Abstract 17963: Potential Mechanistic Insights on Genomic Myocardial Infarction Variants
Background: The mechanistic basis of 9 novel myocardial infarction (MI) risk variants discovered through GWAS is still undefined. We hypothesized that these loci act at different stages in the atherosclerotic pathway culminating in MI and examined their association with focused MI and coronary angiographic phenotypes.
Methods: Single nucleotide polymorphisms (SNPs) at 9 MI risk loci, whose mechanism is currently unknown, were genotyped in 2730 Caucasians undergoing cardiac catheterization (mean age 63, male 67%). We examined their association with angiographic CAD (1) presence/absence (>50% v <10%, n=966/518), (2) severity (Gensini, n=1620) and (3) progression at repeat study (Gensini rate, n=308) in subjects without MI. As testing for association with MI v no MI (n=1110/518) also examines the phenotype of CAD v no CAD, we defined a control population without MI but with CAD (n=1110/926) to test the true phenotype of MI precipitation. To mitigate misclassification here, we also studied a subset of younger cases under 60yrs and older controls over 70yrs (n=692/397).
Results: In subjects without MI, three SNPs at loci 6p24, 1q41 and 9p21 were associated with CAD presence and/or severity, while 9p21 was additionally associated with CAD progression (Figure 1). While we replicated association with MI for these and 2 other SNPs (at 2q33 and 21q22) by using traditional controls (no MI or CAD), there were no significant associations for any SNP when controls had no MI with obstructive CAD. However when younger cases and older controls were studied, a significant association was observed with 2q33 and 21q22 (Figure 1). The remaining 4 variants did not show significant associations with any phenotype.
Conclusions: Risk variants initially associated with MI show differential associations with refined CAD/MI phenotypes, suggesting some loci may influence more upstream atherosclerotic processes while others may affect factors causing precipitation of MI in established CAD.
- © 2010 by American Heart Association, Inc.