The fundamental theme of my work is the application of genetics to improve human health. I view this as a continuum from Discovery -> to the development of Model Systems -> to clinical Translation -> to larger Public Health efforts. Much of my work focuses on discovery of genetic variants underlying cardiovascular disease, particularly coronary disease and insulin resistance through large international studies. We are now creating human induced pluripotent stem cell (iPSC) lines to model the genetic networks that produce disease. We are translating these findings to the clinic in a randomized trial where we are asking if we can improve an individual’s risk by giving them information about their inherited risk of heart disease. Finally, as the Chief Medical Advisor for a patient-led, non-profit (The FH Foundation, www.thefhfoundation.org), we are attempting to raise the profile of familial hypercholesterolemia (FH), an inherited disease that causes extremely elevated LDL cholesterol levels and risk of coronary disease. We have partnered with patients and organizations like the CDC, ACC and AHA to increase public health awareness of FH and have recently launched a national patient registry called “CASCADE FH”.
- Insulin Resistance
- Familial Hypercholesterolemia
- Cardiomyopathy, Hypertrophic
- Cardiovascular Disease
Chief Medical Advisor, The FH Foundation (2012 - Present)
Honors & Awards
National Innovative Research Award, AHA
Dean's Fellowship, Stanford (2005)
Clinical Scholar, Doris Duke Charitable Foundation (6/1/16-6/1/19)
Fellowship Award, Future Leaders in CV Medicine (2006)
Alderman Award for Excellence in Clinical Research, Stanford Cardiovascular Medicine (2008, 2009)
Diplomate, National Lipid Association (2012)
Fellow, AHA (2012)
Fellow, ACC (2012)
National Fellow to Faculty Transition Award, AHA (7/1/10-7/1/15)
Boards, Advisory Committees, Professional Organizations
Board Member, The FH Foundation (2012 - Present)
Board Certification: Cardiovascular Disease, American Board of Internal Medicine (2010)
Fellowship:Stanford University School of Medicine (2010) CA
Residency:Stanford University School of Medicine (2005) CA
Medical Education:University of North Carolina - Chapel Hill (2003) NC
PhD, University of North Carolina, Chapel Hill, Genetics and Molecular Biology (2001)
Community and International Work
The FH Foundation
The FH Foundation
Opportunities for Student Involvement
Arbor Free Clinic
Opportunities for Student Involvement
Current Research and Scholarly Interests
The overall theme of my work is to understand the genetic basis of complex cardiovascular diseases such as coronary disease and insulin resistance. Currently, I am involved in genome wide association (GWA) studies of coronary disease through the NIH-funded ADVANCE study and of insulin resistance through the international GENESIS project. After using the GWA approach to discover and validate interesting candidate genes, I hope to explore the biology underlying these genes and pathways using cell culture and in vivo model systems. I am also using iPSC technology (induced pluripotent stem cells) to develop model systems for the study of insulin resistance through the NIH-funded GENESiPS project.
I also have a strong interest in developing tools to help translate newly emerging genetic data into clinical practice and am currently the PI of a randomized trial where we are examining whether we can improve patient coronary disease risk factor profiles by giving them information about their inherited risk of coronary disease.
Clinically, I am interested in the care of patients with inherited cardiovascular conditions. In particular I am focused on individuals with Familial Hypercholesterolemia. I also have an interest in treating Hypertrophic Cardiomyopathy. I take care of these patients in the Stanford Center for Inherited Cardiovascular Disease.
The role of registries and genetic databases in familial hypercholesterolemia.
Current opinion in lipidology
2017; 28 (2): 152-160
To review how leveraging familial hypercholesterolemia registries can impact molecular genetic research and precision medicine.Familial hypercholesterolemia is both much more common and more phenotypically heterogeneous than previously thought with some evidence for significant genotype to phenotype correlations. Genetic testing for familial hypercholesterolemia is becoming both more widely available and cheaper, spurring conversations about its clinical utility.In most countries, familial hypercholesterolemia is underdiagnosed and diagnosed later in life, often after the onset of coronary heart disease (CHD). Familial hypercholesterolemia is undertreated; low goal attainment and additional modifiable risk factors further increase CHD risk. Familial hypercholesterolemia epitomizes the goal of precision medicine to define a subset of individuals with a high risk of morbidity and mortality through genetic diagnosis to manage and treat the risk accordingly. Genetic cascade screening can be used to identify familial hypercholesterolemia patients at a younger age and start timely treatment to prevent CHD. Familial hypercholesterolemia registries are tools for clinical research and improving healthcare planning and patient care. As genotype and phenotype correlations in familial hypercholesterolemia become increasingly understood, this information will likely play a more important role in diagnosis and treatment especially as the cost of genetic testing continues to decline.
View details for DOI 10.1097/MOL.0000000000000398
View details for PubMedID 28169870
Use of high-intensity statins for patients with atherosclerotic cardiovascular disease in the Veterans Affairs Health System: Practice impact of the new cholesterol guidelines
AMERICAN HEART JOURNAL
2016; 182: 97-102
The November 2013 American College of Cardiology/American Heart Association cholesterol guidelines recommend the use of high-intensity statins for patients with atherosclerotic cardiovascular disease (ASCVD). We sought to determine how these guidelines are being adopted at the Veterans Affairs (VA) Health System and identify treatment gaps.We examined administrative data from the VA 12 months prior to the index dates of April 1, 2013, and after April 1, 2014, to identify patients ≤75 years of age with ≥2 codes for ASCVD. We identified those on high-intensity statin therapy (atorvastatin 40 mg or 80 mg, rosuvastatin 20 mg or 40 mg, and simvastatin 80 mg) during the 6 months after the index date.The study sample included 331,927 and 326,759 eligible adults with ASCVD before and after the release of the new guidelines, respectively. Overall, high-intensity statin use increased from 28% to 35% after guideline release. High-intensity statin use was lowest in Hispanics and Native Americans, although all groups showed an increase over time. Among those on low- or moderate-intensity statin therapy, 15.6% were intensified to a high-intensity statin after guideline release. Groups less likely to undergo statin intensification were older adults (odds ratio=0.78 for each 10-year increase, 95% CI 0.76-0.81), women (odds ratio=0.86, 95% CI 0.75-0.99), and certain minority groups. Academic teaching hospitals and hospitals on the West Coast were more likely to intensify statins after release of the new guidelines.High-intensity statin use increased in the VA following release of the American College of Cardiology/American Heart Association cholesterol treatment guidelines, although disparities persist for certain patient groups including older adults, women, and certain minority groups.
View details for DOI 10.1016/j.ahj.2016.09.007
View details for Web of Science ID 000389136600012
View details for PubMedID 27914506
Novel Therapies for Familial Hypercholesterolemia.
Current treatment options in cardiovascular medicine
2016; 18 (11): 64-?
Both HeFH and HoFH require dietary and lifestyle modification. Pharmacotherapy of adult HeFH patients is largely driven by the American Heart Association (AHA) algorithm. A high-potency statin is started initially with a goal low-density lipoprotein cholesterol (LDL-C) reduction of >50 %. The LDL-C target is adjusted to <100 or <70 mg/dL in subjects with coronary artery disease (CAD) with ezetimibe being second line. If necessary, a third adjunctive therapy, such as a PSCK9 inhibitor (not yet approved in children) or bile acid-binding resin, can be added. Finally, LDL-C apheresis can be considered in patients with LDL-C >300 mg/dL (or >200 mg/dL with significant CAD, although now approved for LDL-C as low as 160 mg/dL with CAD). Due to the early, severe LDL-C elevation in HoFH patients, concerning natural history, rarity of the condition, and nuances of treatment, all HoFH patients should be treated at a pediatric or adult center with HoFH experience. LDL-C apheresis should be considered as early as 5 years of age. However, apheresis availability and tolerability is limited and pharmacotherapy is required. Generally, the AHA algorithm with reference to the European Atherosclerosis Society Consensus Panel recommendations is reasonable with all patients initiated on high-dose, high-potency statin, ezetimibe, and bile acid-binding resins. In most, additional LDL-C lowering is required with PCSK9 inhibitors and/or lomitapide or mipomersen. Liver transplantation can also be considered at experienced centers as a last resort.
View details for DOI 10.1007/s11936-016-0486-2
View details for PubMedID 27620638
Metabolic Markers to Predict Incident Diabetes Mellitus in Statin-Treated Patients (from the Treating to New Targets and the Stroke Prevention by Aggressive Reduction in Cholesterol Levels Trials).
American journal of cardiology
2016; 118 (9): 1275-1281
The goal of this analysis was to evaluate the ability of insulin resistance, identified by the presence of prediabetes mellitus (PreDM) combined with either an elevated triglyceride (TG >1.7 mmol/l) or body mass index (BMI ≥27.0 kg/m(2)), to identify increased risk of statin-associated type 2 diabetes mellitus (T2DM). Consequently, a retrospective analysis of data from subjects without diabetes in the Treating to New Targets and the Stroke Prevention by Aggressive Reduction in Cholesterol Levels randomized controlled trials was performed, subdividing participants into 4 experimental groups: (1) normal fasting glucose (NFG) and TG ≤1.7 mmol/l (42%); (2) NFG and TG >1.7 mmol/l (22%); (3) PreDM and TG ≤1.7 mmol/l (20%); and (4) PreDM and TG >1.7 mmol/l (15%). Comparable groupings were created substituting BMI values (kg/m(2) <27.0 and ≥27.0) for TG concentrations. Patients received atorvastatin or placebo for a median duration of 4.9 years. Incident T2DM, defined by developing at least 2 fasting plasma glucose (FPG) concentrations ≥126 mg/dl, an increase in FPG ≥37 mg/dl, or a clinical diagnosis of T2DM, was observed in 8.2% of the total population. T2DM event rates (statin or placebo) varied from a low of 2.8%/3.2% (NFG and TG ≤1.7 mmol/l) to a high of 22.8%/7.6% (PreDM and TG >1.7 mmol/l) with intermediate values for only an elevated TG >1.7 mmol/l (5.2%/4.3%) or only PreDM (12.8%/7.6%). Comparable differences were observed when BMI values were substituted for TG concentrations. In conclusion, these data suggest that (1) the diabetogenic impact of statin treatment is relatively modest in general; (2) the diabetogenic impact is accentuated relatively dramatically as FPG and TG concentrations and BMI increase; and (3) PreDM, TG concentrations, and BMI identify people at highest risk of statin-associated T2DM.
View details for DOI 10.1016/j.amjcard.2016.07.054
View details for PubMedID 27614854
Nat1 Deficiency Is Associated with Mitochondrial Dysfunction and Exercise Intolerance in Mice
2016; 17 (2): 527-540
We recently identified human N-acetyltransferase 2 (NAT2) as an insulin resistance (IR) gene. Here, we examine the cellular mechanism linking NAT2 to IR and find that Nat1 (mouse ortholog of NAT2) is co-regulated with key mitochondrial genes. RNAi-mediated silencing of Nat1 led to mitochondrial dysfunction characterized by increased intracellular reactive oxygen species and mitochondrial fragmentation as well as decreased mitochondrial membrane potential, biogenesis, mass, cellular respiration, and ATP generation. These effects were consistent in 3T3-L1 adipocytes, C2C12 myoblasts, and in tissues from Nat1-deficient mice, including white adipose tissue, heart, and skeletal muscle. Nat1-deficient mice had changes in plasma metabolites and lipids consistent with a decreased ability to utilize fats for energy and a decrease in basal metabolic rate and exercise capacity without altered thermogenesis. Collectively, our results suggest that Nat1 deficiency results in mitochondrial dysfunction, which may constitute a mechanistic link between this gene and IR.
View details for DOI 10.1016/j.celrep.2016.09.005
View details for Web of Science ID 000385850700019
View details for PubMedID 27705799
US physician practices for diagnosing familial hypercholesterolemia: data from the CASCADE-FH registry
JOURNAL OF CLINICAL LIPIDOLOGY
2016; 10 (5): 1223-1229
In the US familial hypercholesterolemia (FH), patients are underidentified, despite an estimated prevalence of 1:200 to 1:500. Criteria to identify FH patients include Simon Broome, Dutch Lipid Clinic Network (DLCN), or Make Early Diagnosis to Prevent Early Deaths (MEDPED). The use of these criteria in US clinical practices remains unclear.To characterize the FH diagnostic criteria applied by US lipid specialists participating in the FH Foundation's CASCADE FH (CAscade SCreening for Awareness and DEtection of Familial Hypercholesterolemia) patient registry.We performed an observational, cross-sectional analysis of diagnostic criteria chosen for each adult patient, both overall and by baseline patient characteristics, at 15 clinical sites that had contributed data to the registry as of September 8, 2015. A sample of 1867 FH adults was analyzed. The median age at FH diagnosis was 50 years, and the median pretreatment low-density lipoprotein cholesterol (LDL-C) value was 238 mg/dL. The main outcome was the diagnostic criteria chosen. Diagnostic criteria were divided into five nonexclusive categories: "clinical diagnosis," MEDPED, Simon Broome, DLCN, and other.Most adults enrolled in CASCADE FH (55.0%) received a "clinical diagnosis." The most commonly used formal criteria was Simon-Broome only (21%), followed by multiple diagnostic criteria (16%), MEDPED only (7%), DLCN only (1%), and other (0.5%), P < .0001. Of the patients with only a "clinical diagnosis," 93% would have met criteria for Simon Broome, DLCN, or MEDPED based on the data available in the registry.Our findings demonstrate heterogeneity in the application of FH diagnostic criteria in the United States. A nationwide consensus definition may lead to better identification, earlier treatment, and ultimately CHD prevention.
View details for DOI 10.1016/j.jac1.2016.07.011
View details for Web of Science ID 000385903700021
View details for PubMedID 27678440
Hypertriglyceridemia: A simple approach to identify insulin resistance and enhanced cardio-metabolic risk in patients with prediabetes.
Diabetes research and clinical practice
2016; 120: 156-161
Prediabetes (PreDM) is a metabolically heterogeneous condition, differing in degree of insulin resistance and risk of type 2 diabetes mellitus and coronary heart disease (CHD). This study was initiated to evaluate the hypothesis that a fasting plasma triglyceride (TG) concentration ⩾1.7mmol/L can aid in identifying the subset of individuals with PreDM who are most insulin resistant and at greatest risk to develop CHD as well as type 2 diabetes mellitus.In this cross-sectional study, measurements were made of: (1) steady-state plasma glucose (SSPG) concentration during the insulin suppression test to ascertain degree of insulin resistance and (2) conventional CHD risk factors in 587 apparently healthy individuals with normal fasting plasma glucose (NFG, n=370) or PreDM (n=217).Subjects with PreDM were significantly (P<0.001) more insulin resistant (higher SSPG concentrations) and had a more adverse CHD risk profile than those with NFG. A TG concentration ⩾1.7mmol/L identified a subset of individuals with PreDM (38%) who had a higher mean SSPG concentration (11.3±3.5mmol/L vs. 9.3±3.9mmol/L, P<0.001), were more likely to be insulin resistant (66% vs. 39%, P<0.001), and had a more adverse CHD risk factor profile.Measurement of fasting TG concentration in individuals with PreDM may provide a simple clinical approach to identify those who are insulin resistant, at enhanced risk of CHD, and more likely to develop type 2 diabetes mellitus.
View details for DOI 10.1016/j.diabres.2016.07.024
View details for PubMedID 27565692
Treatment Gaps in Adults With Heterozygous Familial Hypercholesterolemia in the United States Data From the CASCADE-FH Registry
2016; 9 (3): 240-?
Cardiovascular disease burden and treatment patterns among patients with familial hypercholesterolemia (FH) in the United States remain poorly described. In 2013, the FH Foundation launched the Cascade Screening for Awareness and Detection (CASCADE) of FH Registry to address this knowledge gap.We conducted a cross-sectional analysis of 1295 adults with heterozygous FH enrolled in the CASCADE-FH Registry from 11 US lipid clinics. Median age at initiation of lipid-lowering therapy was 39 years, and median age at FH diagnosis was 47 years. Prevalent coronary heart disease was reported in 36% of patients, and 61% exhibited 1 or more modifiable risk factors. Median untreated low-density lipoprotein cholesterol (LDL-C) was 239 mg/dL. At enrollment, median LDL-C was 141 mg/dL; 42% of patients were taking high-intensity statin therapy and 45% received >1 LDL-lowering medication. Among FH patients receiving LDL-lowering medication(s), 25% achieved an LDL-C <100 mg/dL and 41% achieved a ≥50% LDL-C reduction. Factors associated with prevalent coronary heart disease included diabetes mellitus (adjusted odds ratio 1.74; 95% confidence interval 1.08-2.82) and hypertension (2.48; 1.92-3.21). Factors associated with a ≥50% LDL-C reduction from untreated levels included high-intensity statin use (7.33; 1.86-28.86) and use of >1 LDL-lowering medication (1.80; 1.34-2.41).FH patients in the CASCADE-FH Registry are diagnosed late in life and often do not achieve adequate LDL-C lowering, despite a high prevalence of coronary heart disease and risk factors. These findings highlight the need for earlier diagnosis of FH and initiation of lipid-lowering therapy, more consistent use of guideline-recommended LDL-lowering therapy, and comprehensive management of traditional coronary heart disease risk factors.
View details for DOI 10.1161/CIRCGENETICS.116.001381
View details for Web of Science ID 000378133100007
View details for PubMedID 27013694
Human induced pluripotent stem cell-derived cardiomyocytes recapitulate the predilection of breast cancer patients to doxorubicin-induced cardiotoxicity
2016; 22 (5): 547-556
Doxorubicin is an anthracycline chemotherapy agent effective in treating a wide range of malignancies, but it causes a dose-related cardiotoxicity that can lead to heart failure in a subset of patients. At present, it is not possible to predict which patients will be affected by doxorubicin-induced cardiotoxicity (DIC). Here we demonstrate that patient-specific human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) can recapitulate the predilection to DIC of individual patients at the cellular level. hiPSC-CMs derived from individuals with breast cancer who experienced DIC were consistently more sensitive to doxorubicin toxicity than hiPSC-CMs from patients who did not experience DIC, with decreased cell viability, impaired mitochondrial and metabolic function, impaired calcium handling, decreased antioxidant pathway activity, and increased reactive oxygen species production. Taken together, our data indicate that hiPSC-CMs are a suitable platform to identify and characterize the genetic basis and molecular mechanisms of DIC.
View details for DOI 10.1038/nm.4087
View details for Web of Science ID 000375514000018
View details for PubMedID 27089514
Impact of Septal Reduction on Left Atrial Size and Diastole in Hypertrophic Cardiomyopathy
ECHOCARDIOGRAPHY-A JOURNAL OF CARDIOVASCULAR ULTRASOUND AND ALLIED TECHNIQUES
2016; 33 (5): 686-694
Both myectomy and alcohol septal ablation (ASA) can substantially reduce left ventricular (LV) outflow obstruction, relieve symptoms, and improve outcomes in hypertrophic cardiomyopathy (HCM). It is unclear whether septal reduction decreases left atrial (LA) size and improves diastolic function. The aim of this study was to analyze the consequences of septal reduction on LA size and diastolic function in a cohort of patients with HCM.Forty patients (mean age: 50 ± 14, male sex 64%) with HCM who underwent septal reduction (myectomy or alcohol septal ablation) were studied. Retrospective analyses of echocardiograms preprocedure, postprocedure, and at 1 year of follow-up were performed.Thirty-one patients had septal myectomy and 9 ASA. The degree of reduction in rest peak LV outflow tract gradient was significant (57 ± 32 vs. 23 ± 20 mmHg at 1 year, P < 0.001). Maximal interventricular septal thickness decreased from 22 ± 6 mm preprocedure to 19 ± 4 mm postprocedure (P < 0.001); moderate-to-severe mitral regurgitation (MR) was initially present in 34% of the sample and only 2% after the procedure. Average LA volume index (LAVI) decreased from 63 ± 20 to 55 ± 20 mL/m(2) at the 1-year follow-up (P < 0.001). We did not observe a significant improvement in diastolic function at Doppler (E/A 1.2 ± 0.4 vs. 1.1 ± 0.5, P = 0.07; E' 7.6 ± 3.6 vs. 6.9 ± 3.0, P = 0.4) pre- and postprocedure, respectively). At 1 year, only 5% of the patients were severely symptomatic (NYHA III). On multivariate analysis, a significant change in the LVOT gradient during stress (Δ gradient ≥30 mmHg) was the only variable independently associated with LAVI reverse remodeling >10 mL/m(2) [OR = 6.4 (CI 95% 1.12-36.44), P = 0.04].Septal reduction is effective in the relief of LV obstruction and symptoms in patients with HCM. The hemodynamic changes result in a significant LA reverse remodeling, but not in an improvement of diastolic function in these patients.
View details for DOI 10.1111/echo.13158
View details for Web of Science ID 000375933100004
View details for PubMedID 26926154
Cardiometabolic Effects of Glucagon-Like Peptide-1 Agonists.
Current atherosclerosis reports
2016; 18 (2): 7-?
Cardiovascular disease is the leading cause of death among adults in the USA. Both type 1 (T1DM) and type 2 diabetes mellitus (T2DM) are known risk factors for cardiovascular disease. Despite the development of numerous effective anti-glycemic therapies, we have been unable to completely mitigate cardiovascular risk with glucose lowering alone, and prevention of cardiovascular disease in patients with diabetes is primarily achieved with the use of medications that address other risk factors such as anti-hypertensives or statins. Glucagon-like peptide-1 (GLP-1) is a key hormone in the pathophysiology of diabetes. GLP-1 agonists have been recently approved for the treatment of T2DM as well as for chronic weight management. In this review, we aim to explore the effects of GLP-1 agonists on cardiovascular health with a focus on cardiometabolic variables and cardiac function.
View details for DOI 10.1007/s11883-016-0558-5
View details for PubMedID 26782825
- Maternal Midpregnancy Glucose Levels and Risk of Congenital Heart Disease in Offspring JAMA PEDIATRICS 2015; 169 (12): 1112-1116
Familial Hypercholesterolemia and the 2013 American College of Cardiology/American Heart Association Guidelines: Myths, Oversimplification, and Misinterpretation Versus Facts
AMERICAN JOURNAL OF CARDIOLOGY
2015; 116 (3): 481-484
Familial hypercholesterolemia (FH) is a genetic condition resulting in severe, lifelong elevations in low-density lipoprotein cholesterol and a marked increased risk of early-onset coronary disease. FH is treatable when identified, yet is vastly under-recognized and undertreated. Although the 2013 American College of Cardiology/American Heart Association guidelines on the treatment of cholesterol presented a paradigm shift, we believe that there have been serious oversimplifications, misinterpretations, and erroneous reporting about the current ACC/AHA cholesterol guidelines that have contributed to suboptimal care for these subjects. In summary, the ACC/AHA guidelines place tremendous emphasis on the identification of patients with FH, the initiation of high-intensity statin therapy, the need to obtain follow-up lipid values to assess the efficacy and compliance to lifestyle and medical therapy, and the role of nonstatin drugs when needed for optimal care of the individual patient.
View details for Web of Science ID 000359034100024
View details for PubMedID 26043952
Using Genetic Variants to Assess the Relationship Between Circulating Lipids and Type 2 Diabetes
2015; 64 (7): 2676-2684
The effects of dyslipidemia on the risk of type 2 diabetes (T2D) and related traits are not clear. We used regression models and 140 lipid-associated genetic variants to estimate associations between circulating HDL cholesterol (HDL-C), LDL cholesterol (LDL-C), and triglycerides and T2D and related traits. Each genetic test was corrected for effects of variants on the other two lipid types and surrogates of adiposity. We used the largest data sets available: 34,840 T2D case and 114,981 control subjects from the DIAGRAM (DIAbetes Genetics Replication And Meta-analysis) consortium and up to 133,010 individuals without diabetes for insulin secretion and sensitivity from the MAGIC (Meta-Analyses of Glucose and Insulin-related traits Consortium) and GENESIS (GENEticS of Insulin Sensitivity) studies. Eight of 21 associations between groups of variants and diabetes traits were significant at the nominal level, including those between genetically determined lower HDL-C (β = -0.12, P = 0.03) and T2D and genetically determined lower LDL-C (β = -0.21, P = 5 × 10(-6)) and T2D. Although some of these may represent causal associations, we discuss why caution must be used when using Mendelian randomization in the context of circulating lipid levels and diabetes traits. In conclusion, we found evidence of links between genetic variants associated with lipids and T2D, but deeper knowledge of the underlying genetic mechanisms of specific lipid variants is needed before drawing definite conclusions about causality based on Mendelian randomization methodology.
View details for DOI 10.2337/db14-1710
View details for Web of Science ID 000356934000049
View details for PubMedID 25948681
- Systematic Comparison of Digital Electrocardiograms From Healthy Athletes and Patients With Hypertrophic Cardiomyopathy. Journal of the American College of Cardiology 2015; 65 (22): 2462-2463
Prevalence and Prognostic Role of Right Ventricular Involvement in Stress-Induced Cardiomyopathy
JOURNAL OF CARDIAC FAILURE
2015; 21 (5): 419-425
Stress-induced cardiomyopathy (SCM) is a reversible cardiomyopathy observed in patients without significant coronary disease. The aim of this study was to assess the incidence and clinical significance of right ventricular (RV) involvement in SCM.We retrospectively analyzed echocardiograms from 40 consecutive patients who presented with SCM at Stanford University Medical Center from September 2000 to November 2010. The primary end point was overall mortality. RV involvement was observed in 20 patients (50%; global RV hypokinesia in 15 patients and focal RV apical akinesia in 5 patients). The independent correlates of RV involvement were older age (odds ratio [OR] 1.09, 95% confidence interval [CI] 1.02-1.7two, P = .01) and LVEF (per 10% decrease: OR 3.60, CI 1.77-7.32; P = .02). At a mean follow-up of 44 ± 32 months, 12 patients (30%) died (in-hospital death in 3 patients). At multivariate analysis, the presence of an RV fractional area change <35% emerged as an independent predictor of death (OR 3.6, CI 1.06-12.41; P = .04).RV involvement is a common finding in SCM, and may present as either global or focal RV apical involvement. Both older age and lower LVEF are associated with a higher risk of RV involvement, which appears to be a major predictor of death.
View details for DOI 10.1016/j.cardfail.2015.02.001
View details for Web of Science ID 000354420600008
View details for PubMedID 25704104
Cardiopulmonary responses and prognosis in hypertrophic cardiomyopathy: a potential role for comprehensive noninvasive hemodynamic assessment.
JACC. Heart failure
2015; 3 (5): 408-418
This study sought to discover the key determinants of exercise capacity, maximal oxygen consumption (oxygen uptake [Vo2]), and ventilatory efficiency (ventilation/carbon dioxide output [VE/Vco2] slope) and assess the prognostic potential of metabolic exercise testing in hypertrophic cardiomyopathy (HCM).The intrinsic mechanisms leading to reduced functional tolerance in HCM are unclear.The study sample included 156 HCM patients consecutively enrolled from January 1, 2007 to January 1, 2012 with a complete clinical assessment, including rest and stress echocardiography and cardiopulmonary exercise test (CPET) with impedance cardiography. Patients were also followed for the composite outcome of cardiac-related death, heart transplant, and functional deterioration leading to septal reduction therapy (myectomy or septal alcohol ablation).Abnormalities in CPET responses were frequent, with 39% (n = 61) of the sample showing a reduced exercise tolerance (Vo2 max <80% of predicted) and 19% (n = 30) characterized by impaired ventilatory efficiency (VE/Vco2 slope >34). The variables most strongly associated with exercise capacity (expressed in metabolic equivalents), were peak cardiac index (r = 0.51, p < 0.001), age (r = -0.25, p < 0.01), male sex (r = 0.24, p = 0.02), and indexed right ventricular end-diastolic area (r = 0.31, p = 0.002), resulting in an R(2) of 0.51, p < 0.001. Peak cardiac index was the main predictor of peak Vo2 (r = 0.61, p < 0.001). The variables most strongly related to VE/VCO2 slope were E/E' (r = 0.23, p = 0.021) and indexed left atrial volume index (LAVI) (r = 0.34, p = 0.005) (model R(2) = 0.15). The composite endpoint occurred in 21 (13%) patients. In an exploratory analysis, 3 variables were independently associated with the composite outcome (mean follow-up 27 ± 11 months): peak Vo2 <80% of predicted (hazard ratio: 4.11; 95% confidence interval [CI]: 1.46 to 11.59; p = 0.008), VE/Vco2 slope >34 (hazard ratio: 3.14; 95% CI: 1.26 to 7.87; p = 0.014), and LAVI >40 ml/m(2) (hazard ratio: 3.32; 95% CI: 1.08 to 10.16; p = 0.036).In HCM, peak cardiac index is the main determinant of exercise capacity, but it is not significantly related to ventilatory efficiency. Peak Vo2, ventilatory inefficiency, and LAVI are associated with an increased risk of major events in the short-term follow-up.
View details for DOI 10.1016/j.jchf.2014.11.011
View details for PubMedID 25863972
Identification and validation of N-acetyltransferase 2 as an insulin sensitivity gene
JOURNAL OF CLINICAL INVESTIGATION
2015; 125 (4): 1739-1751
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
PCSK9 Inhibition: Current Concepts and Lessons from Human Genetics
CURRENT ATHEROSCLEROSIS REPORTS
2015; 17 (3)
Low-density lipoprotein cholesterol (LDL-C) plays a central role in the pathogenesis of atherosclerotic cardiovascular disease (ASCVD). Statins are the cornerstone of therapy for the treatment of elevated LDL-C and for the primary and secondary prevention of ASCVD. However, some patients are intolerant of statins or are unable to achieve acceptable lipid levels on statin-based regimens alone. Proprotein convertase subtilisin/kexin type 9 (PCSK9) serves as an important regulator of hepatocyte LDL receptor expression and degradation, and recent genetic studies have highlighted the critical role of PCSK9 in human disease. Gain-of-function mutations in PCSK9 are associated with familial hypercholesterolemia, whereas loss-of-function mutations are protective against ASCVD. Therefore, PCSK9 inhibition offers a promising supplement or alternative to statin therapy in the reduction of LDL-C. Numerous phase II and III randomized control trials have demonstrated the tolerability of monoclonal antibodies against PCSK9 and their efficacy in lowering LDL-C by an additional 40-70 %. In this article, we review the growing role of PSCK9 inhibition in LDL-C reduction for diverse patient populations.
View details for DOI 10.1007/s11883-015-0487-8
View details for Web of Science ID 000349629400002
View details for PubMedID 25637042
- Genetic Evidence for a Normal-Weight "Metabolically Obese" Phenotype Linking Insulin Resistance, Hypertension, Coronary Artery Disease, and Type 2 Diabetes DIABETES 2014; 63 (12): 4369-4377
- Hyperuricaemia: the unintended consequence of insulin resistance/compensatory hyperinsulinaemia. Philanthropy gone awry. Journal of internal medicine 2014; 276 (2): 196-198
- 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
Impact of type 2 diabetes susceptibility variants on quantitative glycemic traits reveals mechanistic heterogeneity.
2014; 63 (6): 2158-2171
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
- Re: "Temporal relationship between uric acid concentration and risk of diabetes in a community-based study population". American journal of epidemiology 2014; 179 (9): 1147-1148
Latent obstruction and left atrial size are predictors of clinical deterioration leading to septal reduction in hypertrophic cardiomyopathy.
Journal of cardiac failure
2014; 20 (4): 236-243
Exercise echocardiography is a reliable tool to assess left ventricular (LV) dynamic obstruction in hypertrophic cardiomyopathy (HCM). The aim of this study was to determine the role of exercise echocardiography in the evaluation of latent obstruction and in predicting clinical deterioration in HCM patients.We considered 283 HCM patients studied with exercise echocardiography. The end point was clinical deterioration leading to septal reduction (myectomy or alcohol septal ablation). LV latent obstruction was present at enrollment in 67 patients (24%). During a mean follow-up of 42 ± 31 months, 42 patients had clinical deterioration leading to septal reduction therapy: in 12/67 (22%) patients with a latent obstruction at enrollment, in 28/84 (33%) patients with obstruction at rest, and in 2/132 (1.5%) with obstruction neither at rest or during stress. Multivariate analysis identified the following variables as independently associated with the end point: LV gradient >30 mm Hg at rest (hazard ratio [HR] 2.56, 95% CI 1.27-5.14; P = .009), LV gradient >30 mm Hg during stress (HR 4.96, 95% CI 1.81-13.61; P = .002), and indexed left atrial volume (LAVi ) >40 mL/m(2) (HR 2.86, 95% CI 1.47-5.55; P = .002). In patients with a latent obstruction, the strongest independent predictor of outcome was LAVi >40 mL/m(2) (HR 3.75, 95% CI 1.12-12.51; P = .032).Assessment of LV gradient during stress with exercise echocardiography is an important tool for the evaluation of latent obstruction in HCM and may have a role in risk stratification of these patients.
View details for DOI 10.1016/j.cardfail.2014.01.014
View details for PubMedID 24486928
Rationale and design of the familial hypercholesterolemia foundation CAscade SCreening for Awareness and DEtection of Familial Hypercholesterolemia registry.
American heart journal
2014; 167 (3): 342-349 e17
Familial hypercholesterolemia (FH) is a hereditary condition caused by various genetic mutations that lead to significantly elevated low-density lipoprotein cholesterol levels and resulting in a 20-fold increased lifetime risk for premature cardiovascular disease. Although its prevalence in the United States is 1 in 300 to 500 individuals, <10% of FH patients are formally diagnosed, and many are not appropriately treated. Contemporary data are needed to more fully characterize FH disease prevalence, treatment strategies, and patient experiences in the United States.The Familial Hypercholesterolemia Foundation (a patient-led nonprofit organization) has established the CAscade SCreening for Awareness and DEtection of Familial Hypercholesterolemia (CASCADE FH) Registry as a national, multicenter initiative to identify US FH patients, track their treatment, and clinical and patient-reported outcomes over time. The CASCADE FH will use multiple enrollment strategies to maximize identification of FH patients. Electronic health record screening of health care systems will provide an efficient mechanism to identify undiagnosed patients. A group of specialized lipid clinics will enter baseline and annual follow-up data on demographics, laboratory values, treatment, and clinical events. Patients meeting prespecified low-density lipoprotein or total cholesterol criteria suspicious for FH will have the opportunity to self-enroll in an online patient portal with information collected directly from patients semiannually. Registry patients will be provided information on cascade screening and will complete an online pedigree to assist with notification of family members.The Familial Hypercholesterolemia Foundation CASCADE FH Registry represents a novel research paradigm to address gaps in knowledge and barriers to comprehensive FH screening, identification, and treatment.
View details for DOI 10.1016/j.ahj.2013.12.008
View details for PubMedID 24576518
- Rationale and design of the familial hypercholesterolemia foundation CAscade SCreening for Awareness and DEtection of Familial Hypercholesterolemia registry. American heart journal 2014; 167 (3): 342-349 e17
- Unexplained double-chambered left ventricle associated with contracting right ventricular aneurysm and right atrial enlargement. Echocardiography (Mount Kisco, N.Y.) 2014; 31 (3): E80-4
Unexplained double-chambered left ventricle associated with contracting right ventricular aneurysm and right atrial enlargement.
Echocardiography (Mount Kisco, N.Y.)
2014; 31 (3): E80-4
In this article, we describe a double-chambered left ventricle (LV) associated with a functional right ventricular (RV) aneurysm and right atrial (RA) enlargement in an asymptomatic 24-year-old woman with a family history of sudden cardiac death. We will discuss the differential diagnosis, genetic testing and possible prognostic implications.
View details for DOI 10.1111/echo.12467
View details for PubMedID 24299065
Prevalence and clinical correlates of right ventricular dysfunction in patients with hypertrophic cardiomyopathy.
American journal of cardiology
2014; 113 (2): 361-367
Hypertrophic cardiomyopathy (HC) is a disease that mainly affects the left ventricle (LV), however recent studies have suggested that it can also be associated with right ventricular (RV) dysfunction. The objective of this study was to determine the prevalence of RV dysfunction in patients with HC and its relation with LV function and outcome. A total of 324 consecutive patients with HC who received care at Stanford Hospital from 1999 to 2012 were included in the study. A group of 99 prospectively recruited age- and gender-matched healthy volunteers were used as controls. RV function was quantified using the RV fractional area change, tricuspid annular plane systolic excursion (TAPSE), and RV myocardial performance index (RVMPI). Compared with the controls, the patients with HC had a higher RVMPI (0.51 ± 0.18 vs 0.25 ± 0.06, p <0.001) and lower TAPSE (20 ± 3 vs 24 ± 4, p <0.001). RV dysfunction based on an RVMPI >0.4 and TAPSE <16 mm was found in 71% and 11% of the HC and control groups, respectively. Worst LV function and greater pulmonary pressures were independent correlates of RV dysfunction. At an average follow-up of 3.7 ± 2.3 years, 17 patients had died and 4 had undergone heart transplantation. LV ejection fraction <50% and TAPSE <16 mm were independent correlates of outcome (hazard ratio 3.98, 95% confidence interval 1.22 to 13.04, p = 0.02; and hazard ratio 3.66, 95% confidence interval 1.38 to 9.69, p = 0.009, respectively). In conclusion, RV dysfunction based on the RVMPI is common in patients with HC and more frequently observed in patients with LV dysfunction and pulmonary hypertension. RV dysfunction based on the TAPSE was independently associated with an increased likelihood of death or transplantation.
View details for DOI 10.1016/j.amjcard.2013.09.045
View details for PubMedID 24230980
How does morphology impact on diastolic function in hypertrophic cardiomyopathy? A single centre experience.
2014; 4 (6)
It is unclear if morphology impacts on diastole in hypertrophic cardiomyopathy (HCM). We sought to determine the relationship between various parameters of diastolic function and morphology in a large HCM cohort.Tertiary referral centre from Stanford, California, USA.383 patients with HCM and normal systolic function between 1999 and 2011. A group of 100 prospectively recruited age-matched and sex-matched healthy participants were used as controls.Echocardiograms were assessed by two blinded board-certified cardiologists. HCM morphology was classified as described in the literature (reverse, sigmoid, symmetric, apical and undefined).Reverse curvature morphology was most commonly observed (218 (57%). Lateral mitral annular E'<12 cm/s was present in 86% of reverse, 88% of sigmoid, 79% of symmetric, 86% of apical and 81% of undefined morphology, p=0.65. E/E' was similarly elevated (E/E': 12.3±7.9 in reverse curvature, 12.1±6.1 in sigmoid, 12.7±9.5 in symmetric, 9.4±4.0 in apical, 12.7±7.9 in undefined morphology, p=0.71) and indexed left atrial volume (LAVi)>40 mL/m(2) was present in 47% in reverse curvature, 33% in sigmoid, 32% in symmetric, 37% in apical and 32% in undefined, p=0.09. Each morphology showed altered parameters of diastolic function when compared with the control population. Left ventricular (LV) obstruction was independently associated with all three diastolic parameters considered, in particular with LAVi>40 mL/m(2) (OR 2.04 (95% CI 1.23 to 3.39), p=0.005), E/E'>15 (OR 4.66 (95% CI 2.51 to 8.64), p<0.001) and E'<8 (OR 2.55 (95% CI 1.42 to 4.53), p=0.001). Other correlates of diastolic dysfunction were age, LV wall thickness and moderate-to-severe mitral regurgitation.In HCM, diastolic dysfunction is present to similar degrees independently from the morphological pattern. The main correlates of diastolic dysfunction are LV obstruction, age, degree of hypertrophy and degree of mitral regurgitation.
View details for DOI 10.1136/bmjopen-2014-004814
View details for PubMedID 24928584
- How does morphology impact on diastolic function in hypertrophic cardiomyopathy? A single centre experience. BMJ open 2014; 4 (6)
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-?
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
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
2013; 56 (12): 2619-2628
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
Variation in Use of Left Ventriculography in the Veterans Affairs Health Care System
CIRCULATION-CARDIOVASCULAR QUALITY AND OUTCOMES
2013; 6 (6): 687-693
Contrast left ventriculography is a method of measuring left ventricular function usually performed at the discretion of the invasive cardiologist during cardiac catheterization. We sought to determine variation in the use of left ventriculography in the Veterans Affairs (VA) Health Care System.We identified adult patients who underwent cardiac catheterization including coronary angiography between 2000 and 2009 in the VA Health Care System. We determined patient and hospital predictors of the use of left ventriculography as well as the variation in use across VA facilities. Results were validated using data from the VA's Clinical Assessment, Reporting, and Tracking (CART) program. Of 457 170 cardiac catheterization procedures among 336 853 patients, left ventriculography was performed on 263 695 (58%) patients. Use of left ventriculography decreased over time (64% in 2000 to 50% in 2009) and varied markedly across facilities (<1->95% of cardiac catheterizations). Patient factors explained little of the large variation in use between facilities. When the cohort was restricted to those with an echocardiogram in the prior 30 days and no intervening event, left ventriculography was still performed in 50% of cases.There is large variation in the use of left ventriculography across VA facilities that is not explained by patient characteristics.
View details for DOI 10.1161/CIRCOUTCOMES.113.000199
View details for Web of Science ID 000330362400017
View details for PubMedID 24192569
Mendelian randomization studies do not support a causal role for reduced circulating adiponectin levels in insulin resistance and type 2 diabetes.
2013; 62 (10): 3589-3598
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
Genome-wide characterization of shared and distinct genetic components that influence blood lipid levels in ethnically diverse human populations.
American journal of human genetics
2013; 92 (6): 904-916
Blood lipid concentrations are heritable risk factors associated with atherosclerosis and cardiovascular diseases. Lipid traits exhibit considerable variation among populations of distinct ancestral origin as well as between individuals within a population. We performed association analyses to identify genetic loci influencing lipid concentrations in African American and Hispanic American women in the Women's Health Initiative SNP Health Association Resource. We validated one African-specific high-density lipoprotein cholesterol locus at CD36 as well as 14 known lipid loci that have been previously implicated in studies of European populations. Moreover, we demonstrate striking similarities in genetic architecture (loci influencing the trait, direction and magnitude of genetic effects, and proportions of phenotypic variation explained) of lipid traits across populations. In particular, we found that a disproportionate fraction of lipid variation in African Americans and Hispanic Americans can be attributed to genomic loci exhibiting statistical evidence of association in Europeans, even though the precise genes and variants remain unknown. At the same time, we found substantial allelic heterogeneity within shared loci, characterized both by population-specific rare variants and variants shared among multiple populations that occur at disparate frequencies. The allelic heterogeneity emphasizes the importance of including diverse populations in future genetic association studies of complex traits such as lipids; furthermore, the overlap in lipid loci across populations of diverse ancestral origin argues that additional knowledge can be gleaned from multiple populations.
View details for DOI 10.1016/j.ajhg.2013.04.025
View details for PubMedID 23726366
View details for PubMedCentralID PMC3675231
- Genome-wide Characterization of Shared and Distinct Genetic Components that Influence Blood Lipid Levels in Ethnically Diverse Human Populations AMERICAN JOURNAL OF HUMAN GENETICS 2013; 92 (6): 904-916
Identification of heart rate-associated loci and their effects on cardiac conduction and rhythm disorders.
2013; 45 (6): 621-631
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
Genetic variants associated with glycine metabolism and their role in insulin sensitivity and type 2 diabetes.
2013; 62 (6): 2141-2150
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
Drug screening using a library of human induced pluripotent stem cell-derived cardiomyocytes reveals disease-specific patterns of cardiotoxicity.
2013; 127 (16): 1677-1691
Cardiotoxicity is a leading cause for drug attrition during pharmaceutical development and has resulted in numerous preventable patient deaths. Incidents of adverse cardiac drug reactions are more common in patients with preexisting heart disease than the general population. Here we generated a library of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from patients with various hereditary cardiac disorders to model differences in cardiac drug toxicity susceptibility for patients of different genetic backgrounds.Action potential duration and drug-induced arrhythmia were measured at the single cell level in hiPSC-CMs derived from healthy subjects and patients with hereditary long QT syndrome, familial hypertrophic cardiomyopathy, and familial dilated cardiomyopathy. Disease phenotypes were verified in long QT syndrome, hypertrophic cardiomyopathy, and dilated cardiomyopathy hiPSC-CMs by immunostaining and single cell patch clamp. Human embryonic stem cell-derived cardiomyocytes (hESC-CMs) and the human ether-a-go-go-related gene expressing human embryonic kidney cells were used as controls. Single cell PCR confirmed expression of all cardiac ion channels in patient-specific hiPSC-CMs as well as hESC-CMs, but not in human embryonic kidney cells. Disease-specific hiPSC-CMs demonstrated increased susceptibility to known cardiotoxic drugs as measured by action potential duration and quantification of drug-induced arrhythmias such as early afterdepolarizations and delayed afterdepolarizations.We have recapitulated drug-induced cardiotoxicity profiles for healthy subjects, long QT syndrome, hypertrophic cardiomyopathy, and dilated cardiomyopathy patients at the single cell level for the first time. Our data indicate that healthy and diseased individuals exhibit different susceptibilities to cardiotoxic drugs and that use of disease-specific hiPSC-CMs may predict adverse drug responses more accurately than the standard human ether-a-go-go-related gene test or healthy control hiPSC-CM/hESC-CM screening assays.
View details for DOI 10.1161/CIRCULATIONAHA.113.001883
View details for PubMedID 23519760
View details for PubMedCentralID PMC3870148
- Drug screening using a library of human induced pluripotent stem cell-derived cardiomyocytes reveals disease-specific patterns of cardiotoxicity. Circulation 2013; 127 (16): 1677-1691
- Identification of heart rate-associated loci and their effects on cardiac conduction and rhythm disorders. Nature genetics 2013; 45 (6): 621-631
Measurement of insulin-mediated glucose uptake: direct comparison of the modified insulin suppression test and the euglycemic, hyperinsulinemic clamp.
2013; 62 (4): 548-553
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
Role of international registries in enhancing the care of familial hypercholesterolaemia.
International journal of evidence-based healthcare
2013; 11 (2): 134–39
Familial hypercholesterolaemia (FH) is a relatively common genetic disorder associated with high risk of coronary heart disease that is preventable by early diagnosis and treatment. In a previous article, we reviewed the evidence for clinical management, models of care and health economic evaluations. The present commentary emphasises that collective action is needed to strengthen our approaches to evidence-based care, including better diagnosis and access to effective therapies. We detail how contemporary innovations in inter-operable, web-based, open-source and secure registries can provide the supporting infrastructure to: (i) address a current gap in the flow of data for measuring the quality of healthcare; (ii) support basic research through provision of high-quality, de-identified aggregate data; (iii) enable equitable access to clinical trials; and (iv) support efforts to disseminate evidence for best practice and information for care services. We describe how these aspects of enabling infrastructure will be incorporated into the development of a National FH Registry for Australasia, and proffer that a coordinated response to FH would be enhanced through a global network of inter-operable registries.
View details for DOI 10.1111/1744-1609.12023
View details for PubMedID 23750577
- Large-scale association analysis identifies new risk loci for coronary artery disease NATURE GENETICS 2013; 45 (1): 25-U52
Large-scale association analysis identifies new risk loci for coronary artery disease.
2013; 45 (1): 25-33
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
Exploring Predisposition and Treatment Response-the Promise of Genomics
PROGRESS IN CARDIOVASCULAR DISEASES
2012; 55 (1): 56-63
Spurred by large-scale public and private efforts as well as technological developments, the last few years have seen a major leap forward in our understanding of the genetic basis of cardiovascular disease. This revolution is in its infancy and will continue to alter the medical landscape for years to come. There is a need within the general cardiology community to develop a better understanding about how these developments may alter routine clinical care. In this review, we will provide an overview of the current state of genetics as pertains to rare cardiovascular diseases and then review advances in the discovery of the genetic basis of common disease with the potential for improved risk assessment and drug development. We will also outline a few recent examples of pharmacogenetic advances that are already starting to become a part of clinical management and finally discuss the promise as well as the challenges in using next-generation sequencing technologies to provide personalized cardiovascular care.
View details for DOI 10.1016/j.pcad.2012.04.006
View details for Web of Science ID 000307087800007
View details for PubMedID 22824110
- Randomized Trial of Personal Genomics for Preventive Cardiology Design and Challenges CIRCULATION-CARDIOVASCULAR GENETICS 2012; 5 (3): 368-376
The Evolution and Refinement of Traditional Risk Factors for Cardiovascular Disease
CARDIOLOGY IN REVIEW
2012; 20 (3): 118-129
Traditional risk factors for cardiovascular disease such as systemic hypertension and hypercholesterolemia, all described more than half a century ago, are relatively few in number. Efforts to expand the epidemiologic canon have met with limited success because of the high hurdle of causality. Fortunately, another solution to current deficiencies in risk assessment-in particular, the underestimation of risk both before and after initiation of pharmacotherapy-may exist. Parallel to the investigation of novel biomarkers, such as high-sensitivity C-reactive protein, ongoing research has yielded improved metrics of known causative conditions. This evolution of traditional risk factors, heralded by measures such as ambulatory blood pressure, central hemodynamics, low density lipoprotein particle concentration, genetic testing, and "vascular age," may better address the detection gap in cardiovascular disease.
View details for DOI 10.1097/CRD.0b013e318239b924
View details for Web of Science ID 000302772500004
View details for PubMedID 22183062
Use and overuse of left ventriculography
AMERICAN HEART JOURNAL
2012; 163 (4): 617-?
Left ventriculography provided the first imaging of left ventricular function and was historically performed as part of coronary angiography despite a small but significant risk of complications. Because modern noninvasive imaging techniques are more accurate and carry smaller risks, the routine use of left ventriculography is of questionable utility. We sought to analyze the frequency that left ventriculography was performed during coronary angiography in patients with and without a recent alternative assessment of left ventricular function.We performed a retrospective analysis of insurance claims data from the Aetna health care benefits database including all adults who underwent coronary angiography in 2007. The primary outcome was the concomitant use of left ventriculography during coronary angiography.Of 96,235 patients who underwent coronary angiography, left ventriculography was performed in 78,705 (81.8%). Use of left ventriculography was high in all subgroups, with greatest use in younger patients, those with a diagnosis of coronary disease, and those in the Southern United States. In the population who had undergone a very recent ejection fraction assessment by another modality (within 30 days) and who had had no intervening diagnosis of new heart failure, myocardial infarction, hypotension, or shock (37,149 patients), left ventriculography was performed in 32,798 patients (88%)-a rate higher than in the overall cohort.Left ventriculography was performed in most coronary angiography cases and often when an alternative imaging modality had been recently completed. New clinical practice guidelines should be considered to decrease the overuse of this invasive test.
View details for DOI 10.1016/j.ahj.2011.12.018
View details for Web of Science ID 000303106800023
View details for PubMedID 22520528
Phased Whole-Genome Genetic Risk in a Family Quartet Using a Major Allele Reference Sequence
2011; 7 (9)
Whole-genome sequencing harbors unprecedented potential for characterization of individual and family genetic variation. Here, we develop a novel synthetic human reference sequence that is ethnically concordant and use it for the analysis of genomes from a nuclear family with history of familial thrombophilia. We demonstrate that the use of the major allele reference sequence results in improved genotype accuracy for disease-associated variant loci. We infer recombination sites to the lowest median resolution demonstrated to date (< 1,000 base pairs). We use family inheritance state analysis to control sequencing error and inform family-wide haplotype phasing, allowing quantification of genome-wide compound heterozygosity. We develop a sequence-based methodology for Human Leukocyte Antigen typing that contributes to disease risk prediction. Finally, we advance methods for analysis of disease and pharmacogenomic risk across the coding and non-coding genome that incorporate phased variant data. We show these methods are capable of identifying multigenic risk for inherited thrombophilia and informing the appropriate pharmacological therapy. These ethnicity-specific, family-based approaches to interpretation of genetic variation are emblematic of the next generation of genetic risk assessment using whole-genome sequencing.
View details for DOI 10.1371/journal.pgen.1002280
View details for Web of Science ID 000295419100031
View details for PubMedID 21935354
View details for PubMedCentralID PMC3174201
OVERUSE OF LEFT VENTRICULOGRAPHY
60th Annual Scientific Session and Expo of the American-College-of-Cardiology (ACC) / I2 Summit / ACCF/Herman K. Gold Young Investigator's Award in Molecular and Cellular Cardiology
ELSEVIER SCIENCE INC. 2011: E1289–E1289
View details for Web of Science ID 000291695101292
Large-scale association analysis identifies 13 new susceptibility loci for coronary artery disease
2011; 43 (4): 333-U153
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
A Bivariate Genome-Wide Approach to Metabolic Syndrome STAMPEED Consortium
2011; 60 (4): 1329-1339
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
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
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 Web of Science ID 000283538000005
View details for PubMedID 20933357
View details for PubMedCentralID PMC3084526
Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index
2010; 42 (11): 937-U53
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
Hundreds of variants clustered in genomic loci and biological pathways affect human height
2010; 467 (7317): 832-838
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
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
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
Genome-wide meta-analyses identify multiple loci associated with smoking behavior
2010; 42 (5): 441-U134
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
Clinical assessment incorporating a personal genome
2010; 375 (9725): 1525-1535
The cost of genomic information has fallen steeply, but the clinical translation of genetic risk estimates remains unclear. We aimed to undertake an integrated analysis of a complete human genome in a clinical context.We assessed a patient with a family history of vascular disease and early sudden death. Clinical assessment included analysis of this patient's full genome sequence, risk prediction for coronary artery disease, screening for causes of sudden cardiac death, and genetic counselling. Genetic analysis included the development of novel methods for the integration of whole genome and clinical risk. Disease and risk analysis focused on prediction of genetic risk of variants associated with mendelian disease, recognised drug responses, and pathogenicity for novel variants. We queried disease-specific mutation databases and pharmacogenomics databases to identify genes and mutations with known associations with disease and drug response. We estimated post-test probabilities of disease by applying likelihood ratios derived from integration of multiple common variants to age-appropriate and sex-appropriate pre-test probabilities. We also accounted for gene-environment interactions and conditionally dependent risks.Analysis of 2.6 million single nucleotide polymorphisms and 752 copy number variations showed increased genetic risk for myocardial infarction, type 2 diabetes, and some cancers. We discovered rare variants in three genes that are clinically associated with sudden cardiac death-TMEM43, DSP, and MYBPC3. A variant in LPA was consistent with a family history of coronary artery disease. The patient had a heterozygous null mutation in CYP2C19 suggesting probable clopidogrel resistance, several variants associated with a positive response to lipid-lowering therapy, and variants in CYP4F2 and VKORC1 that suggest he might have a low initial dosing requirement for warfarin. Many variants of uncertain importance were reported.Although challenges remain, our results suggest that whole-genome sequencing can yield useful and clinically relevant information for individual patients.National Institute of General Medical Sciences; National Heart, Lung And Blood Institute; National Human Genome Research Institute; Howard Hughes Medical Institute; National Library of Medicine, Lucile Packard Foundation for Children's Health; Hewlett Packard Foundation; Breetwor Family Foundation.
View details for Web of Science ID 000277655100025
View details for PubMedID 20435227
View details for PubMedCentralID PMC2937184
Characterizing the admixed African ancestry of African Americans
2009; 10 (12)
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
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
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
A near null variant of 12/15-LOX encoded by a novel SNP in ALOX15 and the risk of coronary artery disease
2008; 198 (1): 136-144
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
Common polymorphisms of ALOX5 and ALOX5AP and risk of coronary artery disease
2008; 123 (4): 399-408
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
Failure to replicate an association of SNPs in the oxidized LDL receptor gene (OLRI) with CAD
BMC MEDICAL GENETICS
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
Pharmacogenetics of Heart Failure: Evidence, Opportunities, and Challenges for Cardiovascular Pharmacogenomics
JOURNAL OF CARDIOVASCULAR TRANSLATIONAL RESEARCH
2008; 1 (1): 25-36
Heart failure is a significant medical problem affecting more than five million people in the USA alone. Although clinical trials of pharmacological agents have demonstrated significant reductions in the relative risk of mortality across populations, absolute mortality remains high. In addition, individual variation in response is great. Some of this variation may be explained by genetic polymorphism. In this paper, we review the key studies to date in heart failure pharmacogenetics, setting this against a background of recent progress in the genetics of warfarin metabolism. Several polymorphisms that have supporting molecular and clinical data in the heart failure literature are reviewed, among them the beta1-adrenergic receptor variant Arg389Gly and the angiotensin converting enzyme gene insertion/deletion polymorphism. These variants and others are responsible for a fraction of the total variation seen in the treatment response to heart failure. With the dawn of the genomic age, further pharmacogenetic and new pharmacogenomic studies will advance our ability to tailor the treatment of heart failure.
View details for DOI 10.1007/s12265-007-9007-8
View details for Web of Science ID 000207734400008
View details for PubMedID 20559955
Association of polymorphisms in platelet and hemostasis system genes with acute myocardial infarction
AMERICAN HEART JOURNAL
2007; 154 (6): 1052-1058
Genetic polymorphisms may affect the balance between coagulation and fibrinolysis and thereby affect individual vulnerability to acute myocardial infarction (MI) among patients with underlying coronary atherosclerosis.We enrolled 1375 patients with an initial clinical presentation of coronary disease. We genotyped 49 single nucleotide polymorphisms (SNPs) in 9 coagulation system genes and compared patients who had an initial acute MI with patients who presented with stable exertional angina.An SNP in CD36 (rs3211956) was significantly (P = .04) more common among patients who presented with acute MI (minor allele frequency 10.5%) than patients with stable exertional angina (minor allele frequency 8.0%). This association became marginally significant, however, after adjustment for conventional cardiac risk factors in an additive genetic model (odds ratio 1.34, CI 1.00-1.88, P = .053). An SNP in ITGB3 (Leu59Pro, rs5918) was slightly, but not significantly (P = .083), more common among patients with acute MI (minor allele frequency 14.5%) than among patients with stable exertional angina (minor allele frequency 12.0%). Two linked SNPs in THBD (Ala473Val, rs1042579; and rs3176123) were slightly, but not significantly (P = .079 and 0.052, respectively), less common among patients with acute MI (minor allele frequency 16.1%) than among patients with stable exertional angina (18.7% and 19.0%, respectively).Four SNPs in platelet glycoprotein and hemostatic genes were nominally associated with acute MI rather than stable exertional angina as the initial clinical presentation of coronary artery disease. These findings are suggestive but require independent confirmation in larger studies.
View details for DOI 10.1016/j.ahj.2007.05.021
View details for Web of Science ID 000251396200008
View details for PubMedID 18035074
Genetic susceptibility to peripheral arterial disease: A dark corner in vascular biology
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
2007; 27 (10): 2068-2078
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
- A case of complete heart block reverting to normal sinus rhythm after treatment for cardiac invasive Burkitt's lymphoma ANNALS OF HEMATOLOGY 2007; 86 (9): 687-690
Cardiac hypertrophy and sudden death in mice with a genetically clamped renin transgene
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
2004; 101 (9): 3106-3111
Several mouse models have already proved valuable for investigating hypertrophic responses to cardiac stress. Here, we characterize one caused by a well defined single copy transgene, RenTgMK, that genetically clamps plasma renin and thence angiotensin II at high levels. All of the transgenic males develop concentric cardiac hypertrophy with fibrosis but without dilatation. Over half die suddenly aged 6-8 months. Telemetry showed disturbances in diurnal rhythms a few days before death and, later, electrocardiographic disturbances comparable to those in humans with congestive heart failure. Expression of seven hypertrophy-related genes in this and two categorically different models (lack of atrial natriuretic peptide receptor A; overexpression of calsequestrin) were compared. Statistical analyses show that ventricular expressions of the genes coding for atrial natriuretic peptide, beta myosin heavy chain, medium chain acyl-CoA dehydrogenase, and adrenomedullin correlate equally well with the degree of hypertrophy, although their ranges of expression are, respectively, 50-, 30-, 10-, and 3-fold.
View details for DOI 10.1073/pnas.0307333101
View details for Web of Science ID 000220065300082
View details for PubMedID 14978280
Increased atherosclerosis and smooth muscle cell hypertrophy in natriuretic peptide receptor A(-/-) apolipoprotein E-/- mice
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
2003; 23 (6): 1077-1082
Natriuretic peptide signaling is important in the regulation of blood pressure as well as in the growth of multiple cell types. To examine the role of natriuretic peptide signaling in atherosclerosis, we crossbred mice that lack natriuretic peptide receptor A (NPRA; Npr1-/-) with atherosclerosis-prone mice that lack apolipoprotein E (apoE; Apoe-/-).Doubly deficient Npr1-/-Apoe-/- mice have increased blood pressure relative to Npr1+/+Apoe-/- mice (118+/-4 mm Hg compared with 108+/-2 mm Hg, P<0.05) that is coincident with a 64% greater atherosclerotic lesion size (P<0.005) and more advanced plaque morphology. Additionally, aortic medial thickness is increased by 52% in Npr1-/-Apoe-/- mice relative to Npr1+/+Apoe-/- mice (P<0.0001). Npr1-/-Apoe-/- mice also have significantly greater cardiac mass (9.0+/-0.3 mg/g body weight) than either Npr1+/+Apoe-/- mice (5.8+/-0.2 mg/g) or Npr1-/-Apoe+/+ mice (7.1+/-0.2 mg/g), suggesting that the lack of both NPRA and apoE synergistically enhances cardiac hypertrophy.These data provide evidence that NPR1 is an atherosclerosis susceptibility locus and represents a potential link between atherosclerosis and cardiac hypertrophy. Our results also suggest roles for Npr1 as well as Apoe in regulation of hypertrophic cell growth.
View details for DOI 10.1161/01.ATV.0000071702.45741.2E
View details for Web of Science ID 000183527900025
View details for PubMedID 12702516
Common variations in noncoding regions of the human natriuretic peptide receptor A gene have quantitative effects
2003; 112 (1): 62-70
Genetic susceptibility to common conditions, such as essential hypertension and cardiac hypertrophy, is probably determined by various combinations of small quantitative changes in the expression of many genes. NPR1, coding for natriuretic peptide receptor A (NPRA), is a potential candidate, because NPRA mediates natriuretic, diuretic, and vasorelaxing actions of the nariuretic peptides, and because genetically determined quantitative changes in the expression of this gene affect blood pressure and heart weight in a dose-dependent manner in mice. To determine whether there are common quantitative variants in human NPR1, we have sequenced the entire human NPR1 gene and identified 10 polymorphic sites in its non-coding sequence by using DNA from 34 unrelated human individuals. Five of the sites are single nucleotide polymorphisms; the remaining five are length polymorphisms, including a highly variable complex dinucleotide repeat in intron 19. There are three common haplotypes 5' to this dinucleotide repeat and three 3' to it, but the 5' haplotypes and 3' haplotypes appear to be randomly associated. Transient expression analysis in cultured cells of reporter plasmids with the proximal promoter sequences of NPR1 and its 3' untranslated regions showed that these polymorphisms have functional effects. We conclude that common NPR1 alleles can alter expression of the gene as much as two-fold and could therefore significantly affect genetic risks for essential hypertension and cardiac hypertrophy in humans.
View details for DOI 10.1007/s00439-002-0834-z
View details for Web of Science ID 000180552400010
View details for PubMedID 12483301
Ventricular expression of natriuretic peptides in Npr1(-/-) mice with cardiac hypertrophy and fibrosis
AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY
2002; 283 (2): H707-H714
Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are cardiac hormones that regulate blood pressure and volume, and exert their biological actions via the natriuretic peptide receptor-A gene (Npr1). Mice lacking Npr1 (Npr(-/-)) have marked cardiac hypertrophy and fibrosis disproportionate to their increased blood pressure. This study examined the relationships between ANP and BNP gene expression, immunoreactivity and fibrosis in cardiac tissue, circulating ANP levels, and ANP and BNP mRNA during embryogenesis in Npr1(-/-) mice. Disruption of the Npr1 signaling pathway resulted in augmented ANP and BNP gene and ANP protein expression in the cardiac ventricles, most pronounced for ANP mRNA in females [414 +/- 57 in Npr1(-/-) ng/mg and 124 +/- 25 ng/mg in wild-type (WT) by Taqman assay, P < 0.001]. This increased expression was highly correlated to the degree of cardiac hypertrophy and was localized to the left ventricle (LV) inner free wall and to areas of ventricular fibrosis. In contrast, plasma ANP was significantly greater than WT in male but not female Npr1(-/-) mice. Increased ANP and BNP gene expression was observed in Npr1(-/-) embryos from 16 days of gestation. Our study suggests that cardiac ventricular expression of ANP and BNP is more closely associated with local hypertrophy and fibrosis than either systemic blood pressure or circulating ANP levels.
View details for DOI 10.1152/ajpheart.00677.2001
View details for Web of Science ID 000176880500031
View details for PubMedID 12124219
Interactions between endothelial nitric oxide synthase and sex hormones in vascular protection in mice
JOURNAL OF CLINICAL INVESTIGATION
2002; 109 (4): 541-548
The vasculoprotective effects of sex hormones, particularly estrogens, have been attributed to their ability to increase the bioavailability of nitric oxide through activation of endothelial nitric oxide synthase (eNOS). To dissect the relative contribution in vivo of eNOS, sex hormones, and their interaction in two complex vascular phenotypes, hypertension and atherosclerosis, we used mice doubly deficient in eNOS and apoE (nnee) or lacking only apoE (NNee). Females and males were gonadectomized at 1 month of age and implanted either with control pellets or pellets releasing 17beta-estradiol (E2). Hormonally intact nnee mice have elevated blood pressure (BP) and increased atherosclerosis compared with NNee mice, but on removal of gonads, BP and atherosclerosis decreased significantly in nnee mice but not in NNee mice. Three months of treatment with exogenous E2 dramatically reduced atherosclerosis and significantly lowered BP in both NNee and nnee mice compared with animals treated with control pellets. Thus exogenous E2 has strong BP-lowering and atheroprotective effects in apoE-deficient mice, but eNOS is not essential for either effect. Endogenous sex hormones, on the other hand, cause significant damage to the vasculature in the absence of eNOS, but these effects are overridden by interactions between eNOS and sex hormones.
View details for DOI 10.1172/JC1200214066
View details for Web of Science ID 000173965900016
View details for PubMedID 11854327
Evidence for a novel natriuretic peptide receptor that prefers brain natriuretic peptide over atrial natriuretic peptide
2001; 358: 379-387
Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) exert their physiological actions by binding to natriuretic peptide receptor A (NPRA), a receptor guanylate cyclase (rGC) that synthesizes cGMP in response to both ligands. The family of rGCs is rapidly expanding, and it is plausible that there might be additional, as yet undiscovered, rGCs whose function is to provide alternative signalling pathways for one or both of these peptides, particularly given the low affinity of NPRA for BNP. We have investigated this hypothesis, using a genetically modified (knockout) mouse in which the gene encoding NPRA has been disrupted. Enzyme assays and NPRA-specific Western blots performed on tissues from wild-type mice demonstrate that ANP-activated cGMP synthesis provides a good index of NPRA protein expression, which ranges from maximal in adrenal gland, lung, kidney, and testis to minimal in heart and colon. In contrast, immunoreactive NPRA is not detectable in tissues isolated from NPRA knockout animals and ANP- and BNP-stimulatable GC activities are markedly reduced in all mutant tissues. However, testis and adrenal gland retain statistically significant, high-affinity responses to BNP. This residual response to BNP cannot be accounted for by natriuretic peptide receptor B, or any other known mammalian rGC, suggesting the presence of a novel receptor in these tissues that prefers BNP over ANP.
View details for Web of Science ID 000170877900012
View details for PubMedID 11513736
Pressure-independent enhancement of cardiac hypertrophy in natriuretic peptide receptor A-deficient mice
JOURNAL OF CLINICAL INVESTIGATION
2001; 107 (8): 975-984
Mice lacking natriuretic peptide receptor A (NPRA) have marked cardiac hypertrophy and chamber dilatation disproportionate to their increased blood pressure (BP), suggesting, in support of previous in vitro data, that the NPRA system moderates the cardiac response to hypertrophic stimuli. Here, we have followed the changes in cardiac function in response to altered mechanical load on the heart of NPRA-null mice (Npr1-/-). Chronic treatment with either enalapril, furosemide, hydralazine, or losartan were all effective in reducing and maintaining BP at normal levels without affecting heart weight/body weight. In the reverse direction, we used transverse aortic constriction (TAC) to induce pressure overload. In the Npr1-/- mice, TAC resulted in a 15-fold increase in atrial natriuretic peptide (ANP) expression, a 55% increase in left ventricular weight/body weight (LV/BW), dilatation of the LV, and significant decline in cardiac function. In contrast, banded Npr1+/+ mice showed only a threefold increase in ANP expression, an 11% increase in LV/BW, a 0.2 mm decrease in LV end diastolic dimension, and no change in fractional shortening. The activation of mitogen-activated protein kinases that occurs in response to TAC did not differ in the Npr1+/+ and Npr1-/- mice. Taken together, these results suggest that the NPRA system has direct antihypertrophic actions in the heart, independent of its role in BP control.
View details for Web of Science ID 000168152000009
View details for PubMedID 11306601
Genetic modifiers of atherosclerosis in mice
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
2000; 20 (11): 2336-2345
Atherosclerosis is a complex, multifactorial disease with both genetic and environmental determinants. Experimental investigation of the effects of these determinants on the development and progression of atherosclerosis has been greatly facilitated by the use of targeted mouse models of the disease, particularly those resulting from the absence of functional genes for apolipoprotein E or the low density lipoprotein receptor (LDLR). This review focuses on the influence on atherosclerosis of combining apoE or LDLR deficiencies with factors affecting atherogenesis, including (1) inflammatory processes, (2) glucose metabolism, (3) blood pressure, and (4) coagulation and fibrinolysis. We also discuss the general problem of using the mouse to test the effects on atherogenesis of human polymorphic variations and future ways of enhancing the usefulness of these mouse models.
View details for Web of Science ID 000165306600002
View details for PubMedID 11073835
Enhanced atherosclerosis and kidney dysfunction in eNOS(-)/(-)Apo(-)/(-) mice are ameliorated by enalapril treatment
JOURNAL OF CLINICAL INVESTIGATION
2000; 105 (4): 451-458
Hypertension and atherosclerosis are each important causes of morbidity and mortality in the developed world. We have investigated the interaction between these conditions by breeding mice that are atherosclerotic due to lack of apolipoprotein (apo) E with mice that are hypertensive due to lack of endothelial nitric oxide synthase (eNOS). The doubly deficient mice (nnee) have higher blood pressure (BP) and increased atherosclerotic lesion size but no change in plasma lipoprotein profiles compared with normotensive but atherosclerotic (NNee) mice. The nnee mice also develop kidney damage, evidenced by increased plasma creatinine, decreased kidney weight/body weight ratio, and glomerular lipid deposition and calcification. Enalapril treatment abolishes the deleterious effects of eNOS deficiency on BP, atherosclerosis, and kidney dysfunction in nnee mice. In striking contrast, a genetic lack of inducible NOS, which does not affect BP, has no effect on the development of atherosclerotic lesions in Apoe(-/-) mice. We also observed a positive relationship between BP and size of atherosclerotic lesions These results suggest that the atherogenic effects of eNOS deficiency can be partially explained by an increase in BP and reemphasize the importance of controlling hypertension in preventing atherosclerosis.
View details for Web of Science ID 000085446700008
View details for PubMedID 10683374
Low salt intake down-regulates the guanylin signaling pathway in rat distal colon
1996; 111 (6): 1714-1721
Guanylin, an endogenous gastrointestinal peptide, causes the translocation of NaCl from interstitial fluid to the intestinal lumen. The aim of this study was to examine whether changes in dietary salt intake lead to compensatory changes in expression of the guanylin signaling pathway.Rats received low-, normal-, or high-sodium diets for 1 week. Colonic guanylin expression was evaluated by Western and Northern blotting, rates of guanylin secretion by measuring biologically active guanylin released into the medium from colon explants, and expression of the guanylin receptor (C-type guanylate cyclase) by Northern blotting and bioassay.By every criterion, the low-salt diet reduced expression of guanylin to 30%-40% of the level found in control animals. Guanylin receptor expression was also decreased, although less dramatically and with a lower statistical significance. For both guanylin and guanylin receptor, the high-salt diet had no significant effect on expression.The data support the hypothesis that the guanylin pathway is down-regulated as an adaptive response to salt restriction.
View details for Web of Science ID A1996VW29200039
View details for PubMedID 8942754