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Hypertrophic cardiomyopathy (HCM), the most common inherited heart disease, is associated with ventricular arrhythmias and diastolic dysfunction secondary to electrophysiological signal abnormalities. Specifically, myocytes in HCM have prolonged action potentials, primarily during phase 2, which

The CATHeterization GENetics (CATHGEN) biorepository was assembled in four phases. First, project start-up began in 2000. Second, between 2001 and 2010, we collected clinical data and biological samples from 9334 individuals undergoing cardiac catheterization. Samples were matched at the individual level to clinical data collected at the time of catheterization and stored in the Duke Databank for Cardiovascular Diseases (DDCD). Clinical data included the following: subject demographics (birth date, race, gender, etc.); cardiometabolic history including symptoms; coronary anatomy and cardiac function at catheterization; and fasting chemistry data. Third, as part of the DDCD regular follow-up protocol, yearly evaluations included interim information: vital status (verified via National Death Index search and supplemented by Social Security Death Index search), myocardial infarction (MI), stroke, rehospitalization, coronary revascularization procedures, medication use, and lifestyle habits including smoking. Fourth, samples were used to generate molecular data. CATHGEN offers the opportunity to discover biomarkers and explore mechanisms of cardiovascular disease.

Introduction: Women are disproportionately affected by coronary artery disease (CAD). Among major factors such as age and anatomical differences, biologic contributions are purported; yet, little is understood about the underlying genomic architecture that may contribute to female-specific disparities. We explored whether genome-wide variants could predict survival in females with clinically-appreciable CAD, unique to that of male cases. Methods: A sex-stratified genome-wide association analysis was conducted for survivorship in Caucasian patients with CAD in a discovery cohort ( N =1,099; 589 females) and a replication cohort ( N = 404; 198 females), selected from a cardiovascular biorepository consisting of sequential patients referred for cardiac catheterization. CAD cases were defined as having a CAD index >32 (at least one vessel CAD) and indication for catheterization was concern for ischemic heart disease. GWAS genotyping was done using the Illumina Omni Quad v1.0 GWAS chip with stringent QC metrics. Sex-stratified, Cox multivariable regression models for each SNP (additive), adjusted for age and four Eigenstrat-defined principal components, were constructed (R statistical package), with models censored on time from cardiac catheterization to all-cause mortality/last follow-up (med 5.2 yrs). Results: Fourteen SNPs met nominal significance (p-5 ) for increased hazards of all-cause mortality in women; none of these SNPs or genes were even nominally significant at pSLC9A9 ; HR 6.2, 95%CI 2.9-13.3, p discovery =3.2x10 -6 , p replication =0.68, p male =0.87); rs12145981 ( NEK2/LPGAT1 ; HR 3.3, 95%CI 2.0-5.6, p d =4.2x10 -6 , p r =0.05, p m =0.92); and rs7217169 ( RAP1GAP2 ; HR 4.1, 95%CI 2.3-7.5, p d =4.3x10 -6 , p r =0.02, p m =0.44), as they are involved in endosome recycling ( SLC9A9 ), cardiolipin synthesis ( LPGAT1 ), and regulating dense granule secretion from platelets at endothelial damage sites ( RAP1GAP2 ). Conclusions: We present preliminary evidence of genome-wide candidates that appear to uniquely predict mortality risk in women with CAD. Further investigation of genomic variation may help improve understanding of sex differences in CAD disparities.

Survival bias may unduly impact genetic association with complex diseases; gene-specific survival effects may further complicate such investigations. Coronary artery disease (CAD) is a complex phenotype for which little is understood about gene-specific survival effects; yet, such information can offer insight into refining genetic associations, improving replications, and can provide candidate genes for both mortality risk and improved survivorship in CAD. Building on our previous work, the purpose of this current study was to: evaluate LSAMP SNP-specific hazards for all-cause mortality post-catheterization in a larger cohort of our CAD cases; and, perform additional replication in an independent dataset. We examined two LSAMP SNPs-rs1462845 and rs6788787-using CAD case-only Cox proportional hazards regression for additive genetic effects, censored on time-to-all-cause mortality or last follow-up among Caucasian subjects from the Catheterization Genetics Study (CATHGEN; n = 2,224) and the Intermountain Heart Collaborative Study (IMHC; n = 3,008). Only after controlling for age, sex, body mass index, histories of smoking, type 2 diabetes, hyperlipidemia and hypertension (HR = 1.11, 95%CI = 1.01-1.22, p = 0.032), rs1462845 conferred significantly increased hazards of all-cause mortality among CAD cases. Even after controlling for multiple covariates, but in only the primary cohort, rs6788787 conferred significantly improved survival (HR = 0.80, 95% CI = 0.69-0.92, p = 0.002). Post-hoc analyses further stratifying by sex and disease severity revealed replicated effects for rs1462845: even after adjusting for aforementioned covariates and coronary interventional procedures, males with severe burden of CAD had significantly amplified hazards of death with the minor variant of rs1462845 in both cohorts (HR = 1.29, 95% CI = 1.08-1.55, p = 0.00456; replication HR = 1.25, 95% CI = 1.05-1.49, p = 0.013). Kaplan-Meier curves revealed unique cohort-specific genotype effects on survival. Additional analyses demonstrated that the homozygous risk genotype ('A/A') fully explained the increased hazard in both cohorts. None of the post-hoc analyses in control subjects were significant for any model. This suggests that genetic effects of rs1462845 on survival are unique to CAD presence. This represents formal, replicated evidence of genetic contribution of rs1462845 to increased risk for all-cause mortality; the contribution is unique to CAD case status and specific to males with severe burden of CAD.