I am presently a Fellow in Cardiovascular Medicine and Lead Fellow for the Translational Investigator Program (TIP) at Stanford University, where I work in the laboratory of Euan Ashley on a portfolio centering around exercise and physical activity. I previously obtained my MD from the University of Michigan and my PhD in Genome Sciences and MPH in Biostatistics from the University of Washington.

Exercise is the most potent intervention in preventing the common diseases of aging. However, the majority of adults do not meet the recommended amount of exercise by numerous expert consensus groups worldwide. To combat this, we have leveraged digital interventions on smartphones and demonstrate that personalized, AI-driven interventions are more likely to increase short-term physical activity in adults.

Separately, I work on identifying longitudinal (over time) changes in the multi-ome (spanning the genome -> epigenome -> transcriptome -> proteome/metabolome, and post-translational modifications [e.g., phosphorylation]) with endurance exercise training, with a particular focus on changes specific to the heart (my area of clinical interest!).

I have received funding as a principal investigator from the National Institutes of Health (NIH), American Heart Association (AHA), and the Wu Tsai Human Performance Alliance. I am a member of Alpha Omega Alpha (AOA) Medical Honors Society and graduated from the University of Michigan Medical School with distinction in clinical activities (top 10% of class), distinction in research, the Dean's Award for Research Excellence, and the Department of Internal Medicine's Senior Scholarship. At Stanford, I have been awarded the Edwin Alderman award for Excellence in Clinical Research.

Long-term, I will be a physician-scientist working to translate my research findings into actionable therapies for my patients with underlying genetic cardiomyopathies and/or coronary artery disease, and separately, work on innovating technologies to increase physical activity in the general population, with particular attention to the elderly and racial/ethnic minorities.

Clinical Focus

  • Fellow
  • Cardiovascular Disease
  • Cardiovascular Genetics
  • Inherited Cardiomyopathies
  • Exercise Physiology
  • Preventive Cardiology
  • Digital Health

Academic Appointments

Honors & Awards

  • Clinician-Scientist Award, Wu Tsai Human Performance Alliance (2023)
  • Edwin Alderman Award for Excellence in Clinical Research, Stanford University (2023)
  • Loan Repayment Program, National Institutes of Health (NIH) (2023)
  • Dean's Award for Research Excellence, University of Michigan (2019)
  • Department of Internal Medicine Senior Scholarship, University of Michigan (2019)
  • Graduation with Distinction (Top 10% of Class), University of Michigan (2019)
  • Graduation with Distinction in Research, University of Michigan (2019)
  • Alpha Omega Alpha (AOA) Medical Honors Society, University of Michigan (2018)
  • Clinical Comprehensive Assessment (CCA) Commendation, University of Michigan (2018)
  • Dean's Commendation for Excellence in Clinical Skills, University of Michigan (2018)
  • Loan Repayment Program, National Institutes of Health (NIH) (2016)
  • Postdoctoral Fellowship, American Heart Association (AHA), Western States Affiliate (2016)
  • Invited Lecture: High Science HDL Forum, Translational Medicine Academy (2015)
  • J. Maxwell Chamberlain Memorial Paper in Congenital Heart Surgery (Plenary Talk), Society for Thoracic Surgery (2014)
  • Ruth Kirschstein National Research Fellowship for Predoctoral Fellows (F32), National Institutes of Health (NIH) (2013)
  • Alpha Omega Alpha (AOA) Research Fellowship (Declined for Other Funding), University of Michigan (2011)
  • Research Fellowship for Medical Students, Sarnoff Cardiovascular Research Foundation (2011)
  • Award of Research Excellence, University of Michigan (2010)
  • Magna Cum Laude, College of Arts and Sciences, University of Washington (2009)
  • Phi Beta Kappa Honors Society, University of Washington (2008)
  • Space Grant, National Aeronautics and Space Administration (NASA) (2008)
  • Mary Gates Leadership Fellowship for Undergraduates, University of Washington (2007)
  • Research Fellowship for Undergraduates, Washington Research Foundation (2007)
  • Mary Gates Research Fellowship for Undergraduates, University of Washington (2006)
  • Research Experience for Undergraduates, National Science Foundation (2006)
  • Undergraduate Scholar Award, University of Washington (2005)

Professional Education

  • Fellowship, Cardiology, Stanford University, Cardiovascular Disease (2025)
  • Residency, Internal Medicine, Stanford University, Internal Medicine (2021)
  • MD, University of Michigan, Medicine (2019)
  • PhD, University of Washington, Genome Sciences (2015)
  • MPH, University of Washington, Biostatistics (2016)

Current Research and Scholarly Interests

My research projects within the laboratory of Euan Ashley center around the broad topic of exercise, physiology, and cardiovascular disease:
1. Digital health interventions - I previously have published on the topic of digital health interventions delivered via an iPhone app (Kim and Javed et al, European Heart Journal - Digital Health 2023). We found that personalizing interventions based on individual's baseline activity was more effective in increasing short-term physical activity than other "one-size fits all" approaches. In our next phase, we will extend this to under-represented populations in digital health and implement cutting-edge artificial intelligence models to improve our interventions.
2. Molecular mechanisms of exercise physiologic adaptations - using time-series multi-omic data, we aim to map out the molecular responses to endurance exercise training in rats, using data from the Molecular Transducers of Physical Activity Consortium (MoTrPAC). See our recent review in Nature Reviews Genetics - Kim et al, 2021.
3. Effect of physical activity on coronary artery disease symptoms and outcomes - in collaboration with Dr David Maron and the ISCHEMIA study, I am investigating the effects of physical activity and sedentary behavior on symptoms related to known coronary heart disease and separately, the outcome of all-cause mortality.
4. Exercise [hysiology - in collaboration with Dr Francois Haddad and Dr Jonathan Myers, I am working on projects to better standardize reporting of maximal oxygen uptake. In brief, maximal oxygen uptake (VO2 max) is an extremely valuable prognostic, but estimation of this physiologic value is poor in certain populations. We are working to improve estimation of this variable and demonstrating its efficacy in predicting hard outcomes in patients with heart failure.
5. Outcomes in inherited cardiomyopathies - under the mentorship of Dr Euan Ashley, I am building my clinical expertise in treating patients with inherited cardiomyopathies. The Stanford Center for Inherited Cardiovascular Disease (SCICD) is home to clinical care of patients with inherited cardiomyopathies, channelopathies, inherited lipid disorders, neuromuscular disorders (e.g., muscular dystrophy), and vascular disorders (e.g., Marfan's and other aorthopathies). Our clinic is nested within the Heart Failure program and manages those patients who are progressing toward advanced heart failure therapies, such as transplant or left ventricular assist devices. Within this clinic, I am leading projects to describe our experience with mavacamten, a first of its class treatment of hypertrophic cardiomyopathy with obstruction.

Current Clinical Interests

  • Inherited Cardiomyopathies
  • Exercise Physiology
  • Preventive Cardiology

Lab Affiliations

Graduate and Fellowship Programs

All Publications

  • Personalized digital behaviour interventions increase short-term physical activity: a randomized control crossover trial substudy of the MyHeart Counts Cardiovascular Health Study. European heart journal. Digital health Javed, A., Kim, D. S., Hershman, S. G., Shcherbina, A., Johnson, A., Tolas, A., O'Sullivan, J. W., McConnell, M. V., Lazzeroni, L., King, A. C., Christle, J. W., Oppezzo, M., Mattsson, C. M., Harrington, R. A., Wheeler, M. T., Ashley, E. A. 2023; 4 (5): 411-419


    Physical activity is associated with decreased incidence of the chronic diseases associated with aging. We previously demonstrated that digital interventions delivered through a smartphone app can increase short-term physical activity.We offered enrolment to community-living iPhone-using adults aged ≥18 years in the USA, UK, and Hong Kong who downloaded the MyHeart Counts app. After completion of a 1-week baseline period, e-consented participants were randomized to four 7-day interventions. Interventions consisted of: (i) daily personalized e-coaching based on the individual's baseline activity patterns, (ii) daily prompts to complete 10 000 steps, (iii) hourly prompts to stand following inactivity, and (iv) daily instructions to read guidelines from the American Heart Association (AHA) website. After completion of one 7-day intervention, participants subsequently randomized to the next intervention of the crossover trial. The trial was completed in a free-living setting, where neither the participants nor investigators were blinded to the intervention. The primary outcome was change in mean daily step count from baseline for each of the four interventions, assessed in a modified intention-to-treat analysis (modified in that participants had to complete 7 days of baseline monitoring and at least 1 day of an intervention to be included in analyses). This trial is registered with, NCT03090321.Between 1 January 2017 and 1 April 2022, 4500 participants consented to enrol in the trial (a subset of the approximately 50 000 participants in the larger MyHeart Counts study), of whom 2458 completed 7 days of baseline monitoring (mean daily steps 4232 ± 73) and at least 1 day of one of the four interventions. Personalized e-coaching prompts, tailored to an individual based on their baseline activity, increased step count significantly (+402 ± 71 steps from baseline, P = 7.1⨯10-8). Hourly stand prompts (+292 steps from baseline, P = 0.00029) and a daily prompt to read AHA guidelines (+215 steps from baseline, P = 0.021) were significantly associated with increased mean daily step count, while a daily reminder to complete 10 000 steps was not (+170 steps from baseline, P = 0.11). Digital studies have a significant advantage over traditional clinical trials in that they can continuously recruit participants in a cost-effective manner, allowing for new insights provided by increased statistical power and refinement of prior signals. Here, we present a novel finding that digital interventions tailored to an individual are effective in increasing short-term physical activity in a free-living cohort. These data suggest that participants are more likely to react positively and increase their physical activity when prompts are personalized. Further studies are needed to determine the effects of digital interventions on long-term outcomes.

    View details for DOI 10.1093/ehjdh/ztad047

    View details for PubMedID 37794870

    View details for PubMedCentralID PMC10545510

  • Premature ventricular contractions (PVCs) in young athletes. Progress in cardiovascular diseases Gomez, S. E., Hwang, C. E., Kim, D. S., Froelicher, V. F., Wheeler, M. T., Perez, M. V. 2022


    There is a growing body of literature focusing on the morphology, management, and outcomes of PVCs in athletes. This review summarizes this literature and establishes recommendations on management, treatment, and indications for specialist referral in this patient population. The sports medicine physician's responses and recommendation should be made in conjunction with the athletes wishes. Medications or ablations are not always necessary in all athletes if they are followed with regular evaluations.

    View details for DOI 10.1016/j.pcad.2022.10.011

    View details for PubMedID 36309100

  • Mind the Gap: The Complete Human Genome Unlocks Benefits for Clinical Genomics. Clinical chemistry Kim, D. S., Wiel, L., Ashley, E. A. 2022

    View details for DOI 10.1093/clinchem/hvac133

    View details for PubMedID 36112529

  • Lipoprotein(a) and Incident Atrial Fibrillation: Leveraging Nature's Randomization to Identify Novel Causal Associations. Journal of the American College of Cardiology Kim, D. S., Khandelwal, A. 2022; 79 (16): 1591-1593

    View details for DOI 10.1016/j.jacc.2022.02.026

    View details for PubMedID 35450576

  • The genetics of human performance. Nature reviews. Genetics Kim, D. S., Wheeler, M. T., Ashley, E. A. 2021


    Human physiology is likely to have been selected for endurance physical activity. However, modern humans have become largely sedentary, with physical activity becoming a leisure-time pursuit for most. Whereas inactivity is a strong risk factor for disease, regular physical activity reduces the risk of chronic disease and mortality. Although substantial epidemiological evidence supports the beneficial effects of exercise, comparatively little is known about the molecular mechanisms through which these effects operate. Genetic and genomic analyses have identified genetic variation associated with human performance and, together with recent proteomic, metabolomic and multi-omic analyses, are beginning to elucidate the molecular genetic mechanisms underlying the beneficial effects of physical activity on human health.

    View details for DOI 10.1038/s41576-021-00400-5

    View details for PubMedID 34522035

  • Genetics of Type 2 Diabetes: Opportunities for Precision Medicine: JACC Focus Seminar. Journal of the American College of Cardiology Kim, D. S., Gloyn, A. L., Knowles, J. W. 2021; 78 (5): 496-512


    Type 2 diabetes (T2D) is highly prevalent and is a strong contributor for cardiovascular disease. However, there is significant heterogeneity in disease pathogenesis and the risk of complications. Enormous progress has been made in our ability to catalog genetic variation associated with T2D risk and variation in disease-relevant quantitative traits. These discoveries hold the potential to shed light on tractable targets and pathways for safe and effective therapeutic development, but the promise of precision medicine has been slow to be realized. Recent studies have identified subgroups of individuals with differential risk for intermediate phenotypes (eg, lipid levels, fasting insulin, body mass index) that contribute to T2D risk, helping to account for the observed clinical heterogeneity. These "partitioned genetic risk scores" not only have the potential to identify patients at greatest risk of cardiovascular disease and rapid disease progression, but also could aid patient stratification bridging the gap toward precision medicine for T2D.

    View details for DOI 10.1016/j.jacc.2021.03.346

    View details for PubMedID 34325839

  • Loci identified by a genome-wide association study of carotid artery stenosis in the eMERGE network. Genetic epidemiology Palmer, M. R., Kim, D. S., Crosslin, D. R., Stanaway, I. B., Rosenthal, E. A., Carrell, D. S., Cronkite, D. J., Gordon, A., Du, X., Li, Y. K., Williams, M. S., Weng, C., Feng, Q., Li, R., Pendergrass, S. A., Hakonarson, H., Fasel, D., Sohn, S., Sleiman, P., Handelman, S. K., Speliotes, E., Kullo, I. J., Larson, E. B., Jarvik, G. P. 2021; 45 (1): 4-15


    Carotid artery atherosclerotic disease (CAAD) is a risk factor for stroke. We used a genome-wide association (GWAS) approach to discover genetic variants associated with CAAD in participants in the electronic Medical Records and Genomics (eMERGE) Network. We identified adult CAAD cases with unilateral or bilateral carotid artery stenosis and controls without evidence of stenosis from electronic health records at eight eMERGE sites. We performed GWAS with a model adjusting for age, sex, study site, and genetic principal components of ancestry. In eMERGE we found 1793 CAAD cases and 17,958 controls. Two loci reached genome-wide significance, on chr6 in LPA (rs10455872, odds ratio [OR] (95% confidence interval [CI]) = 1.50 (1.30-1.73), p = 2.1 × 10-8 ) and on chr7, an intergenic single nucleotide variant (SNV; rs6952610, OR (95% CI) = 1.25 (1.16-1.36), p = 4.3 × 10-8 ). The chr7 association remained significant in the presence of the LPA SNV as a covariate. The LPA SNV was also associated with coronary heart disease (CHD; 4199 cases and 11,679 controls) in this study (OR (95% CI) = 1.27 (1.13-1.43), p = 5 × 10-5 ) but the chr7 SNV was not (OR (95% CI) = 1.03 (0.97-1.09), p = .37). Both variants replicated in UK Biobank. Elevated lipoprotein(a) concentrations ([Lp(a)]) and LPA variants associated with elevated [Lp(a)] have previously been associated with CAAD and CHD, including rs10455872. With electronic health record phenotypes in eMERGE and UKB, we replicated a previously known association and identified a novel locus associated with CAAD.

    View details for DOI 10.1002/gepi.22360

    View details for PubMedID 32964493

    View details for PubMedCentralID PMC7891640

  • Failure to validate association of mannose-binding lectin deficiency with adverse neurodevelopmental outcomes after cardiac surgery in infants. The Journal of thoracic and cardiovascular surgery Kim, D. S., Newburger, J. W., Bellinger, D. C., Russell, M. W., Goldberg, C. S., Jarvik, G. P., Gaynor, J. W. 2019; 157 (6): e397-e398

    View details for DOI 10.1016/j.jtcvs.2018.10.099

    View details for PubMedID 31307150

  • Hypertriglyceridaemia-induced pancreatitis prompted by acute corticosteroid treatment: caution for clinicians. Internal medicine journal Kim, D. S., O'Hayer, P. J., Rubenfire, M., Brook, R. D. 2019; 49 (3): 411-412

    View details for DOI 10.1111/imj.14228

    View details for PubMedID 30897674

  • Single-Molecule Sequencing Reveals Patterns of Preexisting Drug Resistance That Suggest Treatment Strategies in Philadelphia-Positive Leukemias. Clinical cancer research : an official journal of the American Association for Cancer Research Schmitt, M. W., Pritchard, J. R., Leighow, S. M., Aminov, B. I., Beppu, L., Kim, D. S., Hodgson, J. G., Rivera, V. M., Loeb, L. A., Radich, J. P. 2018; 24 (21): 5321-5334


    Purpose: Sequential treatment with targeted therapies can result in complex combinations of resistance mutations in drug targets. This mutational complexity has spurred the development of pan-target inhibitors, i.e., therapies for which no single target mutation can cause resistance. Because the propensity for on- versus off-target resistance varies across cancer types, a deeper understanding of the mutational burden in drug targets could rationalize treatment outcomes and prioritize pan-target inhibitors for indications where on-target mutations are most likely.Experimental Design: To measure and model the mutational landscape of a drug target at high resolution, we integrated single-molecule Duplex Sequencing of the ABL1 gene in Philadelphia-positive (Ph+) leukemias with computational simulations.Results: A combination of drug target mutational burden and tumor-initiating cell fraction is sufficient to predict that most patients with chronic myeloid leukemia are unlikely to harbor ABL1 resistance mutations at the time of diagnosis, rationalizing the exceptional success of targeted therapy in this setting. In contrast, our analysis predicts that many patients with Ph+ acute lymphoblastic leukemia (Ph+ ALL) harbor multiple preexisting resistant cells with single mutants. The emergence of compound mutations can be traced to initial use of an ABL1 inhibitor that is susceptible to resistance from single point mutations.Conclusions: These results argue that early use of therapies that achieve pan-inhibition of ABL1 resistance mutants might improve outcomes in Ph+ ALL. Our findings show how a deep understanding of the mutational burden in drug targets can be quantitatively coupled to phenotypic heterogeneity to rationalize clinical phenomena. Clin Cancer Res; 24(21); 5321-34. ©2018 AACR.

    View details for DOI 10.1158/1078-0432.CCR-18-0167

    View details for PubMedID 30042204

    View details for PubMedCentralID PMC6214777

  • Identification of seven novel loci associated with amino acid levels using single-variant and gene-based tests in 8545 Finnish men from the METSIM study. Human molecular genetics Teslovich, T. M., Kim, D. S., Yin, X., Stancáková, A., Jackson, A. U., Wielscher, M., Naj, A., Perry, J. R., Huyghe, J. R., Stringham, H. M., Davis, J. P., Raulerson, C. K., Welch, R. P., Fuchsberger, C., Locke, A. E., Sim, X., Chines, P. S., Narisu, N., Kangas, A. J., Soininen, P., Ala-Korpela, M., Gudnason, V., Musani, S. K., Jarvelin, M. R., Schellenberg, G. D., Speliotes, E. K., Kuusisto, J., Collins, F. S., Boehnke, M., Laakso, M., Mohlke, K. L. 2018; 27 (9): 1664-1674


    Comprehensive metabolite profiling captures many highly heritable traits, including amino acid levels, which are potentially sensitive biomarkers for disease pathogenesis. To better understand the contribution of genetic variation to amino acid levels, we performed single variant and gene-based tests of association between nine serum amino acids (alanine, glutamine, glycine, histidine, isoleucine, leucine, phenylalanine, tyrosine, and valine) and 16.6 million genotyped and imputed variants in 8545 non-diabetic Finnish men from the METabolic Syndrome In Men (METSIM) study with replication in Northern Finland Birth Cohort (NFBC1966). We identified five novel loci associated with amino acid levels (P = < 5×10-8): LOC157273/PPP1R3B with glycine (rs9987289, P = 2.3×10-26); ZFHX3 (chr16:73326579, minor allele frequency (MAF) = 0.42%, P = 3.6×10-9), LIPC (rs10468017, P = 1.5×10-8), and WWOX (rs9937914, P = 3.8×10-8) with alanine; and TRIB1 with tyrosine (rs28601761, P = 8×10-9). Gene-based tests identified two novel genes harboring missense variants of MAF <1% that show aggregate association with amino acid levels: PYCR1 with glycine (Pgene = 1.5×10-6) and BCAT2 with valine (Pgene = 7.4×10-7); neither gene was implicated by single variant association tests. These findings are among the first applications of gene-based tests to identify new loci for amino acid levels. In addition to the seven novel gene associations, we identified five independent signals at established amino acid loci, including two rare variant signals at GLDC (rs138640017, MAF=0.95%, Pconditional = 5.8×10-40) with glycine levels and HAL (rs141635447, MAF = 0.46%, Pconditional = 9.4×10-11) with histidine levels. Examination of all single variant association results in our data revealed a strong inverse relationship between effect size and MAF (Ptrend<0.001). These novel signals provide further insight into the molecular mechanisms of amino acid metabolism and potentially, their perturbations in disease.

    View details for DOI 10.1093/hmg/ddy067

    View details for PubMedID 29481666

    View details for PubMedCentralID PMC5905595

  • A novel homozygous ABCA1 variant in an asymptomatic man with profound hypoalphalipoproteinemia. Journal of clinical lipidology Carcora, Y., Brook, R. D., Farhat, L., Willer, C. J., Rubenfire, M., Kim, D. S. 2018; 12 (4): 878-882


    Low high-density lipoprotein cholesterol (HDL-C) can be caused by several acquired secondary causes as well as primary genetic disorders. However, only a few conditions are associated with profoundly reduced levels below 10 mg/dL. We present an unusual case of a healthy man with severely decreased HDL-C because of a novel homozygous variant causing a Proline > Arginine amino acid change at position 1412 in the ATP-binding cassette transporter A1 gene. Homozygous variations in ATP-binding cassette transporter A1 typically cause Tangier disease, a rare autosomal recessive condition linked with several other abnormalities (eg, enlarged discolored tonsils). Despite having an HDL-C below 10 mg/dL, our patient presented without any other clinical symptoms or physical signs suggestive of Tangier disease. This case of presumptive Tangier disease adds support to the growing body of evidence that this genetic disorder may have greater phenotypic heterogeneity along with a more varied presentation than traditionally considered.

    View details for DOI 10.1016/j.jacl.2018.04.005

    View details for PubMedID 29773422

  • Autosomal dominant mannose-binding lectin deficiency is associated with worse neurodevelopmental outcomes after cardiac surgery in infants. The Journal of thoracic and cardiovascular surgery Kim, D. S., Li, Y. K., Kim, J. H., Bergquist, C. S., Gerdes, M., Bernbaum, J. C., Burnham, N., McDonald-McGinn, D. M., Zackai, E. H., Nicolson, S. C., Spray, T. L., Nickerson, D. A., Hakonarson, H., Jarvik, G. P., Gaynor, J. W. 2018; 155 (3): 1139-1147.e2


    The MBL2 gene is the major genetic determinant of mannose-binding lectin (MBL)-an acute phase reactant. Low MBL levels have been associated with adverse outcomes in preterm infants. The MBL2Gly54Asp missense variant causes autosomal dominant MBL deficiency. We tested the hypothesis that MBL2Gly54Asp is associated with worse neurodevelopmental outcomes after cardiac surgery in neonates.This is an analysis of a previously described cohort of patients with nonsyndromic congenital heart disease who underwent cardiac surgery with cardiopulmonary bypass before age 6 months (n = 295). Four-year neurodevelopment was assessed in 3 domains: Full-Scale Intellectual Quotient, the Visual Motor Integration development test, and the Child Behavior Checklist to assess behavior problems. The Child Behavior Checklist measured total behavior problems, pervasive developmental problems, and internalizing/externalizing problems. A multivariable linear regression model, adjusting for confounders, was fit.MBL2Gly54Asp was associated with a significantly increased covariate-adjusted pervasive developmental problem score (β = 3.98; P = .0025). Sensitivity analyses of the interaction between age at first surgery and MBL genotype suggested effect modification for the patients with MBL2Gly54Asp (Pinteraction = .039), with the poorest neurodevelopment outcomes occurring in children who had surgery earlier in life.We report the novel finding that carriers of MBL2Gly54Asp causing autosomal dominant MBL deficiency have increased childhood pervasive developmental problems after cardiac surgery, independent of other covariates. Sensitivity analyses suggest that this effect may be larger in children who underwent surgery at earlier ages. These data support the role of nonsyndromic genetic variation in determining postsurgical neurodevelopment-related outcomes in children with congenital heart disease.

    View details for DOI 10.1016/j.jtcvs.2017.08.035

    View details for PubMedID 29452463

    View details for PubMedCentralID PMC5931363

  • A vascular endothelial growth factor A genetic variant is associated with improved ventricular function and transplant-free survival after surgery for non-syndromic CHD. Cardiology in the young Mavroudis, C. D., Seung Kim, D., Burnham, N., Morss, A. H., Kim, J. H., Burt, A. A., Crosslin, D. R., McDonald-McGinn, D. M., Zackai, E. H., Cohen, M. S., Nicolson, S. C., Spray, T. L., Stanaway, I. B., Nickerson, D. A., Russell, M. W., Hakonarson, H., Jarvik, G. P., Gaynor, J. W. 2018; 28 (1): 39-45


    We have previously shown that the minor alleles of vascular endothelial growth factor A (VEGFA) single-nucleotide polymorphism rs833069 and superoxide dismutase 2 (SOD2) single-nucleotide polymorphism rs2758331 are both associated with improved transplant-free survival after surgery for CHD in infants, but the underlying mechanisms are unknown. We hypothesised that one or both of these minor alleles are associated with better systemic ventricular function, resulting in improved survival.This study is a follow-up analysis of 422 non-syndromic CHD patients who underwent neonatal cardiac surgery with cardiopulmonary bypass. Echocardiographic reports were reviewed. Systemic ventricular function was subjectively categorised as normal, or as mildly, moderately, or severely depressed. The change in function was calculated as the change from the preoperative study to the last available study. Stepwise linear regression, adjusting for covariates, was performed for the outcome of change in ventricular function. Model comparison was performed using Akaike's information criterion. Only variables that improved the model prediction of change in systemic ventricular function were retained in the final model.Genetic and echocardiographic data were available for 335/422 subjects (79%). Of them, 33 (9.9%) developed worse systemic ventricular function during a mean follow-up period of 13.5 years. After covariate adjustment, the presence of the VEGFA minor allele was associated with preserved ventricular function (p=0.011).These data support the hypothesis that the mechanism by which the VEGFA single-nucleotide polymorphism rs833069 minor allele improves survival may be the preservation of ventricular function. Further studies are needed to validate this genotype-phenotype association and to determine whether this mechanism is related to increased vascular endothelial growth factor production.

    View details for DOI 10.1017/S1047951117001391

    View details for PubMedID 28927471

  • HDL and atherosclerotic cardiovascular disease: genetic insights into complex biology. Nature reviews. Cardiology Rosenson, R. S., Brewer, H. B., Barter, P. J., Björkegren, J. L., Chapman, M. J., Gaudet, D., Kim, D. S., Niesor, E., Rye, K. A., Sacks, F. M., Tardif, J. C., Hegele, R. A. 2018; 15 (1): 9-19


    Plasma levels of HDL cholesterol (HDL-C) predict the risk of cardiovascular disease at the epidemiological level, but a direct causal role for HDL in cardiovascular disease remains controversial. Studies in animal models and humans with rare monogenic disorders link only particular HDL-associated mechanisms with causality, including those mechanisms related to particle functionality rather than cholesterol content. Mendelian randomization studies indicate that most genetic variants that affect a range of pathways that increase plasma HDL-C levels are not usually associated with reduced risk of cardiovascular disease, with some exceptions, such as cholesteryl ester transfer protein variants. Furthermore, only a fraction of HDL-C variation has been explained by known loci from genome-wide association studies (GWAS), suggesting the existence of additional pathways and targets. Systems genetics can enhance our understanding of the spectrum of HDL pathways, particularly those pathways that involve new and non-obvious GWAS loci. Bioinformatic approaches can also define new molecular interactions inferred from both large-scale genotypic data and RNA sequencing data to reveal biologically meaningful gene modules and networks governing HDL metabolism with direct relevance to disease end points. Targeting these newly recognized causal networks might inform the development of novel therapeutic strategies to reduce the risk of cardiovascular disease.

    View details for DOI 10.1038/nrcardio.2017.115

    View details for PubMedID 28795686

  • Discovery and replication of SNP-SNP interactions for quantitative lipid traits in over 60,000 individuals. BioData mining Holzinger, E. R., Verma, S. S., Moore, C. B., Hall, M., De, R., Gilbert-Diamond, D., Lanktree, M. B., Pankratz, N., Amuzu, A., Burt, A., Dale, C., Dudek, S., Furlong, C. E., Gaunt, T. R., Kim, D. S., Riess, H., Sivapalaratnam, S., Tragante, V., van Iperen, E. P., Brautbar, A., Carrell, D. S., Crosslin, D. R., Jarvik, G. P., Kuivaniemi, H., Kullo, I. J., Larson, E. B., Rasmussen-Torvik, L. J., Tromp, G., Baumert, J., Cruickshanks, K. J., Farrall, M., Hingorani, A. D., Hovingh, G. K., Kleber, M. E., Klein, B. E., Klein, R., Koenig, W., Lange, L. A., Mӓrz, W., North, K. E., Charlotte Onland-Moret, N., Reiner, A. P., Talmud, P. J., van der Schouw, Y. T., Wilson, J. G., Kivimaki, M., Kumari, M., Moore, J. H., Drenos, F., Asselbergs, F. W., Keating, B. J., Ritchie, M. D. 2017; 10: 25


    The genetic etiology of human lipid quantitative traits is not fully elucidated, and interactions between variants may play a role. We performed a gene-centric interaction study for four different lipid traits: low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC), and triglycerides (TG).Our analysis consisted of a discovery phase using a merged dataset of five different cohorts (n = 12,853 to n = 16,849 depending on lipid phenotype) and a replication phase with ten independent cohorts totaling up to 36,938 additional samples. Filters are often applied before interaction testing to correct for the burden of testing all pairwise interactions. We used two different filters: 1. A filter that tested only single nucleotide polymorphisms (SNPs) with a main effect of p < 0.001 in a previous association study. 2. A filter that only tested interactions identified by Biofilter 2.0. Pairwise models that reached an interaction significance level of p < 0.001 in the discovery dataset were tested for replication. We identified thirteen SNP-SNP models that were significant in more than one replication cohort after accounting for multiple testing.These results may reveal novel insights into the genetic etiology of lipid levels. Furthermore, we developed a pipeline to perform a computationally efficient interaction analysis with multi-cohort replication.

    View details for DOI 10.1186/s13040-017-0145-5

    View details for PubMedID 28770004

    View details for PubMedCentralID PMC5525436

  • Novel association of TM6SF2 rs58542926 genotype with increased serum tyrosine levels and decreased apoB-100 particles in Finns. Journal of lipid research Kim, D. S., Jackson, A. U., Li, Y. K., Stringham, H. M., Kuusisto, J., Kangas, A. J., Soininen, P., Ala-Korpela, M., Burant, C. F., Salomaa, V., Boehnke, M., Laakso, M., Speliotes, E. K. 2017; 58 (7): 1471-1481


    A glutamate-to-lysine variant (rs58542926-T) in transmembrane 6 superfamily member 2 (TM6SF2) is associated with increased fatty liver disease and diabetes in conjunction with decreased cardiovascular disease risk. To identify mediators of the effects of TM6SF2, we tested for associations between rs58542926-T and serum lipoprotein/metabolite measures in cross-sectional data from nondiabetic statin-naïve participants. We identified independent associations between rs58542926-T and apoB-100 particles (β = -0.057 g/l, P = 1.99 × 10-14) and tyrosine levels (β = 0.0020 mmol/l, P = 1.10 × 10-8), controlling for potential confounders, in 6,929 Finnish men. The association between rs58542926-T and apoB-100 was confirmed in an independent sample of 2,196 Finnish individuals from the FINRISK study (βreplication = -0.029, Preplication = 0.029). Secondary analyses demonstrated an rs58542926-T dose-dependent decrease in particle concentration, cholesterol, and triglyceride (TG) content for VLDL and LDL particles (P < 0.001 for all). No significant associations between rs58542926-T and HDL measures were observed. TM6SF2 SNP rs58542926-T and tyrosine levels were associated with increased incident T2D risk in both METSIM and FINRISK. Decreased liver production/secretion of VLDL, decreased cholesterol and TGs in VLDL/LDL particles in serum, and increased tyrosine levels identify possible mechanisms by which rs58542926-T exerts its effects on increasing risk of fatty liver disease, decreasing cardiovascular disease, and increasing diabetes risk, respectively.

    View details for DOI 10.1194/jlr.P076034

    View details for PubMedID 28539357

    View details for PubMedCentralID PMC5496043

  • Sequencing of sporadic Attention-Deficit Hyperactivity Disorder (ADHD) identifies novel and potentially pathogenic de novo variants and excludes overlap with genes associated with autism spectrum disorder. American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics Kim, D. S., Burt, A. A., Ranchalis, J. E., Wilmot, B., Smith, J. D., Patterson, K. E., Coe, B. P., Li, Y. K., Bamshad, M. J., Nikolas, M., Eichler, E. E., Swanson, J. M., Nigg, J. T., Nickerson, D. A., Jarvik, G. P. 2017; 174 (4): 381-389


    Attention-Deficit Hyperactivity Disorder (ADHD) has high heritability; however, studies of common variation account for <5% of ADHD variance. Using data from affected participants without a family history of ADHD, we sought to identify de novo variants that could account for sporadic ADHD. Considering a total of 128 families, two analyses were conducted in parallel: first, in 11 unaffected parent/affected proband trios (or quads with the addition of an unaffected sibling) we completed exome sequencing. Six de novo missense variants at highly conserved bases were identified and validated from four of the 11 families: the brain-expressed genes TBC1D9, DAGLA, QARS, CSMD2, TRPM2, and WDR83. Separately, in 117 unrelated probands with sporadic ADHD, we sequenced a panel of 26 genes implicated in intellectual disability (ID) and autism spectrum disorder (ASD) to evaluate whether variation in ASD/ID-associated genes were also present in participants with ADHD. Only one putative deleterious variant (Gln600STOP) in CHD1L was identified; this was found in a single proband. Notably, no other nonsense, splice, frameshift, or highly conserved missense variants in the 26 gene panel were identified and validated. These data suggest that de novo variant analysis in families with independently adjudicated sporadic ADHD diagnosis can identify novel genes implicated in ADHD pathogenesis. Moreover, that only one of the 128 cases (0.8%, 11 exome, and 117 MIP sequenced participants) had putative deleterious variants within our data in 26 genes related to ID and ASD suggests significant independence in the genetic pathogenesis of ADHD as compared to ASD and ID phenotypes. © 2017 Wiley Periodicals, Inc.

    View details for DOI 10.1002/ajmg.b.32527

    View details for PubMedID 28332277

    View details for PubMedCentralID PMC5467442

  • Limiting Antibiotics When Managing Mandible Fractures May Not Increase Infection Risk. Journal of oral and maxillofacial surgery : official journal of the American Association of Oral and Maxillofacial Surgeons Gaal, A., Bailey, B., Patel, Y., Smiley, N., Dodson, T., Kim, D., Dillon, J. 2016; 74 (10): 2008-18


    To estimate and compare 1) the frequencies of surgical site infections (SSIs) and 2) adverse antibiotic effects (AAEs) between patients who receive only intraoperative antibiotics (study group) and those who receive intraoperative antibiotics plus additional preoperative or postoperative antibiotics (control group) while undergoing operative treatment of open mandibular fractures.The authors designed a retrospective cohort study and enrolled a sample derived from patients presenting to the Harborview Medical Center from 2009 through 2014 for the management of open mandibular fractures. Eligible patients were at least 18 years of age with open, isolated mandibular fractures treated by open reduction and internal fixation using transoral approaches or closed reduction and intermaxillary fixation. The primary predictor variable was antibiotic exposure. The study group received antibiotics administered within 1 hour before the incision, with possible intraoperative re-dosing, and the control group received antibiotics according to the study group plus preoperative or postoperative antibiotics. The primary outcome was SSI frequency. The secondary outcome was AAE frequency. Univariate, bivariate, and multiple logistic regression analyses were performed. Statistical significance was set at a P value less than or equal to .05.The sample was comprised of 510 patients (mean age, 29 ± 11.4 yr; 86% men). The study group had 58 patients (11%) and the control group had 452 patients (89%). The SSI frequencies in the study and control groups were 9 and 17%, respectively (P = .13). There were 5 (1%) AAEs reported, all in the control group. In the multivariable logistic regression model, only tobacco use was associated with an increased risk for SSI (odds ratio = 2.8; 95% confidence interval, 1.5-5.5; P = .0015).Limiting antibiotic exposure to only intraoperative antibiotic prophylaxis in patients undergoing transoral operative treatment of isolated open mandibular fractures was not associated with an increased risk of SSIs.

    View details for DOI 10.1016/j.joms.2016.05.019

    View details for PubMedID 27317592

  • Association Between Absolute Neutrophil Count and Variation at TCIRG1: The NHLBI Exome Sequencing Project. Genetic epidemiology Rosenthal, E. A., Makaryan, V., Burt, A. A., Crosslin, D. R., Kim, D. S., Smith, J. D., Nickerson, D. A., Reiner, A. P., Rich, S. S., Jackson, R. D., Ganesh, S. K., Polfus, L. M., Qi, L., Dale, D. C., Jarvik, G. P. 2016; 40 (6): 470-4


    Neutrophils are a key component of innate immunity. Individuals with low neutrophil count are susceptible to frequent infections. Linkage and association between congenital neutropenia and a single rare missense variant in TCIRG1 have been reported in a single family. Here, we report on nine rare missense variants at evolutionarily conserved sites in TCIRG1 that are associated with lower absolute neutrophil count (ANC; p = 0.005) in 1,058 participants from three cohorts: Atherosclerosis Risk in Communities (ARIC), Coronary Artery Risk Development in Young Adults (CARDIA), and Jackson Heart Study (JHS) of the NHLBI Grand Opportunity Exome Sequencing Project (GO ESP). These results validate the effects of TCIRG1 coding variation on ANC and suggest that this gene may be associated with a spectrum of mild to severe effects on ANC.

    View details for DOI 10.1002/gepi.21976

    View details for PubMedID 27229898

    View details for PubMedCentralID PMC5079157

  • Concentration of Smaller High-Density Lipoprotein Particle (HDL-P) Is Inversely Correlated With Carotid Intima Media Thickening After Confounder Adjustment: The Multi Ethnic Study of Atherosclerosis (MESA). Journal of the American Heart Association Kim, D. S., Li, Y. K., Bell, G. A., Burt, A. A., Vaisar, T., Hutchins, P. M., Furlong, C. E., Otvos, J. D., Polak, J. F., Arnan, M. K., Kaufman, J. D., McClelland, R. L., Longstreth, W. T., Jarvik, G. P. 2016; 5 (5)


    Recent studies have failed to establish a causal relationship between high-density lipoprotein cholesterol levels (HDL-C) and cardiovascular disease (CVD), shifting focus to other HDL measures. We previously reported that smaller/denser HDL levels are protective against cerebrovascular disease. This study sought to determine which of small+medium HDL particle concentration (HDL-P) or large HDL-P was more strongly associated with carotid intima-media thickening (cIMT) in an ethnically diverse cohort.In cross-sectional analyses of participants from the Multi Ethnic Study of Atherosclerosis (MESA), we evaluated the associations of nuclear magnetic resonance spectroscopy-measured small+medium versus large HDL-P with cIMT measured in the common and internal carotid arteries, through linear regression. After adjustment for CVD confounders, low-density lipoprotein cholesterol (LDL-C), HDL-C, and small+medium HDL-P remained significantly and inversely associated with common (coefficient=-1.46 μm; P=0.00037; n=6512) and internal cIMT (coefficient=-3.82 μm; P=0.0051; n=6418) after Bonferroni correction for 4 independent tests (threshold for significance=0.0125; α=0.05/4). Large HDL-P was significantly and inversely associated with both cIMT outcomes before HDL-C adjustment; however, after adjustment for HDL-C, the association of large HDL-P with both common (coefficient=1.55 μm; P=0.30; n=6512) and internal cIMT (coefficient=4.84 μm; P=0.33; n=6418) was attenuated. In a separate sample of 126 men, small/medium HDL-P was more strongly correlated with paraoxonase 1 activity (rp=0.32; P=0.00023) as compared to both total HDL-P (rp=0.27; P=0.0024) and large HDL-P (rp=0.02; P=0.41) measures.Small+medium HDL-P is significantly and inversely correlated with cIMT measurements. Correlation of small+medium HDL-P with cardioprotective paraoxonase 1 activity may reflect a functional aspect of HDL responsible for this finding.

    View details for DOI 10.1161/JAHA.115.002977

    View details for PubMedID 27207961

    View details for PubMedCentralID PMC4889175

  • Burden of potentially pathologic copy number variants is higher in children with isolated congenital heart disease and significantly impairs covariate-adjusted transplant-free survival. The Journal of thoracic and cardiovascular surgery Kim, D. S., Kim, J. H., Burt, A. A., Crosslin, D. R., Burnham, N., Kim, C. E., McDonald-McGinn, D. M., Zackai, E. H., Nicolson, S. C., Spray, T. L., Stanaway, I. B., Nickerson, D. A., Heagerty, P. J., Hakonarson, H., Gaynor, J. W., Jarvik, G. P. 2016; 151 (4): 1147-51.e4


    Copy number variants (CNVs) are duplications or deletions of genomic regions. Large CNVs are potentially pathogenic and are overrepresented in children with congenital heart disease (CHD). We sought to determine the frequency of large CNVs in children with isolated CHD, and to evaluate the relationship of these potentially pathogenic CNVs with transplant-free survival.These cases are derived from a prospective cohort of patients with nonsyndromic CHD (n = 422) identified before first surgery. Healthy pediatric controls (n = 500) were obtained from the electronic Medical Records and Genetic Epidemiology Network, and CNV frequency was contrasted for CHD cases and controls. CNVs were determined algorithmically; subsequently screened for >95% overlap between 2 methods, size (>300 kb), quality score, overlap with a gene, and novelty (absent from databases of known, benign CNVs); and separately validated by quantitative polymerase chain reaction. Survival likelihoods for cases were calculated using Cox proportional hazards modeling to evaluate the joint effect of CNV burden and known confounders on transplant-free survival.Children with nonsyndromic CHD had a higher burden of potentially pathogenic CNVs compared with pediatric controls (12.1% vs 5.0%; P = .00016). Presence of a CNV was associated with significantly decreased transplant-free survival after surgery (hazard ratio, 3.42; 95% confidence interval, 1.66-7.09; P = .00090) with confounder adjustment.We confirm that children with isolated CHD have a greater burden of rare/large CNVs. We report a novel finding that these CNVs are associated with an adjusted 2.55-fold increased risk of death or transplant. These data suggest that CNV burden is an important modifier of survival after surgery for CHD.

    View details for DOI 10.1016/j.jtcvs.2015.09.136

    View details for PubMedID 26704054

    View details for PubMedCentralID PMC4801686

  • PLTP activity inversely correlates with CAAD: effects of PON1 enzyme activity and genetic variants on PLTP activity. Journal of lipid research Kim, D. S., Burt, A. A., Ranchalis, J. E., Vuletic, S., Vaisar, T., Li, W. F., Rosenthal, E. A., Dong, W., Eintracht, J. F., Motulsky, A. G., Brunzell, J. D., Albers, J. J., Furlong, C. E., Jarvik, G. P. 2015; 56 (7): 1351-62


    Recent studies have failed to demonstrate a causal cardioprotective effect of HDL cholesterol levels, shifting focus to the functional aspects of HDL. Phospholipid transfer protein (PLTP) is an HDL-associated protein involved in reverse cholesterol transport. This study sought to determine the genetic and nongenetic predictors of plasma PLTP activity (PLTPa), and separately, to determine whether PLTPa predicted carotid artery disease (CAAD). PLTPa was measured in 1,115 European ancestry participants from a case-control study of CAAD. A multivariate logistic regression model was used to elucidate the relationship between PLTPa and CAAD. Separately, a stepwise linear regression determined the nongenetic clinical and laboratory characteristics that best predicted PLTPa. A final stepwise regression considering both nongenetic and genetic variables identified the combination of covariates that explained maximal PLTPa variance. PLTPa was significantly associated with CAAD (7.90 × 10(-9)), with a 9% decrease in odds of CAAD per 1 unit increase in PLTPa (odds ratio = 0.91). Triglyceride levels (P = 0.0042), diabetes (P = 7.28 × 10(-5)), paraoxonase 1 (PON1) activity (P = 0.019), statin use (P = 0.026), PLTP SNP rs4810479 (P = 6.38 × 10(-7)), and PCIF1 SNP rs181914932 (P = 0.041) were all significantly associated with PLTPa. PLTPa is significantly inversely correlated with CAAD. Furthermore, we report a novel association between PLTPa and PON1 activity, a known predictor of CAAD.

    View details for DOI 10.1194/jlr.P058032

    View details for PubMedID 26009633

    View details for PubMedCentralID PMC4479339

  • Rare and Coding Region Genetic Variants Associated With Risk of Ischemic Stroke: The NHLBI Exome Sequence Project. JAMA neurology Auer, P. L., Nalls, M., Meschia, J. F., Worrall, B. B., Longstreth, W. T., Seshadri, S., Kooperberg, C., Burger, K. M., Carlson, C. S., Carty, C. L., Chen, W. M., Cupples, L. A., DeStefano, A. L., Fornage, M., Hardy, J., Hsu, L., Jackson, R. D., Jarvik, G. P., Kim, D. S., Lakshminarayan, K., Lange, L. A., Manichaikul, A., Quinlan, A. R., Singleton, A. B., Thornton, T. A., Nickerson, D. A., Peters, U., Rich, S. S. 2015; 72 (7): 781-8


    Stroke is the second leading cause of death and the third leading cause of years of life lost. Genetic factors contribute to stroke prevalence, and candidate gene and genome-wide association studies (GWAS) have identified variants associated with ischemic stroke risk. These variants often have small effects without obvious biological significance. Exome sequencing may discover predicted protein-altering variants with a potentially large effect on ischemic stroke risk.To investigate the contribution of rare and common genetic variants to ischemic stroke risk by targeting the protein-coding regions of the human genome.The National Heart, Lung, and Blood Institute (NHLBI) Exome Sequencing Project (ESP) analyzed approximately 6000 participants from numerous cohorts of European and African ancestry. For discovery, 365 cases of ischemic stroke (small-vessel and large-vessel subtypes) and 809 European ancestry controls were sequenced; for replication, 47 affected sibpairs concordant for stroke subtype and an African American case-control series were sequenced, with 1672 cases and 4509 European ancestry controls genotyped. The ESP's exome sequencing and genotyping started on January 1, 2010, and continued through June 30, 2012. Analyses were conducted on the full data set between July 12, 2012, and July 13, 2013.Discovery of new variants or genes contributing to ischemic stroke risk and subtype (primary analysis) and determination of support for protein-coding variants contributing to risk in previously published candidate genes (secondary analysis).We identified 2 novel genes associated with an increased risk of ischemic stroke: a protein-coding variant in PDE4DIP (rs1778155; odds ratio, 2.15; P = 2.63 × 10(-8)) with an intracellular signal transduction mechanism and in ACOT4 (rs35724886; odds ratio, 2.04; P = 1.24 × 10(-7)) with a fatty acid metabolism; confirmation of PDE4DIP was observed in affected sibpair families with large-vessel stroke subtype and in African Americans. Replication of protein-coding variants in candidate genes was observed for 2 previously reported GWAS associations: ZFHX3 (cardioembolic stroke) and ABCA1 (large-vessel stroke).Exome sequencing discovered 2 novel genes and mechanisms, PDE4DIP and ACOT4, associated with increased risk for ischemic stroke. In addition, ZFHX3 and ABCA1 were discovered to have protein-coding variants associated with ischemic stroke. These results suggest that genetic variation in novel pathways contributes to ischemic stroke risk and serves as a target for prediction, prevention, and therapy.

    View details for DOI 10.1001/jamaneurol.2015.0582

    View details for PubMedID 25961151

    View details for PubMedCentralID PMC4673986

  • Actionable exomic incidental findings in 6503 participants: challenges of variant classification GENOME RESEARCH Amendola, L. M., Dorschner, M. O., Robertson, P. D., Salama, J. S., Hart, R., Shirts, B. H., Murray, M. L., Tokita, M. J., Gallego, C. J., Kim, D. S., Bennett, J. T., Crosslin, D. R., Ranchalis, J., Jones, K. L., Rosenthal, E. A., Jarvik, E. R., Itsara, A., Turner, E. H., Herman, D. S., Schleit, J., Burt, A., Jamal, S. M., Abrudan, J. L., Johnson, A. D., Conlin, L. K., Dulik, M. C., Santani, A., Metterville, D. R., Kelly, M., Foreman, A. K., Lee, K., Taylor, K. D., Guo, X., Crooks, K., Kiedrowski, L. A., Raffe, L. J., Gordon, O., Machini, K., Desnick, R., Biesecker, L. G., Lubitz, S. A., Mulchandani, S., Cooper, G. M., Joffe, S., Richards, C. S., Yang, Y., Rotter, J. I., Rich, S. S., O'Donne, C. J., Berg, J. S., Spinner, N. B., Evans, J. P., Fullerton, S. M., Leppig, K. A., Bennett, R. L., Bird, T., Sybert, V. P., Grady, W. M., Tabor, H. K., Kim, J. H., Bamshad, M. J., Wilfond, B., Motulsky, A. G., Scott, R., Pritchard, C. C., Walsh, T. D., Burke, W., Raskind, W. H., Byers, P., Hisama, F. M., Rehm, H., Nickerson, D. A., Jarvik, G. P. 2015; 25 (3): 305-315


    Recommendations for laboratories to report incidental findings from genomic tests have stimulated interest in such results. In order to investigate the criteria and processes for assigning the pathogenicity of specific variants and to estimate the frequency of such incidental findings in patients of European and African ancestry, we classified potentially actionable pathogenic single-nucleotide variants (SNVs) in all 4300 European- and 2203 African-ancestry participants sequenced by the NHLBI Exome Sequencing Project (ESP). We considered 112 gene-disease pairs selected by an expert panel as associated with medically actionable genetic disorders that may be undiagnosed in adults. The resulting classifications were compared to classifications from other clinical and research genetic testing laboratories, as well as with in silico pathogenicity scores. Among European-ancestry participants, 30 of 4300 (0.7%) had a pathogenic SNV and six (0.1%) had a disruptive variant that was expected to be pathogenic, whereas 52 (1.2%) had likely pathogenic SNVs. For African-ancestry participants, six of 2203 (0.3%) had a pathogenic SNV and six (0.3%) had an expected pathogenic disruptive variant, whereas 13 (0.6%) had likely pathogenic SNVs. Genomic Evolutionary Rate Profiling mammalian conservation score and the Combined Annotation Dependent Depletion summary score of conservation, substitution, regulation, and other evidence were compared across pathogenicity assignments and appear to have utility in variant classification. This work provides a refined estimate of the burden of adult onset, medically actionable incidental findings expected from exome sequencing, highlights challenges in variant classification, and demonstrates the need for a better curated variant interpretation knowledge base.

    View details for DOI 10.1101/gr.183483.114

    View details for Web of Science ID 000350526700001

    View details for PubMedID 25637381

    View details for PubMedCentralID PMC4352885

  • Association of exome sequences with plasma C-reactive protein levels in >9000 participants. Human molecular genetics Schick, U. M., Auer, P. L., Bis, J. C., Lin, H., Wei, P., Pankratz, N., Lange, L. A., Brody, J., Stitziel, N. O., Kim, D. S., Carlson, C. S., Fornage, M., Haessler, J., Hsu, L., Jackson, R. D., Kooperberg, C., Leal, S. M., Psaty, B. M., Boerwinkle, E., Tracy, R., Ardissino, D., Shah, S., Willer, C., Loos, R., Melander, O., Mcpherson, R., Hovingh, K., Reilly, M., Watkins, H., Girelli, D., Fontanillas, P., Chasman, D. I., Gabriel, S. B., Gibbs, R., Nickerson, D. A., Kathiresan, S., Peters, U., Dupuis, J., Wilson, J. G., Rich, S. S., Morrison, A. C., Benjamin, E. J., Gross, M. D., Reiner, A. P. 2015; 24 (2): 559-71


    C-reactive protein (CRP) concentration is a heritable systemic marker of inflammation that is associated with cardiovascular disease risk. Genome-wide association studies have identified CRP-associated common variants associated in ∼25 genes. Our aims were to apply exome sequencing to (1) assess whether the candidate loci contain rare coding variants associated with CRP levels and (2) perform an exome-wide search for rare variants in novel genes associated with CRP levels. We exome-sequenced 6050 European-Americans (EAs) and 3109 African-Americans (AAs) from the NHLBI-ESP and the CHARGE consortia, and performed association tests of sequence data with measured CRP levels. In single-variant tests across candidate loci, a novel rare (minor allele frequency = 0.16%) CRP-coding variant (rs77832441-A; p.Thr59Met) was associated with 53% lower mean CRP levels (P = 2.9 × 10(-6)). We replicated the association of rs77832441 in an exome array analysis of 11 414 EAs (P = 3.0 × 10(-15)). Despite a strong effect on CRP levels, rs77832441 was not associated with inflammation-related phenotypes including coronary heart disease. We also found evidence for an AA-specific association of APOE-ε2 rs7214 with higher CRP levels. At the exome-wide significance level (P < 5.0 × 10(-8)), we confirmed associations for reported common variants of HNF1A, CRP, IL6R and TOMM40-APOE. In gene-based tests, a burden of rare/lower frequency variation in CRP in EAs (P ≤ 6.8 × 10(-4)) and in retinoic acid receptor-related orphan receptor α (RORA) in AAs (P = 1.7 × 10(-3)) were associated with CRP levels at the candidate gene level (P < 2.0 × 10(-3)). This inquiry did not elucidate novel genes, but instead demonstrated that variants distributed across the allele frequency spectrum within candidate genes contribute to CRP levels.

    View details for DOI 10.1093/hmg/ddu450

    View details for PubMedID 25187575

    View details for PubMedCentralID PMC4334838

  • Parallel reaction monitoring (PRM) and selected reaction monitoring (SRM) exhibit comparable linearity, dynamic range and precision for targeted quantitative HDL proteomics. Journal of proteomics Ronsein, G. E., Pamir, N., von Haller, P. D., Kim, D. S., Oda, M. N., Jarvik, G. P., Vaisar, T., Heinecke, J. W. 2015; 113: 388-99


    High-density lipoprotein (HDL), a lipid nanoparticle containing many different low abundance proteins, is an attractive target for clinical proteomics because its compositional heterogeneity is linked to its cardioprotective effects. Selected reaction monitoring (SRM) is currently the method of choice for targeted quantification of proteins in such a complex biological matrix. However, model system studies suggest that parallel reaction monitoring (PRM) is more specific than SRM because many product ions can be used to confirm the identity of a peptide. We therefore compared PRM and SRM for their abilities to quantify proteins in HDL, using (15)N-labeled apolipoprotein A-I (HDL's most abundant protein) as the internal standard. PRM and SRM exhibited comparable linearity, dynamic range, precision, and repeatability for protein quantification of HDL. Moreover, the single internal standard protein performed as well as protein-specific peptide internal standards when quantifying 3 different proteins. Importantly, PRM and SRM yielded virtually identical quantitative results for 26 proteins in HDL isolated from 44 subjects. Because PRM requires less method development than SRM and is potentially more specific, our observations indicate that PRM in concert with a single isotope-labeled protein is a promising new strategy for quantifying HDL proteins in translational studies.HDL, a complex matrix composed of lipids and proteins, is implicated in cardioprotection. Its cholesterol content correlates inversely with cardiovascular disease and it is the current metric to assess cardiovascular risk. However, the cholesterol content does not capture HDL's complexity and heterogeneity. Devising metrics that better capture HDL's cardioprotective effects, we developed an optimized method for quantification of HDL proteome, using PRM in concert with a single labeled protein as internal standard. The availability of a method that increases sample throughput without compromising the reproducibility, sensitivity, and accuracy could therefore point to better risk assessment for CVD or other diseases.

    View details for DOI 10.1016/j.jprot.2014.10.017

    View details for PubMedID 25449833

    View details for PubMedCentralID PMC4259393

  • Validation of association of the apolipoprotein E ε2 allele with neurodevelopmental dysfunction after cardiac surgery in neonates and infants. The Journal of thoracic and cardiovascular surgery Gaynor, J. W., Kim, D. S., Arrington, C. B., Atz, A. M., Bellinger, D. C., Burt, A. A., Ghanayem, N. S., Jacobs, J. P., Lee, T. M., Lewis, A. B., Mahle, W. T., Marino, B. S., Miller, S. G., Newburger, J. W., Pizarro, C., Ravishankar, C., Santani, A. B., Wilder, N. S., Jarvik, G. P., Mital, S., Russell, M. W. 2014; 148 (6): 2560-6


    Apolipoprotein E (APOE) genotype is a determinant of neurologic recovery after brain ischemia and traumatic brain injury. The APOE ε2 allele has been associated with worse neurodevelopmental (ND) outcome after repair of congenital heart defects (CHD) in infancy. Replication of this finding in an independent cohort is essential to validate the observed genotype-phenotype association.The association of APOE genotype with ND outcomes was assessed in a combined cohort of patients with single-ventricle CHD enrolled in the Single Ventricle Reconstruction and Infant Single Ventricle trials. ND outcome was assessed at 14 months using the Psychomotor Development Index (PDI) and Mental Development Index (MDI) of the Bayley Scales of Infant Development-II. Stepwise multivariable regression was performed to develop predictive models for PDI and MDI scores.Complete data were available for 298 of 435 patients. After adjustment for preoperative and postoperative covariates, the APOE ε2 allele was associated with a lower PDI score (P = .038). Patients with the ε2 allele had a PDI score approximately 6 points lower than those without the risk allele, explaining 1.04% of overall PDI variance, because the ε2 allele was present in only 11% of the patients. There was a marginal effect of the ε2 allele on MDI scores (P = .058).These data validate the association of the APOE ε2 allele with adverse early ND outcomes after cardiac surgery in infants, independent of patient and operative factors. Genetic variants that decrease neuroresilience and impair neuronal repair after brain injury are important risk factors for ND dysfunction after surgery for CHD.

    View details for DOI 10.1016/j.jtcvs.2014.07.052

    View details for PubMedID 25282659

    View details for PubMedCentralID PMC4376113

  • Controlling for population structure and genotyping platform bias in the eMERGE multi-institutional biobank linked to electronic health records. Frontiers in genetics Crosslin, D. R., Tromp, G., Burt, A., Kim, D. S., Verma, S. S., Lucas, A. M., Bradford, Y., Crawford, D. C., Armasu, S. M., Heit, J. A., Hayes, M. G., Kuivaniemi, H., Ritchie, M. D., Jarvik, G. P., de Andrade, M. 2014; 5: 352


    Combining samples across multiple cohorts in large-scale scientific research programs is often required to achieve the necessary power for genome-wide association studies. Controlling for genomic ancestry through principal component analysis (PCA) to address the effect of population stratification is a common practice. In addition to local genomic variation, such as copy number variation and inversions, other factors directly related to combining multiple studies, such as platform and site recruitment bias, can drive the correlation patterns in PCA. In this report, we describe the combination and analysis of multi-ethnic cohort with biobanks linked to electronic health records for large-scale genomic association discovery analyses. First, we outline the observed site and platform bias, in addition to ancestry differences. Second, we outline a general protocol for selecting variants for input into the subject variance-covariance matrix, the conventional PCA approach. Finally, we introduce an alternative approach to PCA by deriving components from subject loadings calculated from a reference sample. This alternative approach of generating principal components controlled for site and platform bias, in addition to ancestry differences, has the advantage of fewer covariates and degrees of freedom.

    View details for DOI 10.3389/fgene.2014.00352

    View details for PubMedID 25414722

    View details for PubMedCentralID PMC4220165

  • Quantification of HDL particle concentration by calibrated ion mobility analysis. Clinical chemistry Hutchins, P. M., Ronsein, G. E., Monette, J. S., Pamir, N., Wimberger, J., He, Y., Anantharamaiah, G. M., Kim, D. S., Ranchalis, J. E., Jarvik, G. P., Vaisar, T., Heinecke, J. W. 2014; 60 (11): 1393-401


    It is critical to develop new metrics to determine whether HDL is cardioprotective in humans. One promising approach is HDL particle concentration (HDL-P), the size and concentration of HDL in plasma. However, the 2 methods currently used to determine HDL-P yield concentrations that differ >5-fold. We therefore developed and validated an improved approach to quantify HDL-P, termed calibrated ion mobility analysis (calibrated IMA).HDL was isolated from plasma by ultracentrifugation, introduced into the gas phase with electrospray ionization, separated by size, and quantified by particle counting. We used a calibration curve constructed with purified proteins to correct for the ionization efficiency of HDL particles.The concentrations of gold nanoparticles and reconstituted HDLs measured by calibrated IMA were indistinguishable from concentrations determined by orthogonal methods. In plasma of control (n = 40) and cerebrovascular disease (n = 40) participants, 3 subspecies of HDL were reproducibility measured, with an estimated total HDL-P of 13.4 (2.4) μmol/L. HDL-C accounted for 48% of the variance in HDL-P. HDL-P was significantly lower in participants with cerebrovascular disease (P = 0.002), and this difference remained significant after adjustment for HDL cholesterol concentrations (P = 0.02).Calibrated IMA accurately determined the concentration of gold nanoparticles and synthetic HDL, strongly suggesting that the method could accurately quantify HDL particle concentration. The estimated stoichiometry of apolipoprotein A-I determined by calibrated IMA was 3-4 per HDL particle, in agreement with current structural models. Furthermore, HDL-P was associated with cardiovascular disease status in a clinical population independently of HDL cholesterol.

    View details for DOI 10.1373/clinchem.2014.228114

    View details for PubMedID 25225166

    View details for PubMedCentralID PMC4324763

  • Design and Anticipated Outcomes of the eMERGE-PGx Project: A Multicenter Pilot for Preemptive Pharmacogenomics in Electronic Health Record Systems CLINICAL PHARMACOLOGY & THERAPEUTICS Rasmussen-Torvik, L. J., Stallings, S. C., Gordon, A. S., Almoguera, B., Basford, M. A., Bielinski, S. J., Brautbar, A., Brilliant, M. H., Carrell, D. S., Connolly, J. J., Crosslin, D. R., Doheny, K. F., Gallego, C. J., Gottesman, O., Kim, D. S., Leppig, K. A., Li, R., Lin, S., Manzi, S., Mejia, A. R., Pacheco, J. A., Pan, V., Pathak, J., Perry, C. L., Peterson, J. F., Prows, C. A., Ralston, J., Rasmussen, L. V., Ritchie, M. D., Sadhasivam, S., Scott, S. A., Smith, M., Vega, A., Vinks, A. A., Volpi, S., Wolf, W. A., Bottinger, E., Chisholm, R. L., Chute, C. G., Haines, J. L., Harley, J. B., Keating, B., Holm, I. A., Kullo, I. J., Jarvik, G. P., Larson, E. B., Manolio, T., McCarty, C. A., Nickerson, D. A., Scherer, S. E., Williams, M. S., Roden, D. M., Denny, J. C. 2014; 96 (4): 482–89


    We describe here the design and initial implementation of the eMERGE-PGx project. eMERGE-PGx, a partnership of the Electronic Medical Records and Genomics Network and the Pharmacogenomics Research Network, has three objectives: (i) to deploy PGRNseq, a next-generation sequencing platform assessing sequence variation in 84 proposed pharmacogenes, in nearly 9,000 patients likely to be prescribed drugs of interest in a 1- to 3-year time frame across several clinical sites; (ii) to integrate well-established clinically validated pharmacogenetic genotypes into the electronic health record with associated clinical decision support and to assess process and clinical outcomes of implementation; and (iii) to develop a repository of pharmacogenetic variants of unknown significance linked to a repository of electronic health record-based clinical phenotype data for ongoing pharmacogenomics discovery. We describe site-specific project implementation and anticipated products, including genetic variant and phenotype data repositories, novel variant association studies, clinical decision support modules, clinical and process outcomes, approaches to managing incidental findings, and patient and clinician education methods.

    View details for DOI 10.1038/clpt.2014.137

    View details for Web of Science ID 000342675400027

    View details for PubMedID 24960519

    View details for PubMedCentralID PMC4169732

  • Effects of dietary components on high-density lipoprotein measures in a cohort of 1,566 participants. Nutrition & metabolism Kim, D. S., Burt, A. A., Ranchalis, J. E., Jarvik, L. E., Eintracht, J. F., Furlong, C. E., Jarvik, G. P. 2014; 11 (1): 44


    Recent data suggest that an increased level of high-density lipoprotein cholesterol (HDL-C) is not causally protective against heart disease, shifting focus to other sub-phenotypes of HDL. Prior work on the effects of dietary intakes has focused largely on HDL-C. The goal of this study was to identify the dietary intakes that affect HDL-related measures: HDL-C, HDL-2, HDL-3, and apoA1 using data from a carotid artery disease case-control cohort.A subset of 1,566 participants with extensive lipid phenotype data completed the Harvard Standardized Food Frequency Questionnaire to determine their daily micronutrient intake over the past year. Stepwise linear regression was used to separately evaluate the effects of dietary covariates on adjusted levels of HDL-C, HDL-2, HDL-3, and apoA1.Dietary folate intake was positively associated with HDL-C (p = 0.007), HDL-2 (p = 0.0011), HDL-3 (p = 0.0022), and apoA1 (p = 0.001). Alcohol intake and myristic acid (14:0), a saturated fat, were each significantly associated with increased levels of all HDL-related measures studied. Dietary carbohydrate and iron intake were significantly associated with decreased levels of all HDL-related measures. Magnesium intake was positively associated with HDL-C, HDL-2, and HDL-3 levels, but not apoA1 levels, while vitamin C was only associated with apoA1 levels. Dietary fiber and protein intake were both associated with HDL-3 levels alone.This study is the first to report that dietary folate intake is associated with HDL-C, HDL-2, HDL-3, and apoA1 levels in humans. We further identify numerous dietary intake associations with apoA1, HDL-2, and HDL-3 levels. Given the shifting focus away from HDL-C, these data will prove valuable for future epidemiologic investigation of the role of diet and multiple HDL phenotypes in heart disease.

    View details for DOI 10.1186/1743-7075-11-44

    View details for PubMedID 25264450

    View details for PubMedCentralID PMC4177053

  • The relationship between diastolic blood pressure and coronary artery calcification is dependent on single nucleotide polymorphisms on chromosome 9p21.3. BMC medical genetics Kim, D. S., Smith, J. A., Bielak, L. F., Wu, C. Y., Sun, Y. V., Sheedy, P. F., Turner, S. T., Peyser, P. A., Kardia, S. L. 2014; 15: 89


    Single nucleotide polymorphisms (SNPs) within the 9p21.3 genomic region have been consistently associated with coronary heart disease (CHD), myocardial infarction, and quantity of coronary artery calcification (CAC), a marker of subclinical atherosclerosis. Prior studies have established an association between blood pressure measures and CAC. To examine mechanisms by which the 9p21.3 genomic region may influence CHD risk, we investigated whether SNPs in 9p21.3 modified associations between blood pressure and CAC quantity.As part of the Genetic Epidemiology Network of Arteriopathy (GENOA) Study, 974 participants underwent non-invasive computed tomography (CT) to measure CAC quantity. Linear mixed effects models were used to investigate whether seven SNPs in the 9p21.3 region modified the association between blood pressure levels and CAC quantity. Four SNPs of at least marginal significance in GENOA for a SNP-by-diastolic blood pressure (DBP) interaction were then tested for replication in the Framingham Heart Study's Offspring Cohort (N = 1,140).We found replicated evidence that one SNP, rs2069416, in CDKN2B-AS1, significantly modified the association between DBP and CAC quantity (combined P = 0.0065; Bonferroni-corrected combined P = 0.0455).Our results represent a novel finding that the relationship between DBP and CAC is dependent on genetic variation in the 9p21.3 region. Thus, variation in 9p21.3 may not only be an independent genetic risk factor for CHD, but also may modify the association between DBP levels and the extent of subclinical coronary atherosclerosis.

    View details for DOI 10.1186/s12881-014-0089-2

    View details for PubMedID 25185447

    View details for PubMedCentralID PMC4168694

  • Patient genotypes impact survival after surgery for isolated congenital heart disease. The Annals of thoracic surgery Kim, D. S., Kim, J. H., Burt, A. A., Crosslin, D. R., Burnham, N., McDonald-McGinn, D. M., Zackai, E. H., Nicolson, S. C., Spray, T. L., Stanaway, I. B., Nickerson, D. A., Russell, M. W., Hakonarson, H., Gaynor, J. W., Jarvik, G. P. 2014; 98 (1): 104-10; discussion 110-1


    Survival after cardiac surgery in infancy requires adaptive responses from oxidative stress management and vascular regulation pathways. We tested the hypothesis that genetic variation in these pathways influences postoperative survival in nonsyndromic congenital heart disease children.This is an analysis of a cohort of nonsyndromic congenital heart disease patients who underwent cardiac surgery with cardiopulmonary bypass before 6 months of age (n=422). Six single nucleotide polymorphisms (SNPs) in six genes involved in oxidative stress and vascular response pathways, identified through a priori literature search, were tested for effects on transplant-free survival. Survival curves, adjusting for confounding covariates, were calculated using the Cox proportional hazard models.Long-term survival was strongly associated with vascular endothelial growth factor A gene SNP rs833069 (p=7.03×10(-4)) and superoxide dismutase 2 gene SNP rs2758331 (p=0.019). To test for joint effects of the two SNPs on transplant-free survival, the genotypes were grouped to form a risk score reflecting the cumulative number of risk alleles (0 to 4 alleles per patient). A higher risk score based on the VEGFA and SOD2 SNP genotypes was associated with worse transplant-free survival (p=3.02×10(-4)) after confounder adjustment. The total burden of risk alleles was additive; subjects with the highest risk score of 4 (n=59 subjects, 14.2% of the cohort) had a total covariate-adjusted hazard ratio of 15.64 for worse transplant-free survival.After cardiac surgery, infants who are homozygous for the high-risk alleles for both the VEGFA and SOD2 SNPs have an approximately 16-fold increased risk of death or heart transplant, suggesting that genetic variants are important modifiers of survival after surgery for congenital heart disease.

    View details for DOI 10.1016/j.athoracsur.2014.03.017

    View details for PubMedID 24811984

    View details for PubMedCentralID PMC4083015

  • HDL-3 is a superior predictor of carotid artery disease in a case-control cohort of 1725 participants. Journal of the American Heart Association Kim, D. S., Burt, A. A., Rosenthal, E. A., Ranchalis, J. E., Eintracht, J. F., Hatsukami, T. S., Furlong, C. E., Marcovina, S., Albers, J. J., Jarvik, G. P. 2014; 3 (3): e000902


    Recent data suggest that high-density lipoprotein cholesterol (HDL-C) levels are likely not in the causative pathway of atheroprotection, shifting focus from HDL-C to its subfractions and associated proteins. This study's goal was to determine which HDL phenotype was the better predictor of carotid artery disease (CAAD).HDL-2 and HDL-3 were measured in 1725 participants of European ancestry in a prevalent case-control cohort study of CAAD. Stratified analyses were conducted for men (n=1201) and women (n=524). Stepwise linear regression was used to determine whether HDL-C, HDL-2, HDL-3, or apolipoprotein A1 was the best predictor of CAAD, while adjusting for the confounders of censored age, diabetes, and current smoking status. In both men and women, HDL-3 was negatively associated with CAAD (P=0.0011 and 0.033 for men and women, respectively); once HDL-3 was included in the model, no other HDL phenotype was significantly associated with CAAD. Addition of paraoxonase 1 activity to the aforementioned regression model showed a significant and independent (of HDL-3) association with CAAD in men (P=0.001) but not in the smaller female subgroup.This study is the first to contrast the associations of HDL-2 and HDL-3 with CAAD. We found that HDL-3 levels were more predictive of CAAD status than HDL-2, HDL-C, or apolipoprotein A1. In addition, for men, paraoxonase 1 activity improved the overall model prediction for CAAD independently and additively with HDL-3 levels. Further investigation into the molecular mechanisms through which HDL-3 is associated with protection from CAAD is warranted.

    View details for DOI 10.1161/JAHA.114.000902

    View details for PubMedID 24965026

    View details for PubMedCentralID PMC4309059

  • Rare coding variation in paraoxonase-1 is associated with ischemic stroke in the NHLBI Exome Sequencing Project. Journal of lipid research Kim, D. S., Crosslin, D. R., Auer, P. L., Suzuki, S. M., Marsillach, J., Burt, A. A., Gordon, A. S., Meschia, J. F., Nalls, M. A., Worrall, B. B., Longstreth, W. T., Gottesman, R. F., Furlong, C. E., Peters, U., Rich, S. S., Nickerson, D. A., Jarvik, G. P. 2014; 55 (6): 1173-8


    HDL-associated paraoxonase-1 (PON1) is an enzyme whose activity is associated with cerebrovascular disease. Common PON1 genetic variants have not been consistently associated with cerebrovascular disease. Rare coding variation that likely alters PON1 enzyme function may be more strongly associated with stroke. The National Heart, Lung, and Blood Institute Exome Sequencing Project sequenced the coding regions (exomes) of the genome for heart, lung, and blood-related phenotypes (including ischemic stroke). In this sample of 4,204 unrelated participants, 496 had verified, noncardioembolic ischemic stroke. After filtering, 28 nonsynonymous PON1 variants were identified. Analysis with the sequence kernel association test, adjusted for covariates, identified significant associations between PON1 variants and ischemic stroke (P = 3.01 × 10(-3)). Stratified analyses demonstrated a stronger association of PON1 variants with ischemic stroke in African ancestry (AA) participants (P = 5.03 × 10(-3)). Ethnic differences in the association between PON1 variants with stroke could be due to the effects of PON1Val109Ile (overall P = 7.88 × 10(-3); AA P = 6.52 × 10(-4)), found at higher frequency in AA participants (1.16% vs. 0.02%) and whose protein is less stable than the common allele. In summary, rare genetic variation in PON1 was associated with ischemic stroke, with stronger associations identified in those of AA. Increased focus on PON1 enzyme function and its role in cerebrovascular disease is warranted.

    View details for DOI 10.1194/jlr.P049247

    View details for PubMedID 24711634

    View details for PubMedCentralID PMC4031948

  • Gene-centric Meta-analysis in 87,736 Individuals of European Ancestry Identifies Multiple Blood-Pressure-Related Loci. American journal of human genetics Tragante, V., Barnes, M. R., Ganesh, S. K., Lanktree, M. B., Guo, W., Franceschini, N., Smith, E. N., Johnson, T., Holmes, M. V., Padmanabhan, S., Karczewski, K. J., Almoguera, B., Barnard, J., Baumert, J., Chang, Y. C., Elbers, C. C., Farrall, M., Fischer, M. E., Gaunt, T. R., Gho, J. M., Gieger, C., Goel, A., Gong, Y., Isaacs, A., Kleber, M. E., Mateo Leach, I., McDonough, C. W., Meijs, M. F., Melander, O., Nelson, C. P., Nolte, I. M., Pankratz, N., Price, T. S., Shaffer, J., Shah, S., Tomaszewski, M., van der Most, P. J., van Iperen, E. P., Vonk, J. M., Witkowska, K., Wong, C. O., Zhang, L., Beitelshees, A. L., Berenson, G. S., Bhatt, D. L., Brown, M., Burt, A., Cooper-DeHoff, R. M., Connell, J. M., Cruickshanks, K. J., Curtis, S. P., Davey-Smith, G., Delles, C., Gansevoort, R. T., Guo, X., Haiqing, S., Hastie, C. E., Hofker, M. H., Hovingh, G. K., Kim, D. S., Kirkland, S. A., Klein, B. E., Klein, R., Li, Y. R., Maiwald, S., Newton-Cheh, C., O'Brien, E. T., Onland-Moret, N. C., Palmas, W., Parsa, A., Penninx, B. W., Pettinger, M., Vasan, R. S., Ranchalis, J. E., M Ridker, P., Rose, L. M., Sever, P., Shimbo, D., Steele, L., Stolk, R. P., Thorand, B., Trip, M. D., van Duijn, C. M., Verschuren, W. M., Wijmenga, C., Wyatt, S., Young, J. H., Zwinderman, A. H., Bezzina, C. R., Boerwinkle, E., Casas, J. P., Caulfield, M. J., Chakravarti, A., Chasman, D. I., Davidson, K. W., Doevendans, P. A., Dominiczak, A. F., FitzGerald, G. A., Gums, J. G., Fornage, M., Hakonarson, H., Halder, I., Hillege, H. L., Illig, T., Jarvik, G. P., Johnson, J. A., Kastelein, J. J., Koenig, W., Kumari, M., März, W., Murray, S. S., O'Connell, J. R., Oldehinkel, A. J., Pankow, J. S., Rader, D. J., Redline, S., Reilly, M. P., Schadt, E. E., Kottke-Marchant, K., Snieder, H., Snyder, M., Stanton, A. V., Tobin, M. D., Uitterlinden, A. G., van der Harst, P., van der Schouw, Y. T., Samani, N. J., Watkins, H., Johnson, A. D., Reiner, A. P., Zhu, X., de Bakker, P. I., Levy, D., Asselbergs, F. W., Munroe, P. B., Keating, B. J. 2014; 94 (3): 349-360


    Blood pressure (BP) is a heritable risk factor for cardiovascular disease. To investigate genetic associations with systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP), and pulse pressure (PP), we genotyped ~50,000 SNPs in up to 87,736 individuals of European ancestry and combined these in a meta-analysis. We replicated findings in an independent set of 68,368 individuals of European ancestry. Our analyses identified 11 previously undescribed associations in independent loci containing 31 genes including PDE1A, HLA-DQB1, CDK6, PRKAG2, VCL, H19, NUCB2, RELA, HOXC@ complex, FBN1, and NFAT5 at the Bonferroni-corrected array-wide significance threshold (p < 6 × 10(-7)) and confirmed 27 previously reported associations. Bioinformatic analysis of the 11 loci provided support for a putative role in hypertension of several genes, such as CDK6 and NUCB2. Analysis of potential pharmacological targets in databases of small molecules showed that ten of the genes are predicted to be a target for small molecules. In summary, we identified previously unknown loci associated with BP. Our findings extend our understanding of genes involved in BP regulation, which may provide new targets for therapeutic intervention or drug response stratification.

    View details for DOI 10.1016/j.ajhg.2013.12.016

    View details for PubMedID 24560520

  • The HDL particle: frontiers for new discovery in cardiprotection Clinical Laboratory International Kim, D. S., Hutchins, P. M., Jarvik, G. P. 2014
  • Dietary fatty acid intake is associated with paraoxonase 1 activity in a cohort-based analysis of 1,548 subjects. Lipids in health and disease Kim, D. S., Maden, S. K., Burt, A. A., Ranchalis, J. E., Furlong, C. E., Jarvik, G. P. 2013; 12: 183


    Paraoxonase 1 (PON1) is a cardioprotective, HDL-associated glycoprotein enzyme with broad substrate specificity. Our previous work found associations between dietary cholesterol and vitamin C with PON1 activity. The goal of this study was to determine the effect of specific dietary fatty acid (DFA) intake on PON1 activity.1,548 participants with paraoxonase activity measures completed the Harvard Standardized Food Frequency Questionnaire to determine their daily nutrient intake over the past year. Eight saturated, 3 monounsaturated, and 6 polyunsaturated DFAs were measured by the questionnaire. To reduce the number of observations tested, only specific fatty acids that were not highly correlated (r < 0.8) with other DFAs or that were representative of other DFAs through high correlation within each respective group (saturated, monounsaturated, or polyunsaturated) were retained for analysis. Six specific DFA intakes - myristic acid (14 carbon atoms, no double bonds - 14:0), oleic acid (18:1), gadoleic acid (20:1), α-linolenic acid (18:3), arachidonic acid (20:4), and eicosapentaenoic acid (20:5) - were carried forward to stepwise linear regression, which evaluated the effect of each specific DFA on covariate-adjusted PON1 enzyme activity.Four of the 6 tested DFA intakes - myristic acid (p = 0.038), gadoleic acid (p = 6.68 × 10(-7)), arachidonic acid (p = 0.0007), and eicosapentaenoic acid (p = 0.013) - were independently associated with covariate-adjusted PON1 enzyme activity. Myristic acid, a saturated fat, and gadoleic acid, a monounsaturated fat, were both positively associated with PON1 activity. Both of the tested polyunsaturated fats, arachidonic acid and eicosapentaenoic acid, were negatively associated with PON1 activity.This study presents the largest cohort-based analysis of the relationship between dietary lipids and PON1 enzyme activity. Further research is necessary to elucidate and understand the specific biological mechanisms, whether direct or regulatory, through which DFAs affect PON1 activity.

    View details for DOI 10.1186/1476-511X-12-183

    View details for PubMedID 24330840

    View details for PubMedCentralID PMC3878825

  • Actionable, Pathogenic Incidental Findings in 1,000 Participants' Exomes AMERICAN JOURNAL OF HUMAN GENETICS Dorschner, M. O., Amendola, L. M., Turner, E. H., Robertson, P. D., Shirts, B. H., Gallego, C. J., Bennett, R. L., Jones, K. L., Tokita, M. J., Bennett, J. T., Kim, J. H., Rosenthal, E. A., Kim, D. S., Tabor, H. K., Bamshad, M. J., Motulsky, A. G., Scott, C. R., Pritchard, C. C., Walsh, T., Burke, W., Raskind, W. H., Byers, P., Hisama, F. M., Nickerson, D. A., Jarvik, G. P. 2013; 93 (4): 631-640


    The incorporation of genomics into medicine is stimulating interest on the return of incidental findings (IFs) from exome and genome sequencing. However, no large-scale study has yet estimated the number of expected actionable findings per individual; therefore, we classified actionable pathogenic single-nucleotide variants in 500 European- and 500 African-descent participants randomly selected from the National Heart, Lung, and Blood Institute Exome Sequencing Project. The 1,000 individuals were screened for variants in 114 genes selected by an expert panel for their association with medically actionable genetic conditions possibly undiagnosed in adults. Among the 1,000 participants, 585 instances of 239 unique variants were identified as disease causing in the Human Gene Mutation Database (HGMD). The primary literature supporting the variants' pathogenicity was reviewed. Of the identified IFs, only 16 unique autosomal-dominant variants in 17 individuals were assessed to be pathogenic or likely pathogenic, and one participant had two pathogenic variants for an autosomal-recessive disease. Furthermore, one pathogenic and four likely pathogenic variants not listed as disease causing in HGMD were identified. These data can provide an estimate of the frequency (∼3.4% for European descent and ∼1.2% for African descent) of the high-penetrance actionable pathogenic or likely pathogenic variants in adults. The 23 participants with pathogenic or likely pathogenic variants were disproportionately of European (17) versus African (6) descent. The process of classifying these variants underscores the need for a more comprehensive and diverse centralized resource to provide curated information on pathogenicity for clinical use to minimize health disparities in genomic medicine.

    View details for DOI 10.1016/j.ajhg.2013.08.006

    View details for Web of Science ID 000326305600005

    View details for PubMedID 24055113

    View details for PubMedCentralID PMC3791261

  • Pharmacogenetics of paraoxonase activity: elucidating the role of high-density lipoprotein in disease. Pharmacogenomics Kim, D. S., Marsillach, J., Furlong, C. E., Jarvik, G. P. 2013; 14 (12): 1495-515


    PON1 is a key component of high-density lipoproteins (HDLs) and is at least partially responsible for HDL's antioxidant/atheroprotective properties. PON1 is also associated with numerous human diseases, including cardiovascular disease, Parkinson's disease and cancer. In addition, PON1 metabolizes a broad variety of substrates, including toxic organophosphorous compounds, statin adducts, glucocorticoids, the likely atherogenic L-homocysteine thiolactone and the quorum-sensing factor of Pseudomonas aeruginosa. Numerous cardiovascular and antidiabetic pharmacologic agents, dietary macronutrients, lifestyle factors and antioxidant supplements affect PON1 expression and enzyme activity levels. Owing to the importance of PON1 to HDL function and its individual association with diverse human diseases, pharmacogenomic interactions between PON1 and the various factors that alter its expression and activity may represent an important therapeutic target for future investigation.

    View details for DOI 10.2217/pgs.13.147

    View details for PubMedID 24024900

    View details for PubMedCentralID PMC3888096

  • Postoperative electroencephalographic seizures are associated with deficits in executive function and social behaviors at 4 years of age following cardiac surgery in infancy. The Journal of thoracic and cardiovascular surgery Gaynor, J. W., Jarvik, G. P., Gerdes, M., Kim, D. S., Rajagopalan, R., Bernbaum, J., Wernovsky, G., Nicolson, S. C., Spray, T. L., Clancy, R. R. 2013; 146 (1): 132-7


    The occurrence of an electroencephalographic (EEG) seizure after surgery for complex congenital heart defects has been associated with worse neurodevelopmental (ND) outcomes. We previously identified postoperative seizures documented by 48-hour EEG monitoring in 11% of 178 neonates and infants. Evaluation at 1 year of age did not identify an adverse effect of an EEG seizure on ND outcomes. The current study was undertaken to determine if testing in the preschool period would identify deficits that become apparent as children develop.The ND outcomes assessed at 4 years of age included cognition, language, attention, impulsivity, executive function, behavior problems, academic achievement, and visual and fine motor skills.Developmental evaluations were performed in 132 (87%) of 151 survivors. For the entire cohort, the Full-Scale IQ was 95.0 ± 18.5. IQ was 95.1 ± 18.7 for patients without a history of seizure and 93.6 ± 16.7 for those with a history of seizure. After covariate adjustment, occurrence of an EEG seizure was associated with worse executive function (P = .037) and impaired social interactions/restricted behavior (P = .05). Seizures were not significantly associated with worse performance for cognition, language, attention, impulsivity, academic achievement, or motor skills (all P > .1).The occurrence of a postoperative seizure is a biomarker of brain injury. This study confirms that postoperative EEG seizures are associated with worse ND outcomes, characterized by impairments of executive function and a higher prevalence of deficits in social interactions and repetitive/restricted behaviors in preschool survivors of cardiac surgery in infancy. However, EEG seizures were not associated with worse cognitive, language, or motor skills.

    View details for DOI 10.1016/j.jtcvs.2013.04.002

    View details for PubMedID 23768805

    View details for PubMedCentralID PMC4617776

  • Novel gene-by-environment interactions: APOB and NPC1L1 variants affect the relationship between dietary and total plasma cholesterol. Journal of lipid research Kim, D. S., Burt, A. A., Ranchalis, J. E., Jarvik, E. R., Rosenthal, E. A., Hatsukami, T. S., Furlong, C. E., Jarvik, G. P. 2013; 54 (5): 1512-20


    Cardiovascular disease (CVD) is the leading cause of death in developed countries. Plasma cholesterol level is a key risk factor in CVD pathogenesis. Genetic and dietary variation both influence plasma cholesterol; however, little is known about dietary interactions with genetic variants influencing the absorption and transport of dietary cholesterol. We sought to determine whether gut expressed variants predicting plasma cholesterol differentially affected the relationship between dietary and plasma cholesterol levels in 1,128 subjects (772/356 in the discovery/replication cohorts, respectively). Four single nucleotide polymorphisms (SNPs) within three genes (APOB, CETP, and NPC1L1) were significantly associated with plasma cholesterol in the discovery cohort. These were subsequently evaluated for gene-by-environment (GxE) interactions with dietary cholesterol for the prediction of plasma cholesterol, with significant findings tested for replication. Novel GxE interactions were identified and replicated for two variants: rs1042034, an APOB Ser4338Asn missense SNP and rs2072183 (in males only), a synonymous NPC1L1 SNP in linkage disequilibrium with SNPs 5' of NPC1L1. This study identifies the presence of novel GxE and gender interactions implying that differential gut absorption is the basis for the variant associations with plasma cholesterol. These GxE interactions may account for part of the "missing heritability" not accounted for by genetic associations.

    View details for DOI 10.1194/jlr.P035238

    View details for PubMedID 23482652

    View details for PubMedCentralID PMC3622343

  • Novel common and rare genetic determinants of paraoxonase activity: FTO, SERPINA12, and ITGAL. Journal of lipid research Kim, D. S., Burt, A. A., Crosslin, D. R., Robertson, P. D., Ranchalis, J. E., Boyko, E. J., Nickerson, D. A., Furlong, C. E., Jarvik, G. P. 2013; 54 (2): 552-60


    HDL-associated paraoxonase 1 (PON1) activity is associated with cardiovascular and other human diseases. As the role of genetic variants outside of the PON gene cluster on PON1 activity is unknown, we sought to identify common and rare variants in such loci. We typed 33,057 variants on the CVD chip in 1,362 subjects to test for their effects on adjusted-PON1 activity. Three novel genes (FTO, ITGAL, and SERPINA12) and the PON gene cluster had SNPs associated with PON1 arylesterase (AREase) activity. These loci were carried forward for rare-variant analysis using Exome chip genotypes in an overlapping subset of 1,051 subjects using sequence kernel association testing. PON1 (P = 2.24 × 10(-4)), PON3 (P = 0.022), FTO (P = 0.019), and SERPINA12 (P = 0.039) had both common and rare variants associated with PON1 AREase. ITGAL variants were associated with PON1 activity when using weighted sequence kernel association testing (SKAT) analysis (P = 2.63 × 10(-3)). When adjusting for the initial common variants, SERPINA12 became marginally significant (P = 0.09), whereas all other findings remained significant (P < 0.05), suggesting independent rare-variant effects. We present novel findings that common and rare variants in FTO, SERPINA12, and ITGAL predict PON1 activity. These results further link PON1 to diabetes and inflammation and may inform the role of HDL in human disease.

    View details for DOI 10.1194/jlr.P033266

    View details for PubMedID 23160181

    View details for PubMedCentralID PMC3588879

  • Dietary cholesterol increases paraoxonase 1 enzyme activity. Journal of lipid research Kim, D. S., Burt, A. A., Ranchalis, J. E., Richter, R. J., Marshall, J. K., Nakayama, K. S., Jarvik, E. R., Eintracht, J. F., Rosenthal, E. A., Furlong, C. E., Jarvik, G. P. 2012; 53 (11): 2450-8


    HDL-associated paraoxonase 1 (PON1) activity has been consistently associated with cardiovascular and other diseases. Vitamins C and E intake have previously been positively associated with PON1 in a subset of the Carotid Lesion Epidemiology and Risk (CLEAR) cohort. The goal of this study was to replicate these findings and determine whether other nutrient intake affected PON1 activity. To predict nutrient and mineral intake values, 1,402 subjects completed a standardized food frequency survey of their dietary habits over the past year. Stepwise regression was used to evaluate dietary and covariate effects on PON1 arylesterase activity. Five dietary components, cholesterol (P < 2.0 × 10(-16)), alcohol (P = 8.51 × 10(-8)), vitamin C (P = 7.97 × 10(-5)), iron (P = 0.0026), and folic acid (0.037) were independently predictive of PON1 activity. Dietary cholesterol was positively associated and predicted 5.5% of PON1 activity, second in variance explained. This study presents a novel finding of dietary cholesterol, iron, and folic acid predicting PON1 activity in humans and confirms prior reported associations, including that with vitamin C. Identifying and understanding environmental factors that affect PON1 activity is necessary to understand its role and that of HDL in human disease.

    View details for DOI 10.1194/jlr.P030601

    View details for PubMedID 22896672

    View details for PubMedCentralID PMC3466014

  • Results of genome-wide analyses on neurodevelopmental phenotypes at four-year follow-up following cardiac surgery in infancy. PloS one Kim, D. S., Stanaway, I. B., Rajagopalan, R., Bernbaum, J. C., Solot, C. B., Burnham, N., Zackai, E. H., Clancy, R. R., Nicolson, S. C., Gerdes, M., Nickerson, D. A., Hakonarson, H., Gaynor, J. W., Jarvik, G. P. 2012; 7 (9): e45936


    Adverse neurodevelopmental sequelae are reported among children who undergo early cardiac surgery to repair congenital heart defects (CHD). APOE genotype has previously been determined to contribute to the prediction of these outcomes. Understanding further genetic causes for the development of poor neurobehavioral outcomes should enhance patient risk stratification and improve both prevention and treatment strategies.We performed a prospective observational study of children who underwent cardiac surgery before six months of age; this included a neurodevelopmental evaluation between their fourth and fifth birthdays. Attention and behavioral skills were assessed through parental report utilizing the Attention Deficit-Hyperactivity Disorder-IV scale preschool edition (ADHD-IV), and Child Behavior Checklist (CBCL/1.5-5), respectively. Of the seven investigated, three neurodevelopmental phenotypes met genomic quality control criteria. Linear regression was performed to determine the effect of genome-wide genetic variation on these three neurodevelopmental measures in 316 subjects.This genome-wide association study identified single nucleotide polymorphisms (SNPs) associated with three neurobehavioral phenotypes in the postoperative children ADHD-IV Impulsivity/Hyperactivity, CBCL/1.5-5 PDPs, and CBCL/1.5-5 Total Problems. The most predictive SNPs for each phenotype were: a LGALS8 intronic SNP, rs4659682, associated with ADHD-IV Impulsivity (P=1.03 × 10(-6)); a PCSK5 intronic SNP, rs2261722, associated with CBCL/1.5-5 PDPs (P=1.11 × 10(-6)); and an intergenic SNP, rs11617488, 50 kb from FGF9, associated with CBCL/1.5-5 Total Problems (P=3.47 × 10(-7)). 10 SNPs (3 for ADHD-IV Impulsivity, 5 for CBCL/1.5-5 PDPs, and 2 for CBCL/1.5-5 Total Problems) had p<10(-5).No SNPs met genome-wide significance for our three neurobehavioral phenotypes; however, 10 SNPs reached a threshold for suggestive significance (p<10(-5)). Given the unique nature of this cohort, larger studies and/or replication are not possible. Studies to further investigate the mechanisms through which these newly identified genes may influence neurodevelopment dysfunction are warranted.

    View details for DOI 10.1371/journal.pone.0045936

    View details for PubMedID 23049896

    View details for PubMedCentralID PMC3457986

  • Additional Common Polymorphisms in the PON Gene Cluster Predict PON1 Activity but Not Vascular Disease. Journal of lipids Kim, D. S., Burt, A. A., Ranchalis, J. E., Richter, R. J., Marshall, J. K., Eintracht, J. F., Rosenthal, E. A., Furlong, C. E., Jarvik, G. P. 2012; 2012: 476316


    Background. Paraoxonase 1 (PON1) enzymatic activity has been consistently predictive of cardiovascular disease, while the genotypes at the four functional polymorphisms at PON1 have not. The goal of this study was to identify additional variation at the PON gene cluster that improved prediction of PON1 activity and determine if these variants predict carotid artery disease (CAAD). Methods. We considered 1,328 males in a CAAD cohort. 51 tagging single-nucleotide polymorphisms (tag SNPs) across the PON cluster were evaluated to determine their effects on PON1 activity and CAAD status. Results. Six SNPs (four in PON1 and one each in PON2/3) predicted PON1 arylesterase (AREase) activity, in addition to the four previously known functional SNPs. In total, the 10 SNPs explained 30.1% of AREase activity, 5% of which was attributable to the six identified predictive SNPs. We replicate rs854567 prediction of 2.3% of AREase variance, the effects of rs3917510, and a PON3 haplotype that includes rs2375005. While AREase activity strongly predicted CAAD, none of the 10 SNPs predicting AREase predicted CAAD. Conclusions. This study identifies new genetic variants that predict additional PON1 AREase activity. Identification of SNPs associated with PON1 activity is required when evaluating the many phenotypes associated with genetic variation near PON1.

    View details for DOI 10.1155/2012/476316

    View details for PubMedID 22685667

    View details for PubMedCentralID PMC3364586