Abstract 14363: Genetics of Coronary Atherosclerotic Plaque Rupture and Myocardial Infarction
Introduction: While the presence of coronary artery disease (CAD), as measured by angiography, is present in the majority of myocardial infarction (MI) cases, there are many individuals who do not develop MI despite having considerable coronary atherosclerosis. We hypothesized that some genetic risk for plaque rupture and MI is distinct from that which relates to development of atherosclerosis.
Methods: We performed a meta-analysis across eight genome-wide (∼2.3 million genotyped and imputed SNPs) association studies (GWAS) of CAD in European ancestry participants who were phenotyped through coronary angiography. In order to identify loci that predispose to MI in the setting of angiographic CAD (AngCAD; at least one coronary artery with >50% stenosis), we compared patients with AngCAD and MI (AngCADMI+, N=5,783) to those with AngCAD but no MI (AngCADMI-, N=3,644). Using the DAVID Functional Annotation Tool, we examined enrichment for certain functional themes for genes with SNPs with suggestive association (P<0.0001) with AngCADMI+ compared to all genes on the Affymetrix 6.0 array.
Results: Our top finding (described elsewhere) for association with AngCADMI+ was for SNPs at the ABO locus, a glycotransferase gene. Using DAVID, we observed enrichment for certain functional themes, including cell adhesion (enrichment score = 1.81, p=0.01) and immunoglobulins (enrichment score = 1.7, p= 0.0001), as well as fibronectins (enrichment score = 2.13, p=0.0001), and glycoproteins and genes with N-linked glycosylation sites (enrichment score 1.59, p=0.008). Loci (e.g, including 9p21) and pathways (e.g., lipid and fatty acid biosynthetic processes) previously implicated in CAD by GWAS were not enriched in AngCADMI+ patients.
Conclusion: Genetic predisposition to MI in the setting of atherosclerosis may be distinct from that associated with the development of atherosclerosis. Genes that encode proteins involved in cell-cell adhesion and glycomic modifications may modulate plaque rupture and MI. These findings suggest potential novel therapeutic avenues for prevention and treatment of plaque rupture and MI.
- © 2010 by American Heart Association, Inc.