Biology subjects

Heckbert, S. R.

Publications and source records attributed to Heckbert, S. R..

4 recordsLinked to original sources

bioRxiv2018

Association between chronic hepatitis C virus infection and myocardial infarction in people living with HIV in the United States

Hepatitis C virus (HCV) is common among people living with HIV (PLWH). The potential for extrahepatic manifestations of HCV, including myocardial infarction (MI), is a topic of active research. MI is classified into types, predominantly atheroembolic Type 1 MI (T1MI) and supply-demand mismatch Type 2 MI (T2MI). We examined the association between HCV and MI in the CFAR Network of Integrated Clinical Systems (CNICS), a multi-center clinical cohort of PLWH. MIs were centrally adjudicated and categorized by type using the Universal MI definition. We estimated the association between chronic HCV (RNA+) and time to MI adjusting for demographic characteristics, cardiovascular risk factors, clinical characteristics and substance use. Among 24,755 PLWH aged [≥]18, there were 336 T1MI and 330 T2MI during a median of 4.2 years of follow-up. HCV was associated with a 68% greater risk of T2MI (adjusted hazard ratio (aHR) 1.68, 95% CI: 1.22, 2.30) but not T1MI (aHR 0.96, 95% CI: 0.63, 1.45). In a cause-specific analysis of T2MI, HCV was associated with a 2-fold greater risk of T2MI attributed to sepsis (aHR 2.26, 95% CI: 1.34, 3.81). Extrahepatic manifestations of HCV in this high-risk population are an important area for continued research.

epidemiology↗

bioRxiv2018

GWAS of QRS Duration Identifies New Loci Specific to Hispanic/Latino Populations

BackgroundThe electrocardiographically quantified QRS duration measures ventricular depolarization and conduction. QRS prolongation has been associated with poor heart failure prognosis and cardiovascular mortality, including sudden death. While previous genome-wide association studies (GWAS) have identified 32 QRS SNPs across 26 loci among European, African, and Asian-descent populations, the genetics of QRS among Hispanics/Latinos has not been previously explored.\n\nMethodsWe performed a GWAS of QRS duration among Hispanic/Latino ancestry populations (n=15,124) from four studies using 1000 Genomes imputed genotype data (adjusted for age, sex, global ancestry, clinical and study-specific covariates). Study-specific results were combined using fixed-effects, inverse variance-weighted meta-analysis.\n\nResultsWe identified six loci associated with QRS (P<5x10-8), including two novel loci: MYOCD, a nuclear protein expressed in the heart, and SYT1, an integral membrane protein. The top association in the MYOCD locus, intronic SNP rs16946539, was found in Hispanics/Latinos with a minor allele frequency (MAF) of 0.04, but is monomorphic in European and African descent populations. The most significant QRS duration association was for intronic SNP rs3922344 (P= 8.56x10-26) in SCN5A/SCN10A. Three additional previously identified loci, CDKN1A, VTI1A, and HAND1, also exceeded the GWAS significance threshold among Hispanics/Latinos. A total of 27 of 32 previously identified QRS duration SNPs were shown to generalize in Hispanics/Latinos.\n\nConclusionsOur QRS duration GWAS, the first in Hispanic/Latino populations, identified two new loci, underscoring the utility of extending large scale genomic studies to currently under-examined populations.

genetics↗

bioRxiv2017

A Comprehensive Evaluation of the Genetic Architecture of Sudden Cardiac Arrest

BackgroundSudden cardiac arrest (SCA) accounts for 10% of adult mortality in Western populations. While several risk factors are observationally associated with SCA, the genetic architecture of SCA in the general population remains unknown. Furthermore, understanding which risk factors are causal may help target prevention strategies.\n\nMethodsWe carried out a large genome-wide association study (GWAS) for SCA (n=3,939 cases, 25,989 non-cases) to examine common variation genome-wide and in candidate arrhythmia genes. We also exploited Mendelian randomization methods using cross-trait multi-variant genetic risk score associations (GRSA) to assess causal relationships of 18 risk factors with SCA.\n\nResultsNo variants were associated with SCA at genome-wide significance, nor were common variants in candidate arrhythmia genes associated with SCA at nominal significance. Using cross-trait GRSA, we established genetic correlation between SCA and (1) coronary artery disease (CAD) and traditional CAD risk factors (blood pressure, lipids, and diabetes), (2) height and BMI, and (3) electrical instability traits (QT and atrial fibrillation), suggesting etiologic roles for these traits in SCA risk.\n\nConclusionsOur findings show that a comprehensive approach to the genetic architecture of SCA can shed light on the determinants of a complex life-threatening condition with multiple influencing factors in the general population. The results of this genetic analysis, both positive and negative findings, have implications for evaluating the genetic architecture of patients with a family history of SCA, and for efforts to prevent SCA in highrisk populations and the general community.

genetics↗

bioRxiv2017

Multiethnic Meta-analysis Identifies New Loci for Pulmonary Function

Nearly 100 loci have been identified for pulmonary function, almost exclusively in studies of European ancestry populations. We extend previous research by meta-analyzing genome-wide association studies of 1000 Genomes imputed variants in relation to pulmonary function in a multiethnic population of 90,715 individuals of European (N=60,552), African (N=8,429), Asian (N=9,959), and Hispanic/Latino (N=11,775) ethnicities. We identified over 50 novel loci at genome-wide significance in ancestry-specific and/or multiethnic meta-analyses. Recent fine mapping methods incorporating functional annotation, gene expression, and/or differences in linkage disequilibrium between ethnicities identified potential causal variants and genes at known and newly identified loci. Sixteen of the novel genes encode proteins with predicted or established drug targets, including KCNK2 and CDK12.

genetics↗