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Identification of ADAMTS7 as a Novel Locus for Coronary Atherosclerosis and Association of ABO With Myocardial Infarction in the Presence of Coronary Atherosclerosis: Two Genome-Wide Association Studies
Study Questions:
Are there distinct gene variants associated with atherosclerosis and myocardial infarction (MI)?
Methods:
Genome-wide association studies (GWAS) with coronary angiographic phenotyping were performed in participants of European ancestry. To identify loci that predispose to angiographic coronary artery disease (CAD), individuals who had this disorder (n = 12,393) were compared to those who did not (controls, n = 7,383). To identify loci that predispose to MI, patients who had angiographic CAD and MI (n = 5,783) were compared to those who had angiographic CAD, but no MI (n = 3,644).
Results:
In the comparison of patients with angiographic CAD versus controls, a novel locus, ADAMTS7 (p = 4.98 × 10–13), was identified. In the comparison of patients with angiographic CAD who had MI versus those with angiographic CAD but no MI, a novel association at the ABO locus (p = 7.62 × 10–9) was identified. The ABO association was attributable to the enzyme that encodes the ABO blood group O phenotype previously proposed to protect against MI.
Conclusions:
The authors concluded that specific genetic predispositions promote the development of coronary atherosclerosis, whereas others lead to MI in the presence of coronary atherosclerosis. The relation to specific CAD phenotypes might modify how novel loci are applied in personalized risk assessment and used in the development of novel therapies for CAD.
Perspective:
MI typically results from occlusive thrombosis at the site of atherosclerotic plaque disruption. Prevention of atherosclerosis will prevent MI; however, complete prevention of atherosclerosis is not currently feasible and may not be necessary to prevent MI. It may be just as practical to target genes affecting plaque stability and/or the subsequent thrombotic response to plaque rupture. It is not surprising that different genes affect different stages of atherothrombotic disease. To distinguish these relationships, it is important to improve vascular phenotyping strategies in GWAS, as was done in this study using coronary angiography. As a result of this phenotyping strategy, not only were novel genetic associations with atherosclerosis and MI discovered in this study, but it provided some insight into the potential mechanisms by which these genes may promote vascular disease.
Keywords: Coronary Artery Disease, Myocardial Infarction, Atherosclerosis, Plaque, Atherosclerotic, Coronary Angiography, Phenotype, Genome-Wide Association Study, Genetic Predisposition to Disease, Genotype, Risk Assessment
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