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.
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Reilly Muredach P, Li Mingyao, He Jing, Ferguson Jane F, Stylianou Ioannis M, Mehta Nehal N, Burnett Mary Susan, Devaney Joseph M, Knouff Christopher W, Thompson John R, Horne Benjamin D, Stewart Alexandre F R, Assimes Themistocles L, Wild Philipp S, Allayee Hooman, Nitschke Patrick Linsel, Patel Riyaz S, Myocardial Infarction Genetics Consortium, Wellcome Trust Case Control Consortium, Martinelli Nicola, Girelli Domenico, Quyyumi Arshed A, Anderson Jeffrey L, Erdmann Jeanette, Hall Alistair S, Schunkert Heribert, Quertermous Thomas, Blankenberg Stefan, Hazen Stanley L, Roberts Robert, Kathiresan Sekar, Samani Nilesh J, Epstein Stephen E, Rader Daniel J
Аннотация
METHODS: We did two genome-wide association studies (GWAS) with coronary angiographic phenotyping in participants of European ancestry. To identify loci that predispose to angiographic coronary artery disease (CAD), we compared individuals who had this disorder (n=12,393) with those who did not (controls, n=7383). To identify loci that predispose to myocardial infarction, we compared patients who had angiographic CAD and myocardial infarction (n=5783) with those who had angiographic CAD but no myocardial infarction (n=3644).
FINDINGS: In the comparison of patients with angiographic CAD versus controls, we identified a novel locus, ADAMTS7 (p=4·98×10(-13)). In the comparison of patients with angiographic CAD who had myocardial infarction versus those with angiographic CAD but no myocardial infarction, we identified a novel association at the ABO locus (p=7·62×10(-9)). The ABO association was attributable to the glycotransferase-deficient enzyme that encodes the ABO blood group O phenotype previously proposed to protect against myocardial infarction.
INTERPRETATION: Our findings indicate that specific genetic predispositions promote the development of coronary atherosclerosis whereas others lead to myocardial infarction in the presence of coronary atherosclerosis. The relation to specific CAD phenotypes might modify how novel loci are applied in personalised risk assessment and used in the development of novel therapies for CAD.
FUNDING: The PennCath and MedStar studies were supported by the Cardiovascular Institute of the University of Pennsylvania, by the MedStar Health Research Institute at Washington Hospital Center and by a research grant from GlaxoSmithKline. The funding and support for the other cohorts contributing to the paper are described in the webappendix.