Abstract 15504: The Effect of Sequence Variants on the Presence of Coronary Artery Disease Also Predicts Effect on Angiographic Severity
Background: Recent genome-wide association (GWA) studies have yielded numerous variants in the sequence of the genome that confer risk of coronary artery disease (CAD). We hypothesized that these variants mediate their effect by influencing the deposition of coronary atheroma rather than directly precipitating myocardial infarction (MI). To test this hypothesis, we assessed the association of these variants with angiographic severity and MI in individuals with established CAD.
Methods: We tested 50 independent SNPs that had previously been associated with CAD for association with angiographic disease severity, quantified by the number of major epicardial vessels with ≥50% diameter stenosis, in 7,938 Icelanders with angiographic CAD. We then correlated their effect on the risk of CAD, as published in previous GWA studies, with their effect on angiographic disease severity. To further assess this relationship, we constructed a genetic risk score based on the sum of risk alleles for each of the variants weighted by their effect on CAD and tested for association with angiographic disease severity. To determine whether some of these variants may be related to MI rather than coronary atherosclerosis we tested them for association with prior MI, adjusting for angiographic severity.
Results: Two SNPs were associated with angiographic severity of CAD (P<0.001), adjusting for traditional risk factors: rs1333049 (9p21) and rs10455872 (LPA). For the 50 SNPs we evaluated, there was a positive correlation between effect on risk of CAD and effect on angiographic disease severity (r=0.71, P=5.6х10-9). Furthermore, a genetic risk score for CAD was associated with angiographic severity of the disease (P=5.6х10-13). Only one variant, at ABO, was associated with prior myocardial infarction, adjusting for angiographic severity.
Conclusion: The association of known genetic risk variants with angiographic severity in individuals with established CAD is predicted by their effect on the risk of CAD. Our findings suggest that their effect is primarily through promotion and progression of atherosclerosis.
- © 2013 by American Heart Association, Inc.