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

TY - JOUR

T1 - 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

AU - Reilly, Muredach P

AU - Li, Mingyao

AU - He, Jing

AU - Ferguson, Jane F

AU - Stylianou, Ioannis M

AU - Mehta, Nehal N

AU - Burnett, Mary Susan

AU - Devaney, Joseph M

AU - Knouff, Christopher W

AU - Thompson, John R

AU - Horne, Benjamin D

AU - Stewart, Alexandre F R

AU - Assimes, Themistocles L

AU - Wild, Philipp S

AU - Allayee, Hooman

AU - Nitschke, Patrick Linsel

AU - Patel, Riyaz S

AU - Martinelli, Nicola

AU - Girelli, Domenico

AU - Quyyumi, Arshed A

AU - Anderson, Jeffrey L

AU - Erdmann, Jeanette

AU - Hall, Alistair S

AU - Schunkert, Heribert

AU - Quertermous, Thomas

AU - Blankenberg, Stefan

AU - Hazen, Stanley L

AU - Roberts, Robert

AU - Kathiresan, Sekar

AU - Samani, Nilesh J

AU - Epstein, Stephen E

AU - Rader, Daniel J

AU - Myocardial Infarction Genetics Consortium

N1 - Copyright © 2011 Elsevier Ltd. All rights reserved.

PY - 2011/1/29

Y1 - 2011/1/29

N2 - BACKGROUND: We tested whether genetic factors distinctly contribute to either development of coronary atherosclerosis or, specifically, to myocardial infarction in existing coronary atherosclerosis.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.

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

KW - ABO Blood-Group System/genetics

KW - ADAM Proteins/genetics

KW - ADAMTS7 Protein

KW - Adult

KW - Aged

KW - Coronary Angiography

KW - Coronary Artery Disease/blood

KW - Female

KW - Gene Frequency

KW - Genetic Loci

KW - Genetic Predisposition to Disease

KW - Genome-Wide Association Study

KW - Humans

KW - Linkage Disequilibrium

KW - Male

KW - Middle Aged

KW - Myocardial Infarction/blood

KW - Polymorphism, Single Nucleotide

U2 - 10.1016/S0140-6736(10)61996-4

DO - 10.1016/S0140-6736(10)61996-4

M3 - SCORING: Journal article

C2 - 21239051

VL - 377

SP - 383

EP - 392

JO - LANCET

JF - LANCET

SN - 0140-6736

IS - 9763

ER -