Analysis of 17,576 Potentially Functional SNPs in Three Case–Control Studies of Myocardial Infarction

Florian Kronenberg,Dov Shiffman,James J Devlin,Stephen G Ellis,Judy Z Louie,John P Kane,David A Ross,Joseph J Catanese,Andre R Arellano,Mary J Malloy

doi:10.1371/journal.pone.0002895

Florian Kronenberg, Dov Shiffman + Show 8 more

Open Access

https://doi.org/10.1371/journal.pone.0002895

Copy DOI

Abstract

Myocardial infarction (MI) is a common complex disease with a genetic component. While several single nucleotide polymorphisms (SNPs) have been reported to be associated with risk of MI, they do not fully explain the observed genetic component of MI. We have been investigating the association between MI and SNPs that are located in genes and have the potential to affect gene function or expression. We have previously published studies that tested about 12,000 SNPs for association with risk of MI, early-onset MI, or coronary stenosis. In the current study we tested 17,576 SNPs that could affect gene function or expression. In order to use genotyping resources efficiently, we staged the testing of these SNPs in three case–control studies of MI. In the first study (762 cases, 857 controls) we tested 17,576 SNPs and found 1,949 SNPs that were associated with MI (P<0.05). We tested these 1,949 SNPs in a second study (579 cases and 1159 controls) and found that 24 SNPs were associated with MI (1-sided P<0.05) and had the same risk alleles in the first and second study. Finally, we tested these 24 SNPs in a third study (475 cases and 619 controls) and found that 5 SNPs in 4 genes (ENO1, FXN (2 SNPs), HLA-DPB2, and LPA) were associated with MI in the third study (1-sided P<0.05), and had the same risk alleles in all three studies. The false discovery rate for this group of 5 SNPs was 0.23. Thus, we have identified 5 SNPs that merit further examination for their potential association with MI. One of these SNPs (in LPA), has been previously shown to be associated with risk of cardiovascular disease in other studies.

Highlights

Myocardial infarction (MI) is a prevalent and often fatal consequence of coronary heart disease
We measured the allele frequencies of 17,576 putative functional single nucleotide polymorphisms (SNPs) in Study 1 cases and controls using pooled DNA samples and identified 1,949 SNPs that were associated with MI (P,0.05) and had minor allele frequency estimates that were greater than 1%
For those SNPs that were associated with MI and had the same risk alleles in both pooling studies, we confirmed the association of the SNP with MI in Study 1 and Study 2 by genotyping individual DNA samples

Summary

Introduction

Myocardial infarction (MI) is a prevalent and often fatal consequence of coronary heart disease. Each year approximately 865 thousand Americans are diagnosed with MI and about 180 thousand die from the disease [1]. Risk factors for MI include age, sex, elevated LDL-cholesterol, hypertension, low HDL-cholesterol, smoking, type 2 diabetes, and family history of cardiovascular disease. Risk of MI has a genetic component as evidenced by large twin studies [2] which showed that death from cardiovascular disease is more highly correlated among identical twins than fraternal twins. Among genetic variants that are associated with MI, some can affect traditional risk factors [3,4] but for others the underlying biological explanation for the association is not known [5,6]

Methods

Results

Conclusion