Abstract 4874: Large-Scale Candidate Gene Association with Human Heart Failure
Genetic factors that contribute to non-familial heart failure (HF) are largely unknown. Attempts to identify such by whole genome association have implicated genomic loci, but not specific polymorphisms. In contrast, single candidate gene studies have suggested specific variants and mechanisms, but have not all been replicated. Here, we combined the strengths of whole-genome and single candidate gene association studies in the first large-scale candidate gene study of HF in two independent populations. A custom Illumina SNP array containing 45,000 SNPs in ~2,100 genes prioritized by mechanistic relevance in cardiovascular disorders was used to genotype matched Caucasian HF cohorts (ACC/AHA stage C/D; LVEF 31±16%) from two centers, U. of Pennsylvania (708 CHF, 350 controls) and U. of Cincinnati (900 CHF, 300 controls). After careful assessment of genetic ancestry, we compared genotype frequencies in cases vs. controls using logistic regression (PLINK) adjusting for age and gender. To minimize false positives, genes were ranked according to P-value in both study populations and in a combined analysis of all cases vs. all controls. 13 SNPs were associated with all-cause heart failure with P-values ranging from 10−2 to 10−5. These SNPs were located within genes HSPB7, PCSK6, IL1F10, FRMD4B, F2RL1, SLIT2, NOS1AP, MMP12, and IL1RN. Stratified analyses identified 18 SNPs specific for ischemic heart failure (F10, F7, IRS1, NFATC2, IL1R1, SLIT2, CASP8, CORIN, CDKAL1, TRIAD3, CSMD1) and 12 SNPs for non-ischemic heart failure (ACTC1, RYR2, PRKAG2, SCL5A7, ADRA1,TIE1), replicating several previous observations and identifying intriguing new associations. Most of the SNPs were in non-coding regions, and several of these were in genes that show significant changes in expression in failing vs. non-failing human myocardium (NOS1AP, IL1R1, NFATC2). These findings suggest that common variants in cardiovascular genes contribute to the pathogenesis of human heart failure, in part by affecting level of gene expression, and identify specific targets for further mechanistic analyses.