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.

Original publication

DOI

10.1016/s0140-6736(10)61996-4

Type

Journal article

Journal

Lancet (London, England)

Publication Date

14/01/2011

Volume

377

Pages

383 - 392

Addresses

Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA 19104-6160, USA. muredach@mail.med.upenn.edu

Keywords

Myocardial Infarction Genetics Consortium, Wellcome Trust Case Control Consortium, Humans, Myocardial Infarction, Genetic Predisposition to Disease, ABO Blood-Group System, Coronary Angiography, Gene Frequency, Linkage Disequilibrium, Polymorphism, Single Nucleotide, Adult, Aged, Middle Aged, Female, Male, ADAM Proteins, Coronary Artery Disease, Genome-Wide Association Study, Genetic Loci, ADAMTS7 Protein