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

Thomas M Morgan,John A House,John A Spertus,Winfried März,Hooman Allayee,Sharon Cresci,Philip Jones,Stanley L Hazen,Marcus E Kleber,Salina P Waddy,Yesha Patel,Arshed A Quyyumi,Danny J Eapen,Riyaz S Patel,Bernhard O Boehm,Bernhard R Winkelmann,Harlan M Krumholz

doi:10.1186/1471-2350-12-127

Abstract

BackgroundGenome-wide association studies (GWAS) have identified new candidate genes for the occurrence of acute coronary syndrome (ACS), but possible effects of such genes on survival following ACS have yet to be investigated.MethodsWe 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.ResultsAfter 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).ConclusionsWe 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.

Highlights

Genome-wide association studies (GWAS) have identified new candidate genes for the occurrence of acute coronary syndrome (ACS), but possible effects of such genes on survival following ACS have yet to be investigated
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 myocardial infarction (MI) [7]
Study Population and Genotyping Our study design called for testing genetic markers for prognostic association with 3-year mortality in an ACS cohort, and attempting replication of significant associations in additional cohorts of MI and/or coronary artery disease (CAD) patients

Summary

Introduction

Genome-wide association studies (GWAS) have identified new candidate genes for the occurrence of acute coronary syndrome (ACS), but possible effects of such genes on survival following ACS have yet to be investigated. Genome-wide association studies (GWAS) have identified robust genetic associations in a variety of common diseases [1], including myocardial infarction (MI) [2,3,4,5,6]. Association studies of GWAS-generated candidate genes with prognosis following acute coronary syndromes (ACS), including unstable angina, non-ST elevation myocardial infarction (NSTEMI), and ST-elevation myocardial infarction (STEMI), require resource-intensive longitudinal designs and have rarely been performed.

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