Investigation of 95 variants identified in a genome-wide study for association with mortality after acute coronary syndrome

We examined 95 polymorphisms in 69 distinct gene regions identified in a GWAS for premature myocardial infarction for their association with post-ACS mortality among 811 whites recruited from university-affiliated hospitals in Kansas City, Missouri. We then sought replication of a positive genetic association in a large, racially diverse cohort of myocardial infarction patients (N = 2284) using Kaplan-Meier survival analyses and Cox regression to adjust for relevant covariates. Finally, we investigated the apparent association further in 6086 additional coronary artery disease patients.After Cox adjustment for other ACS risk factors, of 95 SNPs tested in 811 whites only the association with the rs6922269 in MTHFD1L was statistically significant, with a 2.6-fold mortality hazard (P = 0.007). The recessive A/A genotype was of borderline significance in an age- and race-adjusted analysis of the entire combined cohort (N = 3095; P = 0.052), but this finding was not confirmed in independent cohorts (N = 6086).We found no support for the hypothesis that the GWAS-identified variants in this study substantially alter the probability of post-ACS survival. Large-scale, collaborative, genome-wide studies may be required in order to detect genetic variants that are robustly associated with survival in patients with coronary artery disease.Genome-wide association studies (GWAS) have identified robust genetic associations in a variety of common diseases [1], including myocardial infarction (MI) [2-6]. The GWAS approach, with its emphasis on large sample sizes and inclusion of hundreds of thousands of genetic markers, has produced a degree of reproducibility that was generally lacking in earlier candidate gene studies of MI [7]. However, nine GWAS-identified genetic susceptibility markers, all meeting criteria for genome-wide statistical significance, collectively account for only 3% of the estimated heritability of early-onset myocardial infarction (MI), raising questions about t