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

Muredach P Reilly, Mingyao Li, Jing He, Jane F Ferguson, Ioannis M Stylianou, Nehal N Mehta, Mary Susan Burnett, Joseph M Devaney, Christopher W Knouff, John R Thompson, Benjamin D Horne, Alexandre F R Stewart, Themistocles L Assimes, Philipp S Wild, Hooman Allayee, Patrick Linsel Nitschke, Riyaz S Patel, Nicola Martinelli, Domenico Girelli, Arshed A Quyyumi & 14 others Jeffrey L Anderson, Jeanette Erdmann, Alistair S Hall, Heribert Schunkert, Thomas Quertermous, Stefan Blankenberg, Stanley L Hazen, Robert Roberts, Sekar Kathiresan, Nilesh J Samani, Stephen E Epstein, Daniel J Rader, Myocardial Infarction Genetics Consortium, David St Clair

Research output: Contribution to journalArticle

329 Citations (Scopus)

Abstract

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.
Original languageEnglish
Pages (from-to)383-392
Number of pages10
JournalThe Lancet
Volume377
Issue number9763
Early online date14 Jan 2011
DOIs
Publication statusPublished - 29 Jan 2011

Fingerprint

Genome-Wide Association Study
Coronary Artery Disease
Myocardial Infarction
Phenotype
Organized Financing
Genetic Predisposition to Disease
Blood Group Antigens

Keywords

  • ABO blood-group system
  • ADAM proteins
  • adult
  • aged
  • coronary angiography
  • coronary artery disease
  • female
  • gene frequency
  • genetic loci
  • genetic predisposition to disease
  • genome-wide association study
  • humans
  • linkage disequilibrium
  • male
  • middle aged
  • myocardial infarction
  • polymorphism, single nucleotide

Cite this

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. / 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; 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; Myocardial Infarction Genetics Consortium ; St Clair, David.

In: The Lancet, Vol. 377, No. 9763, 29.01.2011, p. 383-392.

Research output: Contribution to journalArticle

Reilly, MP, Li, M, He, J, Ferguson, JF, Stylianou, IM, Mehta, NN, Burnett, MS, Devaney, JM, Knouff, CW, Thompson, JR, Horne, BD, Stewart, AFR, Assimes, TL, Wild, PS, Allayee, H, Nitschke, PL, Patel, RS, Martinelli, N, Girelli, D, Quyyumi, AA, Anderson, JL, Erdmann, J, Hall, AS, Schunkert, H, Quertermous, T, Blankenberg, S, Hazen, SL, Roberts, R, Kathiresan, S, Samani, NJ, Epstein, SE, Rader, DJ, Myocardial Infarction Genetics Consortium & St Clair, D 2011, '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', The Lancet, vol. 377, no. 9763, pp. 383-392. https://doi.org/10.1016/S0140-6736(10)61996-4
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 ; 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 ; Myocardial Infarction Genetics Consortium ; St Clair, David. / 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. In: The Lancet. 2011 ; Vol. 377, No. 9763. pp. 383-392.
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abstract = "BackgroundWe tested whether genetic factors distinctly contribute to either development of coronary atherosclerosis or, specifically, to myocardial infarction in existing coronary atherosclerosis.MethodsWe 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).FindingsIn 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.InterpretationOur 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.FundingThe 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.",
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author = "Reilly, {Muredach P} and Mingyao Li and Jing He and Ferguson, {Jane F} and Stylianou, {Ioannis M} and Mehta, {Nehal N} and Burnett, {Mary Susan} and Devaney, {Joseph M} and Knouff, {Christopher W} and Thompson, {John R} and Horne, {Benjamin D} and Stewart, {Alexandre F R} and Assimes, {Themistocles L} and Wild, {Philipp S} and Hooman Allayee and Nitschke, {Patrick Linsel} and Patel, {Riyaz S} and Nicola Martinelli and Domenico Girelli and Quyyumi, {Arshed A} and Anderson, {Jeffrey L} and Jeanette Erdmann and Hall, {Alistair S} and Heribert Schunkert and Thomas Quertermous and Stefan Blankenberg and Hazen, {Stanley L} and Robert Roberts and Sekar Kathiresan and Samani, {Nilesh J} and Epstein, {Stephen E} and Rader, {Daniel J} and {Myocardial Infarction Genetics Consortium} and {St Clair}, David",
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T1 - Identification of ADAMTS7 as a novel locus for coronary atherosclerosis and association of ABO with myocardial infarction in the presence of coronary atherosclerosis

T2 - 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

AU - St Clair, David

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

PY - 2011/1/29

Y1 - 2011/1/29

N2 - BackgroundWe tested whether genetic factors distinctly contribute to either development of coronary atherosclerosis or, specifically, to myocardial infarction in existing coronary atherosclerosis.MethodsWe 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).FindingsIn 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.InterpretationOur 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.FundingThe 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 - BackgroundWe tested whether genetic factors distinctly contribute to either development of coronary atherosclerosis or, specifically, to myocardial infarction in existing coronary atherosclerosis.MethodsWe 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).FindingsIn 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.InterpretationOur 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.FundingThe 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

KW - ADAM proteins

KW - adult

KW - aged

KW - coronary angiography

KW - coronary artery disease

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

KW - polymorphism, single nucleotide

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

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

M3 - Article

VL - 377

SP - 383

EP - 392

JO - The Lancet

JF - The Lancet

SN - 0140-6736

IS - 9763

ER -