Abstract 1438: Myocardial Infarction Associated SNPs on Chromosome 9p21.3 are Associated with Coronary Artery Calcification but Not Carotid Intimal Medial Thickness in the Amish
Multiple genome-wide association studies previously identified a locus in chromosome 9p21.3, in proximity to the CDK2NA/B genes, to be strongly associated with myocardial infarction (MI). Because the mechanisms underlying the association are unknown, we sought to determine if the MI associated single nucleotide polymorphisms (SNPs) were associated with two measures of subclinical vascular disease, carotid intimal medial wall thickness (CIMT) and coronary artery calcification (CAC). Study subjects included Amish adults who were genotyped for 500K SNPs throughout the genome using the Affymetrix Array, which included 20 SNPs in a ~120 kb region at the previously associated chromosome 9p MI locus. Mean far wall common CIMT was measured by ultrasonography (n = 1077) and CAC by electron beam computed tomography (n = 636). Association analyses were adjusted for variation in age and sex using a variance components methodology to account for relatedness of study subjects. CAC quantity was log transformed after adding 1 for analyses. None of the SNPs in the region of interest was associated with variation in CIMT. In contrast, all SNPs in this region were significantly associated with CAC quantity (p-value range: 0.01 - 0.0003), including rs1333049, the peak SNP reported previously to be associated with MI. These SNPs accounted for ~2% of the variation in CAC quantity. Our results suggest that the strong link previously reported between the 9p21.3 locus and MI may be at least partly explained by an effect on CAC, a measure of subclinical coronary artery atherosclerosis. These results may help to understand the pathobiology leading to increased risk for MI associated with this genetic locus.