Journal Article

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

Epstein, Stephen E, Patel, Riyaz S, Anderson, Jeffrey L, Quertermous, Thomas, Nitschke, Patrick Linsel, Devaney, Joseph M, Stewart, Alexandre FR, Quyyumi, Arshed A, He, Jing, Mehta, Nehal N, Thompson, John R, Erdmann, Jeanette, Ferguson, Jane F, Reilly, Muredach P, Knouff, Christopher W, Assimes, Themistocles L, Wild, Philipp S, Martinelli, Nicola, Roberts, Robert, Allayee, Hooman, Samani, Nilesh J, Schunkert, Heribert, Hazen, Stanley L, Hall, Alistair S, Rader, Daniel J, Girelli, Domenico, Stylianou, Ioannis M, Blankenberg, Stefan, Kathiresan, Sekar, Li, Mingyao, Burnett, Mary Susan, Horne, Benjamin D

2011

Overview

We tested whether genetic factors distinctly contribute to either development of coronary atherosclerosis or, specifically, to myocardial infarction in existing coronary atherosclerosis. 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). 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. 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. 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.

• Publisher: Elsevier Ltd,Elsevier,Elsevier Limited
• Subject: ABO Blood-Group System - genetics / ADAM Proteins - genetics / ADAMTS7 Protein / Adult / Aged / ancestry / Atherosclerosis / Atherosclerosis (general aspects, experimental research) / Biological and medical sciences / Blood and lymphatic vessels / blood groups / Cardiology. Vascular system / Cardiovascular disease / Coronary Angiography / coronary artery disease / Coronary Artery Disease - blood / Coronary Artery Disease - complications / Coronary Artery Disease - diagnostic imaging / Coronary Artery Disease - genetics / Coronary heart disease / Data collection / Design / Enzymes / Female / Gene Frequency / General aspects / Genetic factors / Genetic Loci / Genetic Predisposition to Disease / Genome-Wide Association Study / grants / Heart / Heart attacks / Hospitals / Humans / Internal Medicine / Linkage Disequilibrium / loci / Male / Medical imaging / Medical sciences / Middle Aged / Myocardial infarction / Myocardial Infarction - blood / Myocardial Infarction - complications / Myocardial Infarction - diagnostic imaging / Myocardial Infarction - genetics / patients / Pennsylvania / Polymorphism, Single Nucleotide / Risk assessment / Studies