Abstract 3139: Identification and Replication of a Genetic Locus for Myocardial Infarction on Chromosome 1q32.2
Myocardial infarction (MI) arises from unstable atherosclerotic plaque regardless of the degree of luminal narrowing. Individuals with coronary artery disease (CAD) may grow to advanced age with significant narrowings and remain MI-free. To evaluate genetic risk for MI, this study tested genome-wide association of 500,568 single nucleotide polymorphisms (SNPs) compared with MI-free CAD and normal patients. /Cases (n=400) had early MI (age<65 years in females, <55 years in males) and with LDL-C<200 mg/dL. Controls were aged ≥70 years (females) or ≥65 years (males) and had either clinically-significant CAD (≥1 lesion of ≥70% stenosis) but no MI (n=400) or angiographically-normal coronaries (n=400). DNA samples (N1=1,200) were mixed in 18 DNA pools with 50 equimolar samples each and subcategorized as 9 female and 9 male pools (3 each for MI cases, CAD controls, and normals). Quantitative intensity values were extracted to evaluate data clustering by the silhouette score for MI pools vs. the combined CAD and normal pools. Replication by individual genotyping tested the two best SNPs in an independent set of cases and controls (N2=2,129) meeting the same phenotype criteria. All participants were non-smokers. Among the 9 male pools, silhouette scores ranged from −0.04 to 0.58, except for one SNP with score=0.67 (rs3120784, chromosome 1q32.2). In the replication group, individual genotyping of males showed an association with MI: 33%, 29%, and 0% for GG, GA, and AA (OR=0.69/A allele, 95% CI=0.49, 0.97; p-trend=0.029). Though not the best SNP among females in the pooled discovery set, among all replication patients MI was found in 31%, 27%, and 10% for GG, GA, AA (OR=0.74/A allele, CI=0.55, 0.98; p-trend=0.031). In the 9 female pools, silhouette scores ranged from −0.04 to 0.54, with the best SNP being rs2173369 (chromosome 10q21.3), but MI association was not confirmed by individual genotyping in the replication group (MI: 34% in AA, 36% in AG, 33% in GG; p-trend=0.65). A chromosome 1q32.2 locus (rs3120784) for early-onset MI was discovered and replicated when compared with MI-free CAD and normal controls. The region surrounding that SNP deserves further evaluation for an effect on MI precipitation in non-smokers.