as demonstrated by allele-specific transcriptional regulation, transcription factor binding, and chromatin organization, leading to altered TCF21 expression. Further, this element is shown to mediate signaling through platelet-derived growth factor receptor beta (PDGFR-β) and Wilms tumor 1 (WT1) pathways. A second disease allele identified in East Asians also appears to disrupt an AP-1-like element. Thus, both disease-related growth factor and embryonic signaling pathways may regulate CHD risk through two independent alleles at TCF21.
View details for DOI 10.1371/journal.pgen.1003652
View details for Web of Science ID 000322321100049
View details for PubMedID 23874238
View details for PubMedCentralID PMC3715442
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A systems biology framework identifies molecular underpinnings of coronary heart disease.
Arteriosclerosis, thrombosis, and vascular biology
2013; 33 (6): 1427-1434
Abstract
Genetic approaches have identified numerous loci associated with coronary heart disease (CHD). The molecular mechanisms underlying CHD gene-disease associations, however, remain unclear. We hypothesized that genetic variants with both strong and subtle effects drive gene subnetworks that in turn affect CHD. APPROACH AND RESULTS: We surveyed CHD-associated molecular interactions by constructing coexpression networks using whole blood gene expression profiles from 188 CHD cases and 188 age- and sex-matched controls. Twenty-four coexpression modules were identified, including 1 case-specific and 1 control-specific differential module (DM). The DMs were enriched for genes involved in B-cell activation, immune response, and ion transport. By integrating the DMs with gene expression-associated single-nucleotide polymorphisms and with results of genome-wide association studies of CHD and its risk factors, the control-specific DM was implicated as CHD causal based on its significant enrichment for both CHD and lipid expression-associated single-nucleotide polymorphisms. This causal DM was further integrated with tissue-specific Bayesian networks and protein-protein interaction networks to identify regulatory key driver genes. Multitissue key drivers (SPIB and TNFRSF13C) and tissue-specific key drivers (eg, EBF1) were identified.Our network-driven integrative analysis not only identified CHD-related genes, but also defined network structure that sheds light on the molecular interactions of genes associated with CHD risk.
View details for DOI 10.1161/ATVBAHA.112.300112
View details for PubMedID 23539213
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Sex-stratified genome-wide association studies including 270,000 individuals show sexual dimorphism in genetic loci for anthropometric traits.
PLoS genetics
2013; 9 (6)
Abstract
Given the anthropometric differences between men and women and previous evidence of sex-difference in genetic effects, we conducted a genome-wide search for sexually dimorphic associations with height, weight, body mass index, waist circumference, hip circumference, and waist-to-hip-ratio (133,723 individuals) and took forward 348 SNPs into follow-up (additional 137,052 individuals) in a total of 94 studies. Seven loci displayed significant sex-difference (FDR<5%), including four previously established (near GRB14/COBLL1, LYPLAL1/SLC30A10, VEGFA, ADAMTS9) and three novel anthropometric trait loci (near MAP3K1, HSD17B4, PPARG), all of which were genome-wide significant in women (P<5×10(-8)), but not in men. Sex-differences were apparent only for waist phenotypes, not for height, weight, BMI, or hip circumference. Moreover, we found no evidence for genetic effects with opposite directions in men versus women. The PPARG locus is of specific interest due to its role in diabetes genetics and therapy. Our results demonstrate the value of sex-specific GWAS to unravel the sexually dimorphic genetic underpinning of complex traits.
View details for DOI 10.1371/journal.pgen.1003500
View details for PubMedID 23754948
View details for PubMedCentralID PMC3674993
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Genetic variants associated with glycine metabolism and their role in insulin sensitivity and type 2 diabetes.
Diabetes
2013; 62 (6): 2141-2150
Abstract
Circulating metabolites associated with insulin sensitivity may represent useful biomarkers, but their causal role in insulin sensitivity and diabetes is less certain. We previously identified novel metabolites correlated with insulin sensitivity measured by the hyperinsulinemic-euglycemic clamp. The top-ranking metabolites were in the glutathione and glycine biosynthesis pathways. We aimed to identify common genetic variants associated with metabolites in these pathways and test their role in insulin sensitivity and type 2 diabetes. With 1,004 nondiabetic individuals from the RISC study, we performed a genome-wide association study (GWAS) of 14 insulin sensitivity-related metabolites and one metabolite ratio. We replicated our results in the Botnia study (n = 342). We assessed the association of these variants with diabetes-related traits in GWAS meta-analyses (GENESIS [including RISC, EUGENE2, and Stanford], MAGIC, and DIAGRAM). We identified four associations with three metabolites-glycine (rs715 at CPS1), serine (rs478093 at PHGDH), and betaine (rs499368 at SLC6A12; rs17823642 at BHMT)-and one association signal with glycine-to-serine ratio (rs1107366 at ALDH1L1). There was no robust evidence for association between these variants and insulin resistance or diabetes. Genetic variants associated with genes in the glycine biosynthesis pathways do not provide consistent evidence for a role of glycine in diabetes-related traits.
View details for DOI 10.2337/db12-0876
View details for PubMedID 23378610
View details for PubMedCentralID PMC3661655
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Identification of heart rate-associated loci and their effects on cardiac conduction and rhythm disorders.
Nature genetics
2013; 45 (6): 621-631
Abstract
Elevated resting heart rate is associated with greater risk of cardiovascular disease and mortality. In a 2-stage meta-analysis of genome-wide association studies in up to 181,171 individuals, we identified 14 new loci associated with heart rate and confirmed associations with all 7 previously established loci. Experimental downregulation of gene expression in Drosophila melanogaster and Danio rerio identified 20 genes at 11 loci that are relevant for heart rate regulation and highlight a role for genes involved in signal transmission, embryonic cardiac development and the pathophysiology of dilated cardiomyopathy, congenital heart failure and/or sudden cardiac death. In addition, genetic susceptibility to increased heart rate is associated with altered cardiac conduction and reduced risk of sick sinus syndrome, and both heart rate-increasing and heart rate-decreasing variants associate with risk of atrial fibrillation. Our findings provide fresh insights into the mechanisms regulating heart rate and identify new therapeutic targets.
View details for DOI 10.1038/ng.2610
View details for PubMedID 23583979
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Genetic predisposition to higher blood pressure increases coronary artery disease risk.
Hypertension
2013; 61 (5): 995-1001
Abstract
Hypertension is a risk factor for coronary artery disease. Recent genome-wide association studies have identified 30 genetic variants associated with higher blood pressure at genome-wide significance (P<5 × 10(-8)). If elevated blood pressure is a causative factor for coronary artery disease, these variants should also increase coronary artery disease risk. Analyzing genome-wide association data from 22 233 coronary artery disease cases and 64 762 controls, we observed in the Coronary ARtery DIsease Genome-Wide Replication And Meta-Analysis (CARDIoGRAM) consortium that 88% of these blood pressure-associated polymorphisms were likewise positively associated with coronary artery disease, that is, they had an odds ratio >1 for coronary artery disease, a proportion much higher than expected by chance (P=4 × 10(-5)). The average relative coronary artery disease risk increase per each of the multiple blood pressure-raising alleles observed in the consortium was 3.0% for systolic blood pressure-associated polymorphisms (95% confidence interval, 1.8%-4.3%) and 2.9% for diastolic blood pressure-associated polymorphisms (95% confidence interval, 1.7%-4.1%). In substudies, individuals carrying most systolic blood pressure- and diastolic blood pressure-related risk alleles (top quintile of a genetic risk score distribution) had 70% (95% confidence interval, 50%-94%) and 59% (95% confidence interval, 40%-81%) higher odds of having coronary artery disease, respectively, as compared with individuals in the bottom quintile. In conclusion, most blood pressure-associated polymorphisms also confer an increased risk for coronary artery disease. These findings are consistent with a causal relationship of increasing blood pressure to coronary artery disease. Genetic variants primarily affecting blood pressure contribute to the genetic basis of coronary artery disease.
View details for DOI 10.1161/HYPERTENSIONAHA.111.00275
View details for PubMedID 23478099
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CHROMOSOME 9P21 LOCUS AND ANGIOGRAPHIC CORONARY ARTERY DISEASE BURDEN: A COLLABORATIVE META-ANALYSIS
BMJ PUBLISHING GROUP. 2013: A75
View details for DOI 10.1136/heartjnl-2013-304019.126
View details for Web of Science ID 000331214700138
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Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture.
Nature genetics
2013; 45 (5): 501-512
Abstract
Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups.
View details for DOI 10.1038/ng.2606
View details for PubMedID 23563607
View details for PubMedCentralID PMC3973018
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Measurement of insulin-mediated glucose uptake: direct comparison of the modified insulin suppression test and the euglycemic, hyperinsulinemic clamp.
Metabolism
2013; 62 (4): 548-553
Abstract
Two direct measurements of peripheral insulin sensitivity are the M value derived from the euglycemic, hyperinsulinemic clamp (EC) and the steady-state plasma glucose (SSPG) concentration derived from the insulin suppression test (IST). Prior work suggests that these measures are highly correlated, but the agreement between them is unknown. To determine the agreement between SSPG and M and to develop transformation equations to convert SSPG to M and vice versa, we directly compared these two measurements in the same individuals.A total of 15 nondiabetic subjects (9 women and 6 men) underwent both an EC and a modified version of the IST within a median interval of 5days. We performed standard correlation metrics of the two measures and developed transformation regression equations for the two measures.The mean±SD age of the subjects was 57±7years and body mass index, 27.7±3.9kg/m(2). The median (interquartile range) SSPG concentration was 6.7 (5.1, 9.8) mmol/L and M value, 49.6 (28.9, 64.2) μmol/min/kg-LBM. There was a highly significant correlation between SSPG and M (r=-0.87, P <0.001). The relationship was best fit by regression models with exponential/logarithmic functions (R(2)=0.85). Bland-Altman plots demonstrated an excellent agreement between these measures of insulin action.The SSPG and M are highly related measures of insulin sensitivity and the results provide the means to directly compare the two measurements.
View details for DOI 10.1016/j.metabol.2012.10.002
View details for PubMedID 23151437
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Association Between the Chromosome 9p21 Locus and Angiographic Coronary Artery Disease Burden A Collaborative Meta-Analysis
JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
2013; 61 (9): 957-970
Abstract
This study sought to ascertain the relationship of 9p21 locus with: 1) angiographic coronary artery disease (CAD) burden; and 2) myocardial infarction (MI) in individuals with underlying CAD.Chromosome 9p21 variants have been robustly associated with coronary heart disease, but questions remain on the mechanism of risk, specifically whether the locus contributes to coronary atheroma burden or plaque instability.We established a collaboration of 21 studies consisting of 33,673 subjects with information on both CAD (clinical or angiographic) and MI status along with 9p21 genotype. Tabular data are provided for each cohort on the presence and burden of angiographic CAD, MI cases with underlying CAD, and the diabetic status of all subjects.We first confirmed an association between 9p21 and CAD with angiographically defined cases and control subjects (pooled odds ratio [OR]: 1.31, 95% confidence interval [CI]: 1.20 to 1.43). Among subjects with angiographic CAD (n = 20,987), random-effects model identified an association with multivessel CAD, compared with those with single-vessel disease (OR: 1.10, 95% CI: 1.04 to 1.17)/copy of risk allele). Genotypic models showed an OR of 1.15, 95% CI: 1.04 to 1.26 for heterozygous carrier and OR: 1.23, 95% CI: 1.08 to 1.39 for homozygous carrier. Finally, there was no significant association between 9p21 and prevalent MI when both cases (n = 17,791) and control subjects (n = 15,882) had underlying CAD (OR: 0.99, 95% CI: 0.95 to 1.03)/risk allele.The 9p21 locus shows convincing association with greater burden of CAD but not with MI in the presence of underlying CAD. This adds further weight to the hypothesis that 9p21 locus primarily mediates an atherosclerotic phenotype.
View details for DOI 10.1016/j.jacc.2012.10.051
View details for Web of Science ID 000315294100012
View details for PubMedID 23352782
View details for PubMedCentralID PMC3653306
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Large-scale association analysis identifies new risk loci for coronary artery disease.
Nature genetics
2013; 45 (1): 25-33
Abstract
Coronary artery disease (CAD) is the commonest cause of death. Here, we report an association analysis in 63,746 CAD cases and 130,681 controls identifying 15 loci reaching genome-wide significance, taking the number of susceptibility loci for CAD to 46, and a further 104 independent variants (r(2) < 0.2) strongly associated with CAD at a 5% false discovery rate (FDR). Together, these variants explain approximately 10.6% of CAD heritability. Of the 46 genome-wide significant lead SNPs, 12 show a significant association with a lipid trait, and 5 show a significant association with blood pressure, but none is significantly associated with diabetes. Network analysis with 233 candidate genes (loci at 10% FDR) generated 5 interaction networks comprising 85% of these putative genes involved in CAD. The four most significant pathways mapping to these networks are linked to lipid metabolism and inflammation, underscoring the causal role of these activities in the genetic etiology of CAD. Our study provides insights into the genetic basis of CAD and identifies key biological pathways.
View details for DOI 10.1038/ng.2480
View details for PubMedID 23202125
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Disease-related growth factor and embryonic signaling pathways modulate an enhancer of TCF21 expression at the 6q23.2 coronary heart disease locus.
PLoS genetics
2013; 9 (7)
Abstract
Coronary heart disease (CHD) is the leading cause of mortality in both developed and developing countries worldwide. Genome-wide association studies (GWAS) have now identified 46 independent susceptibility loci for CHD, however, the biological and disease-relevant mechanisms for these associations remain elusive. The large-scale meta-analysis of GWAS recently identified in Caucasians a CHD-associated locus at chromosome 6q23.2, a region containing the transcription factor TCF21 gene. TCF21 (Capsulin/Pod1/Epicardin) is a member of the basic-helix-loop-helix (bHLH) transcription factor family, and regulates cell fate decisions and differentiation in the developing coronary vasculature. Herein, we characterize a cis-regulatory mechanism by which the lead polymorphism rs12190287 disrupts an atypical activator protein 1 (AP-1) element, as demonstrated by allele-specific transcriptional regulation, transcription factor binding, and chromatin organization, leading to altered TCF21 expression. Further, this element is shown to mediate signaling through platelet-derived growth factor receptor beta (PDGFR-β) and Wilms tumor 1 (WT1) pathways. A second disease allele identified in East Asians also appears to disrupt an AP-1-like element. Thus, both disease-related growth factor and embryonic signaling pathways may regulate CHD risk through two independent alleles at TCF21.
View details for DOI 10.1371/journal.pgen.1003652
View details for PubMedID 23874238
View details for PubMedCentralID PMC3715442
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Long-Term Use of Angiotensin Receptor Blockers and the Risk of Cancer
PLOS ONE
2012; 7 (12)
Abstract
The association between angiotensin receptor blockers (ARBs) and cancer is controversial with meta-analyses of randomized controlled trials and observational studies reporting conflicting results. Thus, the objective of this study was to determine whether ARBs are associated with an overall increased risk of the four most common cancers, namely, lung, colorectal, breast and prostate cancers, and to explore these effects separately for each cancer type. We conducted a retrospective cohort study using a nested case-control analysis within the United Kingdom (UK) General Practice Research Database. We assembled a cohort of patients prescribed antihypertensive agents between 1995, the year the first ARB (losartan) entered the UK market, and 2008, with follow-up until December 31, 2010. Cases were patients newly-diagnosed with lung, colorectal, breast and prostate cancer during follow-up. We used conditional logistic regression to estimate adjusted rate ratios (RRs) and 95% confidence intervals (CIs) of cancer incidence, comparing ever use of ARBs with ever use of diuretics and/or beta-blockers. The cohort included 1,165,781 patients, during which 41,059 patients were diagnosed with one of the cancers under study (rate 554/100,000 person-years). When compared to diuretics and/or beta-blockers, ever use of ARBs was not associated with an increased rate of cancer overall (RR: 1.00; 95% CI: 0.96-1.03) or with each cancer site separately. The use of angiotensin-converting enzyme inhibitors and calcium channel blockers was associated with an increased rate of lung cancer (RR: 1.13; 95% CI: 1.06-1.20 and RR: 1.19; 95% CI: 1.12-1.27, respectively). This study provides additional evidence that the use of ARBs does not increase the risk of cancer overall or any of the four major cancer sites. Additional research is needed to further investigate a potentially increased risk of lung cancer with angiotensin-converting enzyme inhibitors and calcium channel blockers.
View details for DOI 10.1371/journal.pone.0050893
View details for Web of Science ID 000313236200045
View details for PubMedID 23251399
View details for PubMedCentralID PMC3521027
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Mendelian Randomization Studies Do Not Support a Causal Effect of Plasma Lipids on Insulin Sensitivity
LIPPINCOTT WILLIAMS & WILKINS. 2012
View details for Web of Science ID 000208885001108
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FTO genotype is associated with phenotypic variability of body mass index
NATURE
2012; 490 (7419): 267-?
Abstract
There is evidence across several species for genetic control of phenotypic variation of complex traits, such that the variance among phenotypes is genotype dependent. Understanding genetic control of variability is important in evolutionary biology, agricultural selection programmes and human medicine, yet for complex traits, no individual genetic variants associated with variance, as opposed to the mean, have been identified. Here we perform a meta-analysis of genome-wide association studies of phenotypic variation using ∼170,000 samples on height and body mass index (BMI) in human populations. We report evidence that the single nucleotide polymorphism (SNP) rs7202116 at the FTO gene locus, which is known to be associated with obesity (as measured by mean BMI for each rs7202116 genotype), is also associated with phenotypic variability. We show that the results are not due to scale effects or other artefacts, and find no other experiment-wise significant evidence for effects on variability, either at loci other than FTO for BMI or at any locus for height. The difference in variance for BMI among individuals with opposite homozygous genotypes at the FTO locus is approximately 7%, corresponding to a difference of ∼0.5 kilograms in the standard deviation of weight. Our results indicate that genetic variants can be discovered that are associated with variability, and that between-person variability in obesity can partly be explained by the genotype at the FTO locus. The results are consistent with reported FTO by environment interactions for BMI, possibly mediated by DNA methylation. Our BMI results for other SNPs and our height results for all SNPs suggest that most genetic variants, including those that influence mean height or mean BMI, are not associated with phenotypic variance, or that their effects on variability are too small to detect even with samples sizes greater than 100,000.
View details for DOI 10.1038/nature11401
View details for Web of Science ID 000309733300051
View details for PubMedID 22982992
View details for PubMedCentralID PMC3564953
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Randomized Trial of Personal Genomics for Preventive Cardiology Design and Challenges
CIRCULATION-CARDIOVASCULAR GENETICS
2012; 5 (3): 368-376
View details for DOI 10.1161/CIRCGENETICS.112.962746
View details for PubMedID 22715281
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Genetic Variants Associated With Diabetes Related Circulating Metabolite Levels and Their Role in Type 2 Diabetes and Insulin Sensitivity
AMER DIABETES ASSOC. 2012: A397
View details for Web of Science ID 000209842903192
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Genetic determinants of the ankle-brachial index: A meta-analysis of a cardiovascular candidate gene 50K SNP panel in the candidate gene association resource (CARe) consortium
ATHEROSCLEROSIS
2012; 222 (1): 138-147
Abstract
Candidate gene association studies for peripheral artery disease (PAD), including subclinical disease assessed with the ankle-brachial index (ABI), have been limited by the modest number of genes examined. We conducted a two stage meta-analysis of ∼50,000 SNPs across ∼2100 candidate genes to identify genetic variants for ABI.We studied subjects of European ancestry from 8 studies (n=21,547, 55% women, mean age 44-73 years) and African American ancestry from 5 studies (n=7267, 60% women, mean age 41-73 years) involved in the candidate gene association resource (CARe) consortium. In each ethnic group, additive genetic models were used (with each additional copy of the minor allele corresponding to the given beta) to test each SNP for association with continuous ABI (excluding ABI>1.40) and PAD (defined as ABI<0.90) using linear or logistic regression with adjustment for known PAD risk factors and population stratification. We then conducted a fixed-effects inverse-variance weighted meta-analyses considering a p<2×10(-6) to denote statistical significance.In the European ancestry discovery meta-analyses, rs2171209 in SYTL3 (β=-0.007, p=6.02×10(-7)) and rs290481 in TCF7L2 (β=-0.008, p=7.01×10(-7)) were significantly associated with ABI. None of the SNP associations for PAD were significant, though a SNP in CYP2B6 (p=4.99×10(-5)) was among the strongest associations. These 3 genes are linked to key PAD risk factors (lipoprotein(a), type 2 diabetes, and smoking behavior, respectively). We sought replication in 6 population-based and 3 clinical samples (n=15,440) for rs290481 and rs2171209. However, in the replication stage (rs2171209, p=0.75; rs290481, p=0.19) and in the combined discovery and replication analysis the SNP-ABI associations were no longer significant (rs2171209, p=1.14×10(-3); rs290481, p=8.88×10(-5)). In African Americans, none of the SNP associations for ABI or PAD achieved an experiment-wide level of significance.Genetic determinants of ABI and PAD remain elusive. Follow-up of these preliminary findings may uncover important biology given the known gene-risk factor associations. New and more powerful approaches to PAD gene discovery are warranted.
View details for DOI 10.1016/j.atherosclerosis.2012.01.039
View details for Web of Science ID 000302960600022
View details for PubMedID 22361517
View details for PubMedCentralID PMC3596171
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PREDICTING ACUTE SUDDEN CARDIAC DEATH
49th Congress of the European-Renal-Association/European-Dialysis-and-Transplant-Association (ERA-EDTA)
OXFORD UNIV PRESS. 2012: 59–59
View details for Web of Science ID 000311494700134
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Central obesity is important but not essential component of the metabolic syndrome for predicting diabetes mellitus in a hypertensive family-based cohort. Results from the Stanford Asia-pacific program for hypertension and insulin resistance (SAPPHIRe) Taiwan follow-up study
CARDIOVASCULAR DIABETOLOGY
2012; 11
Abstract
Metabolic abnormalities have a cumulative effect on development of diabetes, but only central obesity has been defined as the essential criterion of metabolic syndrome (MetS) by the International Diabetes Federation. We hypothesized that central obesity contributes to a higher risk of new-onset diabetes than other metabolic abnormalities in the hypertensive families.Non-diabetic Chinese were enrolled and MetS components were assessed to establish baseline data in a hypertensive family-based cohort study. Based on medical records and glucose tolerance test (OGTT), the cumulative incidence of diabetes was analyzed in this five-year study by Cox regression models. Contribution of central obesity to development of new-onset diabetes was assessed in subjects with the same number of positive MetS components.Among the total of 595 subjects who completed the assessment, 125 (21.0%) developed diabetes. Incidence of diabetes increased in direct proportion to the number of positive MetS components (P ≪ 0.001). Although subjects with central obesity had a higher incidence of diabetes than those without (55.7 vs. 30.0 events/1000 person-years, P ≪ 0.001), the difference became non-significant after adjusting of the number of positive MetS components (hazard ratio = 0.72, 95%CI: 0.45-1.13). Furthermore, in all participants with three positive MetS components, there was no difference in the incidence of diabetes between subjects with and without central obesity (hazard ratio = 1.04, 95%CI: 0.50-2.16).In Chinese hypertensive families, the incidence of diabetes in subjects without central obesity was similar to that in subjects with central obesity when they also had the same number of positive MetS components. We suggest that central obesity is very important, but not the essential component of the metabolic syndrome for predicting of new-onset diabetes. (Trial registration: NCT00260910, ClinicalTrials.gov).
View details for DOI 10.1186/1475-2840-11-43
View details for Web of Science ID 000308428000001
View details for PubMedID 22537054
View details for PubMedCentralID PMC3476431
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Evaluation of the Metabochip Genotyping Array in African Americans and Implications for Fine Mapping of GWAS-Identified Loci: The PAGE Study
PLOS ONE
2012; 7 (4)
Abstract
The Metabochip is a custom genotyping array designed for replication and fine mapping of metabolic, cardiovascular, and anthropometric trait loci and includes low frequency variation content identified from the 1000 Genomes Project. It has 196,725 SNPs concentrated in 257 genomic regions. We evaluated the Metabochip in 5,863 African Americans; 89% of all SNPs passed rigorous quality control with a call rate of 99.9%. Two examples illustrate the value of fine mapping with the Metabochip in African-ancestry populations. At CELSR2/PSRC1/SORT1, we found the strongest associated SNP for LDL-C to be rs12740374 (p = 3.5 × 10(-11)), a SNP indistinguishable from multiple SNPs in European ancestry samples due to high correlation. Its distinct signal supports functional studies elsewhere suggesting a causal role in LDL-C. At CETP we found rs17231520, with risk allele frequency 0.07 in African Americans, to be associated with HDL-C (p = 7.2 × 10(-36)). This variant is very rare in Europeans and not tagged in common GWAS arrays, but was identified as associated with HDL-C in African Americans in a single-gene study. Our results, one narrowing the risk interval and the other revealing an associated variant not found in Europeans, demonstrate the advantages of high-density genotyping of common and rare variation for fine mapping of trait loci in African American samples.
View details for DOI 10.1371/journal.pone.0035651
View details for Web of Science ID 000305341000054
View details for PubMedID 22539988
View details for PubMedCentralID PMC3335090
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Interleukin-6 receptor pathways in coronary heart disease: a collaborative meta-analysis of 82 studies
LANCET
2012; 379 (9822): 1205-1213
Abstract
Persistent inflammation has been proposed to contribute to various stages in the pathogenesis of cardiovascular disease. Interleukin-6 receptor (IL6R) signalling propagates downstream inflammation cascades. To assess whether this pathway is causally relevant to coronary heart disease, we studied a functional genetic variant known to affect IL6R signalling.In a collaborative meta-analysis, we studied Asp358Ala (rs2228145) in IL6R in relation to a panel of conventional risk factors and inflammation biomarkers in 125,222 participants. We also compared the frequency of Asp358Ala in 51,441 patients with coronary heart disease and in 136,226 controls. To gain insight into possible mechanisms, we assessed Asp358Ala in relation to localised gene expression and to postlipopolysaccharide stimulation of interleukin 6.The minor allele frequency of Asp358Ala was 39%. Asp358Ala was not associated with lipid concentrations, blood pressure, adiposity, dysglycaemia, or smoking (p value for association per minor allele ≥0·04 for each). By contrast, for every copy of 358Ala inherited, mean concentration of IL6R increased by 34·3% (95% CI 30·4-38·2) and of interleukin 6 by 14·6% (10·7-18·4), and mean concentration of C-reactive protein was reduced by 7·5% (5·9-9·1) and of fibrinogen by 1·0% (0·7-1·3). For every copy of 358Ala inherited, risk of coronary heart disease was reduced by 3·4% (1·8-5·0). Asp358Ala was not related to IL6R mRNA levels or interleukin-6 production in monocytes.Large-scale human genetic and biomarker data are consistent with a causal association between IL6R-related pathways and coronary heart disease.British Heart Foundation; UK Medical Research Council; UK National Institute of Health Research, Cambridge Biomedical Research Centre; BUPA Foundation.
View details for DOI 10.1016/S0140-6736(11)61931-4
View details for Web of Science ID 000302230400033
View details for PubMedID 22421339
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A LARGE-SCALE MULTI ETHNIC STUDY OF A DIRECT MEASURE OF INSULIN SENSITIVITY DEMONSTRATES THAT SOUTH ASIANS ARE THE MOST INSULIN RESISTANT ETHNIC GROUP IN THE US
61st Annual Scientific Session and Expo of the American-College-of-Cardiology (ACC)/Conference on ACC-i2 with TCT
ELSEVIER SCIENCE INC. 2012: E1792–E1792
View details for Web of Science ID 000302326702003
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Age-Related Somatic Structural Changes in the Nuclear Genome of Human Blood Cells
AMERICAN JOURNAL OF HUMAN GENETICS
2012; 90 (2): 217-228
Abstract
Structural variations are among the most frequent interindividual genetic differences in the human genome. The frequency and distribution of de novo somatic structural variants in normal cells is, however, poorly explored. Using age-stratified cohorts of 318 monozygotic (MZ) twins and 296 single-born subjects, we describe age-related accumulation of copy-number variation in the nuclear genomes in vivo and frequency changes for both megabase- and kilobase-range variants. Megabase-range aberrations were found in 3.4% (9 of 264) of subjects ≥60 years old; these subjects included 78 MZ twin pairs and 108 single-born individuals. No such findings were observed in 81 MZ pairs or 180 single-born subjects who were ≤55 years old. Recurrent region- and gene-specific mutations, mostly deletions, were observed. Longitudinal analyses of 43 subjects whose data were collected 7-19 years apart suggest considerable variation in the rate of accumulation of clones carrying structural changes. Furthermore, the longitudinal analysis of individuals with structural aberrations suggests that there is a natural self-removal of aberrant cell clones from peripheral blood. In three healthy subjects, we detected somatic aberrations characteristic of patients with myelodysplastic syndrome. The recurrent rearrangements uncovered here are candidates for common age-related defects in human blood cells. We anticipate that extension of these results will allow determination of the genetic age of different somatic-cell lineages and estimation of possible individual differences between genetic and chronological age. Our work might also help to explain the cause of an age-related reduction in the number of cell clones in the blood; such a reduction is one of the hallmarks of immunosenescence.
View details for DOI 10.1016/j.ajhg.2011.12.009
View details for Web of Science ID 000300742200003
View details for PubMedID 22305530
View details for PubMedCentralID PMC3276669
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Homocysteine and Coronary Heart Disease: Meta-analysis of MTHFR Case-Control Studies, Avoiding Publication Bias
PLOS MEDICINE
2012; 9 (2)
Abstract
Moderately elevated blood levels of homocysteine are weakly correlated with coronary heart disease (CHD) risk, but causality remains uncertain. When folate levels are low, the TT genotype of the common C677T polymorphism (rs1801133) of the methylene tetrahydrofolate reductase gene (MTHFR) appreciably increases homocysteine levels, so "Mendelian randomization" studies using this variant as an instrumental variable could help test causality.Nineteen unpublished datasets were obtained (total 48,175 CHD cases and 67,961 controls) in which multiple genetic variants had been measured, including MTHFR C677T. These datasets did not include measurements of blood homocysteine, but homocysteine levels would be expected to be about 20% higher with TT than with CC genotype in the populations studied. In meta-analyses of these unpublished datasets, the case-control CHD odds ratio (OR) and 95% CI comparing TT versus CC homozygotes was 1.02 (0.98-1.07; p = 0.28) overall, and 1.01 (0.95-1.07) in unsupplemented low-folate populations. By contrast, in a slightly updated meta-analysis of the 86 published studies (28,617 CHD cases and 41,857 controls), the OR was 1.15 (1.09-1.21), significantly discrepant (p = 0.001) with the OR in the unpublished datasets. Within the meta-analysis of published studies, the OR was 1.12 (1.04-1.21) in the 14 larger studies (those with variance of log OR<0.05; total 13,119 cases) and 1.18 (1.09-1.28) in the 72 smaller ones (total 15,498 cases).The CI for the overall result from large unpublished datasets shows lifelong moderate homocysteine elevation has little or no effect on CHD. The discrepant overall result from previously published studies reflects publication bias or methodological problems.
View details for DOI 10.1371/journal.pmed.1001177
View details for Web of Science ID 000301222600009
View details for PubMedID 22363213
View details for PubMedCentralID PMC3283559
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Association Between Chromosome 9p21 Variants and the Ankle-Brachial Index Identified by a Meta-Analysis of 21 Genome-Wide Association Studies
CIRCULATION-CARDIOVASCULAR GENETICS
2012; 5 (1): 100-112
Abstract
Genetic determinants of peripheral arterial disease (PAD) remain largely unknown. To identify genetic variants associated with the ankle-brachial index (ABI), a noninvasive measure of PAD, we conducted a meta-analysis of genome-wide association study data from 21 population-based cohorts.Continuous ABI and PAD (ABI ≤0.9) phenotypes adjusted for age and sex were examined. Each study conducted genotyping and imputed data to the ≈2.5 million single nucleotide polymorphisms (SNPs) in HapMap. Linear and logistic regression models were used to test each SNP for association with ABI and PAD using additive genetic models. Study-specific data were combined using fixed effects inverse variance weighted meta-analyses. There were a total of 41 692 participants of European ancestry (≈60% women, mean ABI 1.02 to 1.19), including 3409 participants with PAD and with genome-wide association study data available. In the discovery meta-analysis, rs10757269 on chromosome 9 near CDKN2B had the strongest association with ABI (β=-0.006, P=2.46×10(-8)). We sought replication of the 6 strongest SNP associations in 5 population-based studies and 3 clinical samples (n=16 717). The association for rs10757269 strengthened in the combined discovery and replication analysis (P=2.65×10(-9)). No other SNP associations for ABI or PAD achieved genome-wide significance. However, 2 previously reported candidate genes for PAD and 1 SNP associated with coronary artery disease were associated with ABI: DAB21P (rs13290547, P=3.6×10(-5)), CYBA (rs3794624, P=6.3×10(-5)), and rs1122608 (LDLR, P=0.0026).Genome-wide association studies in more than 40 000 individuals identified 1 genome wide significant association on chromosome 9p21 with ABI. Two candidate genes for PAD and 1 SNP for coronary artery disease are associated with ABI.
View details for DOI 10.1161/CIRCGENETICS.111.961292
View details for Web of Science ID 000309884100017
View details for PubMedID 22199011
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Novel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits: a multi-ethnic meta-analysis of 45,891 individuals.
PLoS genetics
2012; 8 (3)
Abstract
Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P = 4.5×10(-8)-1.2×10(-43)). Using a novel method to combine data across ethnicities (N = 4,232 African Americans, N = 1,776 Asians, and N = 29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p<3×10(-4)). We next developed a multi-SNP genotypic risk score to test the association of adiponectin decreasing risk alleles on metabolic traits and diseases using consortia-level meta-analytic data. This risk score was associated with increased risk of T2D (p = 4.3×10(-3), n = 22,044), increased triglycerides (p = 2.6×10(-14), n = 93,440), increased waist-to-hip ratio (p = 1.8×10(-5), n = 77,167), increased glucose two hours post oral glucose tolerance testing (p = 4.4×10(-3), n = 15,234), increased fasting insulin (p = 0.015, n = 48,238), but with lower in HDL-cholesterol concentrations (p = 4.5×10(-13), n = 96,748) and decreased BMI (p = 1.4×10(-4), n = 121,335). These findings identify novel genetic determinants of adiponectin levels, which, taken together, influence risk of T2D and markers of insulin resistance.
View details for DOI 10.1371/journal.pgen.1002607
View details for PubMedID 22479202
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Abdominal Aortic Aneurysm Is Associated with a Variant in Low-Density Lipoprotein Receptor-Related Protein 1
AMERICAN JOURNAL OF HUMAN GENETICS
2011; 89 (5): 619-627
Abstract
Abdominal aortic aneurysm (AAA) is a common cause of morbidity and mortality and has a significant heritability. We carried out a genome-wide association discovery study of 1866 patients with AAA and 5435 controls and replication of promising signals (lead SNP with a p value < 1 × 10(-5)) in 2871 additional cases and 32,687 controls and performed further follow-up in 1491 AAA and 11,060 controls. In the discovery study, nine loci demonstrated association with AAA (p < 1 × 10(-5)). In the replication sample, the lead SNP at one of these loci, rs1466535, located within intron 1 of low-density-lipoprotein receptor-related protein 1 (LRP1) demonstrated significant association (p = 0.0042). We confirmed the association of rs1466535 and AAA in our follow-up study (p = 0.035). In a combined analysis (6228 AAA and 49182 controls), rs1466535 had a consistent effect size and direction in all sample sets (combined p = 4.52 × 10(-10), odds ratio 1.15 [1.10-1.21]). No associations were seen for either rs1466535 or the 12q13.3 locus in independent association studies of coronary artery disease, blood pressure, diabetes, or hyperlipidaemia, suggesting that this locus is specific to AAA. Gene-expression studies demonstrated a trend toward increased LRP1 expression for the rs1466535 CC genotype in arterial tissues; there was a significant (p = 0.029) 1.19-fold (1.04-1.36) increase in LRP1 expression in CC homozygotes compared to TT homozygotes in aortic adventitia. Functional studies demonstrated that rs1466535 might alter a SREBP-1 binding site and influence enhancer activity at the locus. In conclusion, this study has identified a biologically plausible genetic variant associated specifically with AAA, and we suggest that this variant has a possible functional role in LRP1 expression.
View details for DOI 10.1016/j.ajhg.2011.10.002
View details for Web of Science ID 000297090100003
View details for PubMedID 22055160
View details for PubMedCentralID PMC3213391
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Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk
NATURE
2011; 478 (7367): 103-109
Abstract
Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140 mm Hg systolic blood pressure or ≥90 mm Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention.
View details for DOI 10.1038/nature10405
View details for Web of Science ID 000295575400043
View details for PubMedID 21909115
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Immortal Person Time Bias in Pharmacoepidemiological Studies of Antihypertensive Drugs
AMERICAN JOURNAL OF CARDIOLOGY
2011; 108 (6): 902-903
View details for DOI 10.1016/j.amjcard.2011.06.031
View details for Web of Science ID 000295352700029
View details for PubMedID 21884882
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Human metabolic individuality in biomedical and pharmaceutical research
NATURE
2011; 477 (7362): 54-U60
Abstract
Genome-wide association studies (GWAS) have identified many risk loci for complex diseases, but effect sizes are typically small and information on the underlying biological processes is often lacking. Associations with metabolic traits as functional intermediates can overcome these problems and potentially inform individualized therapy. Here we report a comprehensive analysis of genotype-dependent metabolic phenotypes using a GWAS with non-targeted metabolomics. We identified 37 genetic loci associated with blood metabolite concentrations, of which 25 show effect sizes that are unusually high for GWAS and account for 10-60% differences in metabolite levels per allele copy. Our associations provide new functional insights for many disease-related associations that have been reported in previous studies, including those for cardiovascular and kidney disorders, type 2 diabetes, cancer, gout, venous thromboembolism and Crohn's disease. The study advances our knowledge of the genetic basis of metabolic individuality in humans and generates many new hypotheses for biomedical and pharmaceutical research.
View details for DOI 10.1038/nature10354
View details for Web of Science ID 000294404300029
View details for PubMedID 21886157
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Large-Scale Gene-Centric Analysis Identifies Novel Variants for Coronary Artery Disease
PLOS GENETICS
2011; 7 (9)
Abstract
Coronary artery disease (CAD) has a significant genetic contribution that is incompletely characterized. To complement genome-wide association (GWA) studies, we conducted a large and systematic candidate gene study of CAD susceptibility, including analysis of many uncommon and functional variants. We examined 49,094 genetic variants in ∼2,100 genes of cardiovascular relevance, using a customised gene array in 15,596 CAD cases and 34,992 controls (11,202 cases and 30,733 controls of European descent; 4,394 cases and 4,259 controls of South Asian origin). We attempted to replicate putative novel associations in an additional 17,121 CAD cases and 40,473 controls. Potential mechanisms through which the novel variants could affect CAD risk were explored through association tests with vascular risk factors and gene expression. We confirmed associations of several previously known CAD susceptibility loci (eg, 9p21.3:p<10(-33); LPA:p<10(-19); 1p13.3:p<10(-17)) as well as three recently discovered loci (COL4A1/COL4A2, ZC3HC1, CYP17A1:p<5×10(-7)). However, we found essentially null results for most previously suggested CAD candidate genes. In our replication study of 24 promising common variants, we identified novel associations of variants in or near LIPA, IL5, TRIB1, and ABCG5/ABCG8, with per-allele odds ratios for CAD risk with each of the novel variants ranging from 1.06-1.09. Associations with variants at LIPA, TRIB1, and ABCG5/ABCG8 were supported by gene expression data or effects on lipid levels. Apart from the previously reported variants in LPA, none of the other ∼4,500 low frequency and functional variants showed a strong effect. Associations in South Asians did not differ appreciably from those in Europeans, except for 9p21.3 (per-allele odds ratio: 1.14 versus 1.27 respectively; P for heterogeneity = 0.003). This large-scale gene-centric analysis has identified several novel genes for CAD that relate to diverse biochemical and cellular functions and clarified the literature with regard to many previously suggested genes.
View details for DOI 10.1371/journal.pgen.1002260
View details for Web of Science ID 000295419100015
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Low lifetime recreational activity is a risk factor for peripheral arterial disease
JOURNAL OF VASCULAR SURGERY
2011; 54 (2): 427-432
Abstract
The relationship between lifetime physical activity and the risk of developing peripheral arterial disease (PAD) is not known.We studied 1381 patients referred for elective coronary angiography in a point prevalence analysis. PAD was defined as ankle-brachial index (ABI) <0.9 at the time or a history of revascularization of the lower extremities regardless of ABI measure. We used a validated physical activity questionnaire to retrospectively measure each patient's lifetime recreational activity (LRA). Multivariate and logistic regression analyses were used to assess the independent association of LRA to ABI and the presence of PAD.PAD was present in 19% (n = 258) of all subjects. Subjects reporting no regular LRA had greater diastolic blood pressure and were more likely to be female. They had lower average ABI, and a higher proportion had PAD (25.6%). In a regression model, including traditional risk factors and LRA, multivariate analysis showed that age (P < .001), female gender (P < .001), systolic blood pressure (P = .014), fasting glucose (P < .001), serum triglycerides (P = .02), and cumulative pack years (P < .001) were independent negative predictors of ABI, and LRA was a positive predictor of ABI (P < .001). History of sedentary lifestyle independently increased the odds ratio for PAD (odds ratio, 0.46; 95% confidence interval, 1.01-2.10) when assessed by logistic regression. Intriguingly, there is a correlation between physical activity and gender, such that women with low LRA are at greatest risk.Recalled LRA is positively correlated to ABI and associated with PAD. Whereas the mechanism for this effect is not clear, LRA may be a useful clinical screening tool for PAD risk, and strategies to increase adult recreational activity may reduce the burden of PAD later in life.
View details for DOI 10.1016/j.jvs.2011.02.052
View details for Web of Science ID 000293814400025
View details for PubMedID 21664093
View details for PubMedCentralID PMC3152670
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A Bivariate Genome-Wide Approach to Metabolic Syndrome STAMPEED Consortium
DIABETES
2011; 60 (4): 1329-1339
Abstract
OBJECTIVE The metabolic syndrome (MetS) is defined as concomitant disorders of lipid and glucose metabolism, central obesity, and high blood pressure, with an increased risk of type 2 diabetes and cardiovascular disease. This study tests whether common genetic variants with pleiotropic effects account for some of the correlated architecture among five metabolic phenotypes that define MetS. RESEARCH DESIGN AND METHODS Seven studies of the STAMPEED consortium, comprising 22,161 participants of European ancestry, underwent genome-wide association analyses of metabolic traits using a panel of ∼2.5 million imputed single nucleotide polymorphisms (SNPs). Phenotypes were defined by the National Cholesterol Education Program (NCEP) criteria for MetS in pairwise combinations. Individuals exceeding the NCEP thresholds for both traits of a pair were considered affected. RESULTS Twenty-nine common variants were associated with MetS or a pair of traits. Variants in the genes LPL, CETP, APOA5 (and its cluster), GCKR (and its cluster), LIPC, TRIB1, LOC100128354/MTNR1B, ABCB11, and LOC100129150 were further tested for their association with individual qualitative and quantitative traits. None of the 16 top SNPs (one per gene) associated simultaneously with more than two individual traits. Of them 11 variants showed nominal associations with MetS per se. The effects of 16 top SNPs on the quantitative traits were relatively small, together explaining from ∼9% of the variance in triglycerides, 5.8% of high-density lipoprotein cholesterol, 3.6% of fasting glucose, and 1.4% of systolic blood pressure. CONCLUSIONS Qualitative and quantitative pleiotropic tests on pairs of traits indicate that a small portion of the covariation in these traits can be explained by the reported common genetic variants.
View details for DOI 10.2337/db10-1011
View details for Web of Science ID 000289496100029
View details for PubMedID 21386085
View details for PubMedCentralID PMC3064107
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Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease
NATURE GENETICS
2011; 43 (4): 333-U153
Abstract
We performed a meta-analysis of 14 genome-wide association studies of coronary artery disease (CAD) comprising 22,233 individuals with CAD (cases) and 64,762 controls of European descent followed by genotyping of top association signals in 56,682 additional individuals. This analysis identified 13 loci newly associated with CAD at P < 5 × 10⁻⁸ and confirmed the association of 10 of 12 previously reported CAD loci. The 13 new loci showed risk allele frequencies ranging from 0.13 to 0.91 and were associated with a 6% to 17% increase in the risk of CAD per allele. Notably, only three of the new loci showed significant association with traditional CAD risk factors and the majority lie in gene regions not previously implicated in the pathogenesis of CAD. Finally, five of the new CAD risk loci appear to have pleiotropic effects, showing strong association with various other human diseases or traits.
View details for DOI 10.1038/ng.784
View details for Web of Science ID 000288903700013
View details for PubMedID 21378990
View details for PubMedCentralID PMC3119261
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Genome-Wide Association Analysis Identifies Variants Associated with Nonalcoholic Fatty Liver Disease That Have Distinct Effects on Metabolic Traits
PLOS GENETICS
2011; 7 (3)
Abstract
Nonalcoholic fatty liver disease (NAFLD) clusters in families, but the only known common genetic variants influencing risk are near PNPLA3. We sought to identify additional genetic variants influencing NAFLD using genome-wide association (GWA) analysis of computed tomography (CT) measured hepatic steatosis, a non-invasive measure of NAFLD, in large population based samples. Using variance components methods, we show that CT hepatic steatosis is heritable (∼26%-27%) in family-based Amish, Family Heart, and Framingham Heart Studies (n = 880 to 3,070). By carrying out a fixed-effects meta-analysis of genome-wide association (GWA) results between CT hepatic steatosis and ∼2.4 million imputed or genotyped SNPs in 7,176 individuals from the Old Order Amish, Age, Gene/Environment Susceptibility-Reykjavik study (AGES), Family Heart, and Framingham Heart Studies, we identify variants associated at genome-wide significant levels (p<5×10(-8)) in or near PNPLA3, NCAN, and PPP1R3B. We genotype these and 42 other top CT hepatic steatosis-associated SNPs in 592 subjects with biopsy-proven NAFLD from the NASH Clinical Research Network (NASH CRN). In comparisons with 1,405 healthy controls from the Myocardial Genetics Consortium (MIGen), we observe significant associations with histologic NAFLD at variants in or near NCAN, GCKR, LYPLAL1, and PNPLA3, but not PPP1R3B. Variants at these five loci exhibit distinct patterns of association with serum lipids, as well as glycemic and anthropometric traits. We identify common genetic variants influencing CT-assessed steatosis and risk of NAFLD. Hepatic steatosis associated variants are not uniformly associated with NASH/fibrosis or result in abnormalities in serum lipids or glycemic and anthropometric traits, suggesting genetic heterogeneity in the pathways influencing these traits.
View details for DOI 10.1371/journal.pgen.1001324
View details for Web of Science ID 000288996600006
View details for PubMedID 21423719
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Family History of Heart Disease The Re-Emergence of a Traditional Risk Factor
JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
2011; 57 (5): 628-629
View details for DOI 10.1016/j.jacc.2010.09.036
View details for Web of Science ID 000286622400015
View details for PubMedID 21272755
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Identification of ADAMTS7 as a novel locus for coronary atherosclerosis and association of ABO with myocardial infarction in the presence of coronary atherosclerosis: two genome-wide association studies
LANCET
2011; 377 (9763): 383-392
Abstract
We tested whether genetic factors distinctly contribute to either development of coronary atherosclerosis or, specifically, to myocardial infarction in existing coronary atherosclerosis.We did two genome-wide association studies (GWAS) with coronary angiographic phenotyping in participants of European ancestry. To identify loci that predispose to angiographic coronary artery disease (CAD), we compared individuals who had this disorder (n=12,393) with those who did not (controls, n=7383). To identify loci that predispose to myocardial infarction, we compared patients who had angiographic CAD and myocardial infarction (n=5783) with those who had angiographic CAD but no myocardial infarction (n=3644).In the comparison of patients with angiographic CAD versus controls, we identified a novel locus, ADAMTS7 (p=4·98×10(-13)). In the comparison of patients with angiographic CAD who had myocardial infarction versus those with angiographic CAD but no myocardial infarction, we identified a novel association at the ABO locus (p=7·62×10(-9)). The ABO association was attributable to the glycotransferase-deficient enzyme that encodes the ABO blood group O phenotype previously proposed to protect against myocardial infarction.Our findings indicate that specific genetic predispositions promote the development of coronary atherosclerosis whereas others lead to myocardial infarction in the presence of coronary atherosclerosis. The relation to specific CAD phenotypes might modify how novel loci are applied in personalised risk assessment and used in the development of novel therapies for CAD.The PennCath and MedStar studies were supported by the Cardiovascular Institute of the University of Pennsylvania, by the MedStar Health Research Institute at Washington Hospital Center and by a research grant from GlaxoSmithKline. The funding and support for the other cohorts contributing to the paper are described in the webappendix.
View details for DOI 10.1016/S0140-6736(10)61996-4
View details for Web of Science ID 000287337000028
View details for PubMedID 21239051
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Sex differences in the prevalence of peripheral artery disease in patients undergoing coronary catheterization
VASCULAR MEDICINE
2010; 15 (6): 443-450
Abstract
To determine whether there are sex differences in the prevalence of peripheral artery disease, we performed an observational study of 1014 men and 547 women, aged ≥ 40 years, referred for elective coronary angiography. Women were slightly older, more obese, had higher low-density lipoprotein cholesterol (LDL-C) levels and systolic blood pressure (BP), and were more likely to be African American. Women had higher high-density lipoprotein cholesterol (HDL-C) levels, lower diastolic BP, and were less likely to smoke or to have a history of cardiovascular disease. Women had less prevalent (62% vs 81%) and less severe coronary artery disease (CAD) (p < 0.001 for both) by coronary angiography, but more prevalent peripheral artery disease (PAD) as determined by the ankle-brachial index (ABI) than men (23.6% versus 17.2%). Independent predictors of lower ABI were female sex, black race, older age, tobacco use, CAD, diabetes, and triglyceride level. In a full multivariable logistic regression model, women had a risk-adjusted odds ratio for PAD of 1.78 (95% CI 1.25-2.54) relative to men. Among patients referred for coronary angiography, women have less prevalent and less severe CAD, but more prevalent PAD, a sex difference that is not explained by traditional cardiovascular disease risk factors or CAD severity. Clinical Trial Registration-URL: http://clinicaltrials.gov. Unique identifier: NCT00380185.
View details for DOI 10.1177/1358863X10388345
View details for Web of Science ID 000285574400002
View details for PubMedID 21183651
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Genetics of Coronary Atherosclerotic Plaque Rupture and Myocardial Infarction
LIPPINCOTT WILLIAMS & WILKINS. 2010
View details for Web of Science ID 000208231601546
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Lack of Association Between the Trp719Arg Polymorphism in Kinesin-Like Protein-6 and Coronary Artery Disease in 19 Case-Control Studies
JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY
2010; 56 (19): 1552-1563
Abstract
We sought to replicate the association between the kinesin-like protein 6 (KIF6) Trp719Arg polymorphism (rs20455), and clinical coronary artery disease (CAD).Recent prospective studies suggest that carriers of the 719Arg allele in KIF6 are at increased risk of clinical CAD compared with noncarriers.The KIF6 Trp719Arg polymorphism (rs20455) was genotyped in 19 case-control studies of nonfatal CAD either as part of a genome-wide association study or in a formal attempt to replicate the initial positive reports.A total of 17,000 cases and 39,369 controls of European descent as well as a modest number of South Asians, African Americans, Hispanics, East Asians, and admixed cases and controls were successfully genotyped. None of the 19 studies demonstrated an increased risk of CAD in carriers of the 719Arg allele compared with noncarriers. Regression analyses and fixed-effects meta-analyses ruled out with high degree of confidence an increase of ≥2% in the risk of CAD among European 719Arg carriers. We also observed no increase in the risk of CAD among 719Arg carriers in the subset of Europeans with early-onset disease (younger than 50 years of age for men and younger than 60 years of age for women) compared with similarly aged controls as well as all non-European subgroups.The KIF6 Trp719Arg polymorphism was not associated with the risk of clinical CAD in this large replication study.
View details for DOI 10.1016/j.jacc.2010.06.022
View details for PubMedID 20933357
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Meta-analysis identifies 13 new loci associated with waist-hip ratio and reveals sexual dimorphism in the genetic basis of fat distribution
NATURE GENETICS
2010; 42 (11): 949-U160
Abstract
Waist-hip ratio (WHR) is a measure of body fat distribution and a predictor of metabolic consequences independent of overall adiposity. WHR is heritable, but few genetic variants influencing this trait have been identified. We conducted a meta-analysis of 32 genome-wide association studies for WHR adjusted for body mass index (comprising up to 77,167 participants), following up 16 loci in an additional 29 studies (comprising up to 113,636 subjects). We identified 13 new loci in or near RSPO3, VEGFA, TBX15-WARS2, NFE2L3, GRB14, DNM3-PIGC, ITPR2-SSPN, LY86, HOXC13, ADAMTS9, ZNRF3-KREMEN1, NISCH-STAB1 and CPEB4 (P = 1.9 × 10⁻⁹ to P = 1.8 × 10⁻⁴⁰) and the known signal at LYPLAL1. Seven of these loci exhibited marked sexual dimorphism, all with a stronger effect on WHR in women than men (P for sex difference = 1.9 × 10⁻³ to P = 1.2 × 10⁻¹³). These findings provide evidence for multiple loci that modulate body fat distribution independent of overall adiposity and reveal strong gene-by-sex interactions.
View details for DOI 10.1038/ng.685
View details for Web of Science ID 000283540500011
View details for PubMedID 20935629
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Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index
NATURE GENETICS
2010; 42 (11): 937-U53
Abstract
Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and ∼ 2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 × 10⁻⁸), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation.
View details for DOI 10.1038/ng.686
View details for Web of Science ID 000283540500010
View details for PubMedID 20935630
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Hundreds of variants clustered in genomic loci and biological pathways affect human height
NATURE
2010; 467 (7317): 832-838
Abstract
Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.
View details for DOI 10.1038/nature09410
View details for Web of Science ID 000282898700065
View details for PubMedID 20881960
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Design of the Coronary ARtery DIsease Genome-Wide Replication And Meta-Analysis (CARDIoGRAM) Study A Genome-Wide Association Meta-analysis Involving More Than 22 000 Cases and 60 000 Controls
CIRCULATION-CARDIOVASCULAR GENETICS
2010; 3 (5): 475-U186
Abstract
Recent genome-wide association studies (GWAS) of myocardial infarction (MI) and other forms of coronary artery disease (CAD) have led to the discovery of at least 13 genetic loci. In addition to the effect size, power to detect associations is largely driven by sample size. Therefore, to maximize the chance of finding novel susceptibility loci for CAD and MI, the Coronary ARtery DIsease Genome-wide Replication And Meta-analysis (CARDIoGRAM) consortium was formed.CARDIoGRAM combines data from all published and several unpublished GWAS in individuals with European ancestry; includes >22 000 cases with CAD, MI, or both and >60 000 controls; and unifies samples from the Atherosclerotic Disease VAscular functioN and genetiC Epidemiology study, CADomics, Cohorts for Heart and Aging Research in Genomic Epidemiology, deCODE, the German Myocardial Infarction Family Studies I, II, and III, Ludwigshafen Risk and Cardiovascular Heath Study/AtheroRemo, MedStar, Myocardial Infarction Genetics Consortium, Ottawa Heart Genomics Study, PennCath, and the Wellcome Trust Case Control Consortium. Genotyping was carried out on Affymetrix or Illumina platforms followed by imputation of genotypes in most studies. On average, 2.2 million single nucleotide polymorphisms were generated per study. The results from each study are combined using meta-analysis. As proof of principle, we meta-analyzed risk variants at 9p21 and found that rs1333049 confers a 29% increase in risk for MI per copy (P=2×10⁻²⁰).CARDIoGRAM is poised to contribute to our understanding of the role of common genetic variation on risk for CAD and MI.
View details for DOI 10.1161/CIRCGENETICS.109.899443
View details for Web of Science ID 000283163100012
View details for PubMedID 20923989
View details for PubMedCentralID PMC3070269
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Call to Action: Cardiovascular Disease in Asian Americans A Science Advisory From the American Heart Association
CIRCULATION
2010; 122 (12): 1242-1252
View details for DOI 10.1161/CIR.0b013e3181f22af4
View details for Web of Science ID 000282042100014
View details for PubMedID 20733105
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Biological, clinical and population relevance of 95 loci for blood lipids
NATURE
2010; 466 (7307): 707-713
Abstract
Plasma concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with plasma lipids in >100,000 individuals of European ancestry. Here we report 95 significantly associated loci (P < 5 x 10(-8)), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (for example, CYP7A1, NPC1L1 and SCARB1) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and have an impact on lipid traits in three non-European populations (East Asians, South Asians and African Americans). Our results identify several novel loci associated with plasma lipids that are also associated with CAD. Finally, we validated three of the novel genes-GALNT2, PPP1R3B and TTC39B-with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD.
View details for DOI 10.1038/nature09270
View details for Web of Science ID 000280562500029
View details for PubMedID 20686565
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An "Almost Exhaustive" Search-Based Sequential Permutation Method for Detecting Epistasis in Disease Association Studies
GENETIC EPIDEMIOLOGY
2010; 34 (5): 434-443
Abstract
Due to the complex nature of common diseases, their etiology is likely to involve "uncommon but strong" (UBS) interactive effects--i.e. allelic combinations that are each present in only a small fraction of the patients but associated with high disease risk. However, the identification of such effects using standard methods for testing association can be difficult. In this work, we introduce a method for testing interactions that is particularly powerful in detecting UBS effects. The method consists of two modules--one is a pattern counting algorithm designed for efficiently evaluating the risk significance of each marker combination, and the other is a sequential permutation scheme for multiple testing correction. We demonstrate the work of our method using a candidate gene data set for cardiovascular and coronary diseases with an injected UBS three-locus interaction. In addition, we investigate the power and false rejection properties of our method using data sets simulated from a joint dominance three-locus model that gives rise to UBS interactive effects. The results show that our method can be much more powerful than standard approaches such as trend test and multifactor dimensionality reduction for detecting UBS interactions.
View details for DOI 10.1002/gepi.20496
View details for Web of Science ID 000280349600007
View details for PubMedID 20583286
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Detailed Physiologic Characterization Reveals Diverse Mechanisms for Novel Genetic Loci Regulating Glucose and Insulin Metabolism in Humans
59th Annual Meeting of the American-Society-of-Human-Genetics
AMER DIABETES ASSOC. 2010: 1266–75
Abstract
OBJECTIVE Recent genome-wide association studies have revealed loci associated with glucose and insulin-related traits. We aimed to characterize 19 such loci using detailed measures of insulin processing, secretion, and sensitivity to help elucidate their role in regulation of glucose control, insulin secretion and/or action. RESEARCH DESIGN AND METHODS We investigated associations of loci identified by the Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) with circulating proinsulin, measures of insulin secretion and sensitivity from oral glucose tolerance tests (OGTTs), euglycemic clamps, insulin suppression tests, or frequently sampled intravenous glucose tolerance tests in nondiabetic humans (n = 29,084). RESULTS The glucose-raising allele in MADD was associated with abnormal insulin processing (a dramatic effect on higher proinsulin levels, but no association with insulinogenic index) at extremely persuasive levels of statistical significance (P = 2.1 x 10(-71)). Defects in insulin processing and insulin secretion were seen in glucose-raising allele carriers at TCF7L2, SCL30A8, GIPR, and C2CD4B. Abnormalities in early insulin secretion were suggested in glucose-raising allele carriers at MTNR1B, GCK, FADS1, DGKB, and PROX1 (lower insulinogenic index; no association with proinsulin or insulin sensitivity). Two loci previously associated with fasting insulin (GCKR and IGF1) were associated with OGTT-derived insulin sensitivity indices in a consistent direction. CONCLUSIONS Genetic loci identified through their effect on hyperglycemia and/or hyperinsulinemia demonstrate considerable heterogeneity in associations with measures of insulin processing, secretion, and sensitivity. Our findings emphasize the importance of detailed physiological characterization of such loci for improved understanding of pathways associated with alterations in glucose homeostasis and eventually type 2 diabetes.
View details for DOI 10.2337/DB09-1568
View details for Web of Science ID 000277554700019
View details for PubMedID 20185807
View details for PubMedCentralID PMC2857908
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Genome-wide meta-analyses identify multiple loci associated with smoking behavior
NATURE GENETICS
2010; 42 (5): 441-U134
Abstract
Consistent but indirect evidence has implicated genetic factors in smoking behavior. We report meta-analyses of several smoking phenotypes within cohorts of the Tobacco and Genetics Consortium (n = 74,053). We also partnered with the European Network of Genetic and Genomic Epidemiology (ENGAGE) and Oxford-GlaxoSmithKline (Ox-GSK) consortia to follow up the 15 most significant regions (n > 140,000). We identified three loci associated with number of cigarettes smoked per day. The strongest association was a synonymous 15q25 SNP in the nicotinic receptor gene CHRNA3 (rs1051730[A], beta = 1.03, standard error (s.e.) = 0.053, P = 2.8 x 10(-73)). Two 10q25 SNPs (rs1329650[G], beta = 0.367, s.e. = 0.059, P = 5.7 x 10(-10); and rs1028936[A], beta = 0.446, s.e. = 0.074, P = 1.3 x 10(-9)) and one 9q13 SNP in EGLN2 (rs3733829[G], beta = 0.333, s.e. = 0.058, P = 1.0 x 10(-8)) also exceeded genome-wide significance for cigarettes per day. For smoking initiation, eight SNPs exceeded genome-wide significance, with the strongest association at a nonsynonymous SNP in BDNF on chromosome 11 (rs6265[C], odds ratio (OR) = 1.06, 95% confidence interval (Cl) 1.04-1.08, P = 1.8 x 10(-8)). One SNP located near DBH on chromosome 9 (rs3025343[G], OR = 1.12, 95% Cl 1.08-1.18, P = 3.6 x 10(-8)) was significantly associated with smoking cessation.
View details for DOI 10.1038/ng.571
View details for Web of Science ID 000277179500017
View details for PubMedID 20418890
View details for PubMedCentralID PMC2914600
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Use of venlafaxine compared with other antidepressants and the risk of sudden cardiac death or near death: a nested case-control study
BRITISH MEDICAL JOURNAL
2010; 340
Abstract
To assess whether use of the antidepressant venlafaxine is associated with an increased risk of sudden cardiac death or near death compared with other commonly used antidepressants.Population based observational study.We did a nested case-control analysis within a new user cohort formed using the United Kingdom General Practice Research Database.New users of venlafaxine, fluoxetine, citalopram, or dosulepin on or after 1 January 1995, aged 18 to 89 years, with a diagnosis of depression or anxiety. Participants were followed-up until February 2005, or the occurrence of sudden cardiac death or near death, identified from medical records indicating non-fatal acute ventricular tachyarrhythmia, sudden death due to cardiac causes, or out of hospital deaths from acute ischaemic cardiac events. For each case, 30 controls were selected matched for age, sex, calendar time, and indication. We used conditional logistic regression to calculate the adjusted odds ratio of sudden cardiac death or near death associated with current use of venlafaxine compared with current use of fluoxetine, citalopram or dosulepin.207 384 participants were followed-up for an average of 3.3 years. There were 568 cases of sudden cardiac death or near death, which were matched to 14 812 controls. The adjusted odds ratio of sudden cardiac death or near death associated with venlafaxine use was 0.66 (95% confidence interval 0.38 to 1.14) relative to fluoxetine use, whereas compared with citalopram it was 0.89 (0.50 to 1.60) and with dosulepin 0.83 (0.46 to 1.52).In this large, population based study, the use of venlafaxine was not associated with an excess risk of sudden cardiac death or near death compared with fluoxetine, dosulepin, or citalopram, in patients with depression or anxiety.
View details for DOI 10.1136/bmj.c249
View details for Web of Science ID 000274343700003
View details for PubMedID 20139216
View details for PubMedCentralID PMC2817047
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Age at incident treatment of hypertension and risk of cancer: a population study
CANCER CAUSES & CONTROL
2009; 20 (10): 1811-1820
Abstract
To determine the effect of treated hypertension on the risk of cancer.Population based external comparison study using the Saskatchewan Health databases.A total of 42,270 subjects were followed for a median of 17.9 years after initiating antihypertensives for hypertension. The effect of hypertension on the risk of cancer varied significantly by age (interaction p < 0.001). Compared with the general population, subjects under 60 years at the time of initiation of antihypertensives had a significantly increased risk of cancer (RR 1.34, 95% CI 1.18–1.52 adjusted for age, sex, and calendar year) while subjects over 60 had a significantly decreased risk (RR 0.88, 95% CI 0.78–0.98). Similar results were obtained for cancer death outcomes. In each subgroup, relative risks across most cancer sites were similar in magnitude and direction. Results were essentially unchanged when analyses were restricted to cancers diagnosed after the first 10 years of follow-up.The effect of treated hypertension on cancer risk varies by the age at incident treatment of hypertension.These findings are not a result of reverse causality or detection bias. However, they may in part be a consequence of residual confounding and/or reflect the type of hypertension being treated.
View details for DOI 10.1007/s10552-009-9374-3
View details for Web of Science ID 000271809000003
View details for PubMedID 19533392
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Characterizing the admixed African ancestry of African Americans
GENOME BIOLOGY
2009; 10 (12)
Abstract
Accurate, high-throughput genotyping allows the fine characterization of genetic ancestry. Here we applied recently developed statistical and computational techniques to the question of African ancestry in African Americans by using data on more than 450,000 single-nucleotide polymorphisms (SNPs) genotyped in 94 Africans of diverse geographic origins included in the HGDP, as well as 136 African Americans and 38 European Americans participating in the Atherosclerotic Disease Vascular Function and Genetic Epidemiology (ADVANCE) study. To focus on African ancestry, we reduced the data to include only those genotypes in each African American determined statistically to be African in origin.From cluster analysis, we found that all the African Americans are admixed in their African components of ancestry, with the majority contributions being from West and West-Central Africa, and only modest variation in these African-ancestry proportions among individuals. Furthermore, by principal components analysis, we found little evidence of genetic structure within the African component of ancestry in African Americans.These results are consistent with historic mating patterns among African Americans that are largely uncorrelated to African ancestral origins, and they cast doubt on the general utility of mtDNA or Y-chromosome markers alone to delineate the full African ancestry of African Americans. Our results also indicate that the genetic architecture of African Americans is distinct from that of Africans, and that the greatest source of potential genetic stratification bias in case-control studies of African Americans derives from the proportion of European ancestry.
View details for DOI 10.1186/gb-2009-10-12-r141
View details for Web of Science ID 000274289000011
View details for PubMedID 20025784
View details for PubMedCentralID PMC2812948
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Digital ischemia
JOURNAL OF CARDIOVASCULAR MEDICINE
2008; 9 (12): 1285-1286
Abstract
In this report, we describe the case of a 43-year-old mechanic who presented with very painful, numb, and cold left middle and fourth fingers. The diagnosis of the hypothenar hammer syndrome was made by history, physical examination, and characteristic findings on diagnostic imaging. This syndrome often goes unrecognized by physicians yet rapid recognition and treatment are crucial to avoid permanent injury. As the differential diagnosis for isolated digital ischemia is broad, physicians need to remain aware of this rare acquired vascular disorder, especially in susceptible patients.
View details for DOI 10.2459/JCM.0b013e3283168d50
View details for Web of Science ID 000261209200017
View details for PubMedID 19001942
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Long-term use of antihypertensive drugs and risk of cancer
PHARMACOEPIDEMIOLOGY AND DRUG SAFETY
2008; 17 (11): 1039-1049
Abstract
Determine the relative risk of cancer users of commonly prescribed antihypertensive drugs with a focus on documenting risk in long-term users (>7.5 years).We conducted a nested case-control study using the Saskatchewan Health databases. Cancer risks in users of beta-blockers, calcium channel blockers (CCBs), and rennin-angiotensin system inhibitors (RASIs), respectively, were compared to risks in users of thiazide diuretics.A total of 11,697 first cases of cancer and the subset of 6918 subjects who died from cancer were each matched to 10 controls. The mean total duration of use of the four classes of antihypertensive drugs (estimated by dispensation of prescriptions) ranged from 3.6 to 5.7 years. A subgroup of cases was exposed long term (mean total duration of use: 9.7-11.4 years, range: 7.5-23.1 years). Modest differences in risk between users of the four classes were detected for colon, head & neck, lung, and hematological cancers but none of these associations demonstrated a clear dose response relationship for both first cancer and fatal cancer. Otherwise, for cancer at all sites combined and for the four most common cancers, we were able to rule out, with reasonable confidence, small to modest differences in the risk of cancer among users of any duration (upper 95% confidence intervals (CIs): 1.45) and modest to large differences in risk among long-term users (upper 95%CI: 3.06).The long-term use of commonly prescribed classes of antihypertensive drugs does not appear to promote or initiate cancer.
View details for DOI 10.1002/pds.1656
View details for Web of Science ID 000261011600001
View details for PubMedID 18780400
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Sax Differences In Peripheral Arterial Disease
81st Annual Scientific Session of the American-Heart-Association
LIPPINCOTT WILLIAMS & WILKINS. 2008: S811–S811
View details for Web of Science ID 000262104502719
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Susceptibility locus for clinical and subclinical coronary artery disease at chromosome 9p21 in the multi-ethnic ADVANCE study
HUMAN MOLECULAR GENETICS
2008; 17 (15): 2320-2328
Abstract
A susceptibility locus for coronary artery disease (CAD) at chromosome 9p21 has recently been reported, which may influence the age of onset of CAD. We sought to replicate these findings among white subjects and to examine whether these results are consistent with other racial/ethnic groups by genotyping three single nucleotide polymorphisms (SNPs) in the risk interval in the Atherosclerotic Disease, Vascular Function, and Genetic Epidemiology (ADVANCE) study. One or more of these SNPs was associated with clinical CAD in whites, U.S. Hispanics and U.S. East Asians. None of the SNPs were associated with CAD in African Americans although the power to detect an odds ratio (OR) in this group equivalent to that seen in whites was only 24-30%. ORs were higher in Hispanics and East Asians and lower in African Americans, but in all groups the 95% confidence intervals overlapped with ORs observed in whites. High-risk alleles were also associated with increased coronary artery calcification in controls and the magnitude of these associations by racial/ethnic group closely mirrored the magnitude observed for clinical CAD. Unexpectedly, we noted significant genotype frequency differences between male and female cases (P = 0.003-0.05). Consequently, men tended towards a recessive and women tended towards a dominant mode of inheritance. Finally, an effect of genotype on the age of onset of CAD was detected but only in men carrying two versus one or no copy of the high-risk allele and presenting with CAD at age >50 years. Further investigations in other populations are needed to confirm or refute our findings.
View details for DOI 10.1093/hmg/ddn132
View details for Web of Science ID 000257788300007
View details for PubMedID 18443000
View details for PubMedCentralID PMC2733811
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A near null variant of 12/15-LOX encoded by a novel SNP in ALOX15 and the risk of coronary artery disease
ATHEROSCLEROSIS
2008; 198 (1): 136-144
Abstract
Murine genetic models suggest that function of the 12/15-LOX enzyme promotes atherosclerosis. We tested the hypothesis that exonic and/or promoter single nucleotide polymorphisms (SNPs) in the human 12/15-LOX gene (ALOX15) alter the risk of symptomatic coronary artery disease (CAD).We resequenced ALOX15 and then genotyped a common promoter and a less common novel coding SNP (T560M) in 1809 subjects with CAD and 1734 controls from Kaiser Permanente including a subset of participants of the Coronary Artery Risk Development in Young Adults study. We found no association between the promoter SNP and the risk of CAD. However, heterozygote carriers of the 560M allele had an increased risk of CAD (adjusted OR, 1.62; P=0.02) compared to non-carriers. In vitro studies demonstrated a 20-fold reduction in the catalytic activity of 560M when compared to 560T. We then genotyped T560M in 12,974 participants of the Atherosclerosis Risk in Communities study and similarly found that heterozygote carriers had an increased risk of CAD compared to non-carriers (adjusted HR, 1.31; P=0.06). In both population studies, homozygote carriers were rare and associated with a non-significant decreased risk of CAD compared to non-carriers (adjusted OR, 0.55; P=0.63 and HR, 0.93; P=0.9).A coding SNP in ALOX15 (T560M) results in a near null variant of human 12/15-LOX. Assuming a co-dominant mode of inheritance, this variant does not protect against CAD. Assuming a recessive mode of inheritance, the effect of this mutation remains unclear, but is unlikely to provide a protective effect to the degree suggested by mouse knockout studies.
View details for DOI 10.1016/j.atheroscierosis.2007.09.003
View details for Web of Science ID 000255491800016
View details for PubMedID 17959182
View details for PubMedCentralID PMC2440699
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Common polymorphisms of ALOX5 and ALOX5AP and risk of coronary artery disease
HUMAN GENETICS
2008; 123 (4): 399-408
Abstract
Recent human genetic studies suggest that allelic variants of leukotriene pathway genes influence the risk of clinical and subclinical atherosclerosis. We sequenced the promoter, exonic, and splice site regions of ALOX5 and ALOX5AP and then genotyped 7 SNPs in ALOX5 and 6 SNPs in ALOX5AP in 1,552 cases with clinically significant coronary artery disease (CAD) and 1,583 controls from Kaiser Permanente including a subset of participants of the coronary artery risk development in young adults study. A nominally significant association was detected between a promoter SNP in ALOX5 (rs12762303) and CAD in our subset of white/European subjects (adjusted odds ratio per minor allele, log-additive model, 1.32; P = 0.002). In this race/ethnic group, rs12762303 has a minor allele frequency of 15% and is tightly linked to variation at the SP1 variable tandem repeat promoter polymorphism. However, the association between CAD and rs12762303 could not be reproduced in the atherosclerosis risk in communities study (hazard rate ratio per minor allele; 1.08, P = 0.1). Assuming a recessive mode of inheritance, the association was not significant in either population study but our power to detect modest effects was limited. No significant associations were observed between all other SNPs and the risk of CAD. Overall, our findings do not support a link between common allelic variation in or near ALOX5 or ALOX5AP and the risk of CAD. However, additional studies are needed to exclude modest effects of promoter variation in ALOX5 on the risk of CAD assuming a recessive mode of inheritance.
View details for DOI 10.1007/s00439-008-0489-5
View details for Web of Science ID 000254959600008
View details for PubMedID 18369664
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Failure to replicate an association of SNPs in the oxidized LDL receptor gene (OLRI) with CAD
BMC MEDICAL GENETICS
2008; 9
Abstract
The lectin-like oxidized LDL receptor LOX-1 (encoded by OLR1) is believed to play a key role in atherogenesis and some reports suggest an association of OLR1 polymorphisms with myocardial infarction (MI). We tested whether single nucleotide polymorphisms (SNPs) in OLR1 are associated with clinically significant CAD in the Atherosclerotic Disease, VAscular FuNction, & Geneti C Epidemiology (ADVANCE) study.ADVANCE is a population-based case-control study of subjects receiving care within Kaiser Permanente of Northern California including a subset of participants of the Coronary Artery Risk Development in Young Adults (CARDIA) study. We first resequenced the promoter, exonic, and splice site regions of OLR1 and then genotyped four single nucleotide polymorphisms (SNPs), including a non-synonymous SNP (rs11053646, Lys167Asn) as well as an intronic SNP (rs3736232) previously associated with CAD.In 1,809 cases with clinical CAD and 1,734 controls, the minor allele of the coding SNP was nominally associated with a lower odds ratio (OR) of CAD across all ethnic groups studied (minimally adjusted OR 0.8, P = 0.007; fully adjusted OR 0.8, P = 0.01). The intronic SNP was nominally associated with an increased risk of CAD (minimally adjusted OR 1.12, p = 0.03; fully adjusted OR 1.13, P = 0.03). However, these associations were not replicated in over 13,200 individuals (including 1,470 cases) in the Atherosclerosis Risk in Communities (ARIC) study.Our results do not support the presence of an association between selected common SNPs in OLR1 and the risk of clinical CAD.
View details for DOI 10.1186/1471-2350-9-23
View details for Web of Science ID 000255652400001
View details for PubMedID 18384690
View details for PubMedCentralID PMC2322963
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Associations Among Multiple Markers and Complex Disease: Models, Algorithms, and Applications
GENETIC DISSECTION OF COMPLEX TRAITS, 2ND EDITION
2008; 60: 437-464
Abstract
This chapter is a report on collaborations among its authors and others over many years. It devolves from our goal of understanding genes, their main and epistatic effects combined with interactions involving demographic and environmental features also, as together they predict genetically complex diseases. Thus, our goal is "association." Particular phenotypes of interest to us are hypertension, insulin resistance, angina, and myocardial infarction. Prediction of complex disease is notoriously difficult, though it would be made easier were we given strand-specific information on genotype. Unfortunately, with current technology, genotypic information comes to us "unphased." While obviously we have strand-specific information when genotype is homozygous, we do not have such information when genotype is heterozygous. To summarize, the ultimate goals of approaches we provide is to predict phenotype, typically untoward or not, within a specific window of time. Our approach is neither through linkage nor from finding haplotype frequencies per se.
View details for DOI 10.1016/S0065-2660(07)00416-6
View details for Web of Science ID 000280575900018
View details for PubMedID 18358329
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Polymorphisms in hypoxia inducible factor 1 and the initial clinical presentation of coronary disease
AMERICAN HEART JOURNAL
2007; 154 (6): 1035-1042
Abstract
Only some patients with coronary artery disease (CAD) develop acute myocardial infarction (MI), and emerging evidence suggests vulnerability to MI varies systematically among patients and may have a genetic component. The goal of this study was to assess whether polymorphisms in genes encoding elements of pathways mediating the response to ischemia affect vulnerability to MI among patients with underlying CAD.We prospectively identified patients at the time of their initial clinical presentation of CAD who had either an acute MI or stable exertional angina. We collected clinical data and genotyped 34 polymorphisms in 6 genes (ANGPT1, HIF1A, THBS1, VEGFA, VEGFC, VEGFR2).The 909 patients with acute MI were significantly more likely than the 466 patients with stable angina to be male, current smokers, and hypertensive, and less likely to be taking beta-blockers or statins. Three polymorphisms in HIF1A (Pro582Ser, rs11549465; rs1087314; and Thr418Ile, rs41508050) were significantly more common in patients who presented with stable exertional angina rather than acute MI, even after statistical adjustment for cardiac risk factors and medications. The HIF-mediated transcriptional activity was significantly lower when HIF1A null fibroblasts were transfected with variant HIF1A alleles than with wild-type HIF1A alleles.Polymorphisms in HIF1A were associated with development of stable exertional angina rather than acute MI as the initial clinical presentation of CAD.
View details for DOI 10.1016/j.ahj.2007.07.042
View details for Web of Science ID 000251396200006
View details for PubMedID 18035072
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Circulating chemokines accurately identify individuals with clinically significant atherosclerotic heart disease
PHYSIOLOGICAL GENOMICS
2007; 31 (3): 402-409
Abstract
Serum inflammatory markers correlate with outcome and response to therapy in subjects with cardiovascular disease. However, current individual markers lack specificity for the diagnosis of coronary artery disease (CAD). We hypothesize that a multimarker proteomic approach measuring serum levels of vascular derived inflammatory biomarkers could reveal a "signature of disease" that can serve as a highly accurate method to assess for the presence of coronary atherosclerosis. We simultaneously measured serum levels of seven chemokines [CXCL10 (IP-10), CCL11 (eotaxin), CCL3 (MIP1 alpha), CCL2 (MCP1), CCL8 (MCP2), CCL7 (MCP3), and CCL13 (MCP4)] in 48 subjects with clinically significant CAD ("cases") and 44 controls from the ADVANCE Study. We applied three classification algorithms to identify the combination of variables that would best predict case-control status and assessed the diagnostic performance of these models with receiver operating characteristic (ROC) curves. The serum levels of six chemokines were significantly higher in cases compared with controls (P < 0.05). All three classification algorithms entered three chemokines in their final model, and only logistic regression selected clinical variables. Logistic regression produced the highest ROC of the three algorithms (AUC = 0.95; SE = 0.03), which was markedly better than the AUC for the logistic regression model of traditional risk factors of CAD without (AUC = 0.67; SE = 0.06) or with CRP (AUC = 0.68; SE = 0.06). A combination of serum levels of multiple chemokines identifies subjects with clinically significant atherosclerotic heart disease with a very high degree of accuracy. These results need to be replicated in larger cross-sectional studies and their prognostic value explored.
View details for DOI 10.1152/physiolgenomics.00104.2007
View details for Web of Science ID 000251780600005
View details for PubMedID 17698927
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Genetic susceptibility to peripheral arterial disease: A dark corner in vascular biology
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
2007; 27 (10): 2068-2078
Abstract
Peripheral arterial disease (PAD) is characterized by reduced blood flow to the limbs, usually as a consequence of atherosclerosis, and affects approximately 12 million Americans. It is a common cause of cardiovascular morbidity and an independent predictor of cardiovascular mortality. Similar to other atherosclerotic diseases, such as coronary artery disease, PAD is the result of the complex interplay between injurious environmental stimuli and genetic predisposing factors of the host. Genetic susceptibility to PAD is likely contributed by sequence variants in multiple genes, each with modest effects. Although many of these variants probably alter susceptibility both to PAD and to coronary artery disease, it is likely that there exists a set of variants specifically to alter susceptibility to PAD. Despite the prevalence of PAD and its high societal burden, relatively little is known about such genetic variants. This review summarizes our limited present knowledge and gives an overview of recent, more powerful approaches to elucidating the genetic basis of PAD. We discuss the advantages and limitations of genetic studies and highlight the need for collaborative networks of PAD investigators for shedding light on this dark corner of vascular biology.
View details for DOI 10.1161/01.ATV.0000282199.66398.8c
View details for Web of Science ID 000249587000002
View details for PubMedID 17656669
View details for PubMedCentralID PMC4321902
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Heritability of left ventricular mass in Japanese families living in Hawaii: the SAPPHIRe Study
JOURNAL OF HYPERTENSION
2007; 25 (5): 985-992
Abstract
Established determinants of left ventricular (LV) mass explain only a modest fraction of its variability. Family studies to date suggest that a proportion of the unexplained variability can be accounted for by additive polygenic effects. An estimate of this proportion has not been reported previously in an East Asian population. The objective of this study was to estimate the heritability of LV mass in Japanese families living in Hawaii.We analyzed data by components of variance in a sample of 169 hypertensive families (n = 476 subjects) and, separately, in a population-based sample of 256 families (n = 501 subjects) participating in the Honolulu Heart Program.In multivariate models, established predictors of LV mass explained about half the total variance of LV mass. Using SOLAR, our estimates of the narrow sense heritability of LV mass ranged from 42.5% (SE 9.8, P < 0.0001) in our sample of hypertensive families to 60.6% (SE 11.7, P < 0.0001) in our population-based sample of families. Parametric bootstrap analyses confirmed that the inference for each sample was appropriate.Assuming the absence of shared familial environmental effects, close to half of the unexplained variance of LV mass in Japanese subjects living in Hawaii is genetic in nature. This estimate was observed in two independent samples. Therefore, the pursuit of novel genetic determinants of LV mass through either whole genome or candidate gene association studies of this population may be worthwhile. Such studies are certainly feasible.
View details for Web of Science ID 000245741200015
View details for PubMedID 17414662
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Does left ventricular mass differ between apparently normal adults of different ethnicities? The family blood pressure program
47th Annual Conference on Cardiovascular Disease Epidemiology and Prevention
LIPPINCOTT WILLIAMS & WILKINS. 2007: E288–E288
View details for Web of Science ID 000244482200370
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Plasma asymmetric dimethylarginine is an independent marker of peripheral artery disease but not coronary artery disease: A novel marker of atherosclerosis with topographical specificity
79th Annual Scientific Session of the American-Heart-Association
LIPPINCOTT WILLIAMS & WILKINS. 2006: 775–76
View details for Web of Science ID 000241792805111
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Plasma asymmetric dimethylarginine is an independent marker for the presence and severity of peripheral artery disease
55th Annual Scientific Session of the American-College-of-Cardiology
ELSEVIER SCIENCE INC. 2006: 294A–294A
View details for Web of Science ID 000235530402070
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Cardiac outcomes occurred more frequently with PCI than CABG or medical therapy in coronary artery disease.
ACP journal club
2004; 141 (3): 57-?
View details for PubMedID 15518441
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Inhaled corticosteroid use in asthma and the prevention of myocardial infarction
AMERICAN JOURNAL OF MEDICINE
2003; 115 (5): 377-381
Abstract
Asthma patients may be at increased risk of cardiovascular outcomes due to hypoxemia from asthma exacerbations and bronchodilator-induced tachycardia. We investigated whether inhaled corticosteroids, which are known to improve asthma control and reduce exacerbations, are associated with a lower rate of myocardial infarction.We used the Saskatchewan Health databases to form a population-based cohort of subjects aged 5 to 44 years who were using antiasthma drugs between 1975 and 1991. Subjects were followed until 1997, the age of 55 years, or death. A nested case-control approach was used where each subject with a first myocardial infarction was matched on calendar time, age, and sex with up to 10 controls randomly selected from the cohort.The cohort consisted of 30,569 subjects, including 105 patients with myocardial infarction who were matched with 933 controls. The adjusted rate ratio of myocardial infarction for inhaled corticosteroid use during the year before the index date was 0.56 (95% confidence interval [CI]: 0.32 to 0.99) as compared with no use. Myocardial infarction decreased by 12% (95% CI: 0% to 23%) with each additional canister used during this 1-year period. The rate ratio of myocardial infarction for inhaled corticosteroid use was 0.78 (95% CI: 0.41 to 1.51) among patients with milder asthma and 0.19 (95% CI: 0.04 to 0.97) among those with more severe asthma.Inhaled corticosteroid use may reduce the risk of myocardial infarction in asthma patients, particularly those with more severe disease.
View details for DOI 10.1016/S0002-9343(03)00393-0
View details for Web of Science ID 000185776400006
View details for PubMedID 14553873
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Inhaled short acting beta agonist use in COPD and the risk of acute myocardial infarction
THORAX
2003; 58 (1): 43-46
Abstract
A recent study found that short acting beta agonists used in the treatment of asthma and chronic obstructive pulmonary disease (COPD) may increase the risk of acute myocardial infarction. We investigated this hypothesis in patients with COPD already at high risk of cardiac disease.The Saskatchewan Health Services databases were used to form a population based cohort of all patients newly diagnosed with COPD over the age of 55 years identified between 1980 and 1997. All subjects were followed up until 1999, death, or the first occurrence of acute myocardial infarction. Those with a first acute myocardial infarction, fatal or non-fatal, were matched on calendar time and age with cohort members.The cohort consisted of 12 090 subjects including 1127 cases with fatal or non-fatal acute myocardial infarction. The adjusted rate ratio for current use of inhaled beta agonists was 1.12 (95% confidence interval (CI) 0.95 to 1.33), and for first time use it was 1.02 (95% CI 0.52 to 2.00). There was also no significant increase in risk when the analysis was restricted to subjects with cardiac risk factors such as hypertension and diabetes, or to subjects not having been prescribed beta blocker medications.Short acting inhaled beta agonist use among patients with COPD does not appear to increase the risk of fatal or non-fatal acute myocardial infarction.
View details for Web of Science ID 000180487700008
View details for PubMedID 12511719
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The use of perioperative corticosteroids in craniomaxillofacial surgery
PLASTIC AND RECONSTRUCTIVE SURGERY
1999; 103 (1): 313-321
Abstract
A literature search could not identify a study on the prevalence of the use of perioperative corticosteroids by surgeons performing craniomaxillofacial surgery. To gather this information, we conducted a survey of North American members of the American Society of Maxillofacial Surgeons classified as "active" in the society's roster. The first 90 members in forward and reverse alphabetical order who were capable of receiving a fax transmission were faxed our survey. Sixty surgeons responded, for a response rate of 66.7 percent. Twenty-eight (46.7 percent) reported using short-term, high-dose, perioperative corticosteroids to control postsurgical inflammation. Surgeons performing facial aesthetic surgery alone or in addition to craniomaxillofacial surgery were more likely to be using steroids (Fisher's exact test, p = 0.038). A variety of steroid drugs and regimens were cited by steroid users. The most common reason for using steroids was to decrease edema. Thirty-two (53.3 percent) responders reported that they were not using steroids. The most common reason for not using them was a lack of literature to support their effectiveness. All responders were asked to report any complications encountered with the use of steroids. The majority (78.3 percent) reported no complications. The most common complication encountered was euphoria (13.3 percent). No one reported the occurrence of avascular necrosis of the hip or humerus with the use of steroids. Based on a literature review, an analysis of the steroid regimens and complications reported revealed that steroid use was generally safe. Nevertheless, in addition to the traditional steroid contraindications, consideration should be given to withholding steroids in patients with any of the known risk factors for avascular necrosis, in patients who are or recently have been on nonsteroidal anti-inflammatory drugs, and in aspirin-sensitive asthmatics. These patients may be at increased risk for serious adverse effects with the use of steroids. More research is required to objectively measure the effect of steroids on edema and, if beneficial, to determine the optimal drug regimen.
View details for Web of Science ID 000077707200050
View details for PubMedID 9915196
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Torsade de pointes with sotalol overdose treated successfully with lidocaine
CANADIAN JOURNAL OF CARDIOLOGY
1998; 14 (5): 753-756
Abstract
Torsade de pointes is a polymorphic ventricular tachyarrhythmia associated with a long QT interval. The prognosis is excellent if torsade is recognized early. In the acquired long QT syndrome, measures should be taken quickly to identify and correct all predisposing conditions and to treat or prevent torsade. Established treatments of acquired torsade are magnesium bolus, electrolyte replacement, isoproterenol infusion and cardiac pacing. Sotalol overdose causing torsade is reported in which lidocaine appears to have suppressed an episode of torsade as well as prevented further episodes. Current understanding of the electrophysiological mechanisms of torsade and lidocaine, a review of the literature and the author's experience indicate that lidocaine is a potentially useful therapy in torsade.
View details for Web of Science ID 000074005600021
View details for PubMedID 9627533