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Multicenter Study
. 2011 Jan 29;377(9763):383-92.
doi: 10.1016/S0140-6736(10)61996-4. Epub 2011 Jan 14.

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  1 , 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; Myocardial Infarction Genetics Consortium; Wellcome Trust Case Control Consortium; Nicola Martinelli, Domenico Girelli, Arshed A Quyyumi, 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
Collaborators, Affiliations
Multicenter Study

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 et al. Lancet. .

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.

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Conflict of interest statement

Conflicts of interest

MPR, MSB, JMD, SEE, and DJR received research grant support from GlaxoSmithKline. CWK was an employee of GlaxoSmithKline at the time of the study. ML, JH, JFF, IMS, NNM, JRT, BDH, AFRS, TLA, PSW, HA, PLN, RSP, NM, DG, AAQ, JLA, JE, ASH, HS, TQ, SB, SLH, RR, SK, and NJS declare that they have no conflicts of interest.

Figures

Figure 1
Figure 1. Study design
Cleveland Clinic GeneBank Study 1 was derived from a GWAS of CAD cases with in-stent restenosis. Cleveland Clinic GeneBank Study 2 was derived from a GWAS study of angiographic CAD cases without diabetes mellitus. GWAS=genome-wide association study. CAD=coronary artery disease. AngCADMI+=angiographic CAD with myocardial infacrtion. AngCADMI–=angiographic CAD without myocardial infarction. WTCCC=Wellcome Trust Case-Control Consortium. OHGS=Ottawa Heart Genomics Study. CADomics=Coronary Artery Disease and genomics. ADVANCE=Atherosclerotic Disease Vascular Function and Genetic Epidemiology study. Cleveland GB=Cleveland Clinic GeneBank. Emory GB=Emory GeneBank Study. Utah IHCS=Utah Intermountain Heart Collaborative Study.
Figure 2
Figure 2. Association of rs1994016 at the ADAMTS7 locus with (A) angiographic CAD (AngCAD vs control) and (B) early-onset myocardial infarction (myocardial infarction vs control)
Forest plots are presented for the association of rs1994016 with (A) angiographic CAD versus controls in each individual study and overall in meta-analysis of eight studies, and (B) myocardial infarction versus control in two separate studies of early-onset myocardial infarction and in their meta-analysis. WTCCC=Wellcome Trust Case-Control Consortium. OHGS=Ottawa Heart Genomics Study. Emory GB=Emory GeneBank Study. Utah IHCS=Utah Intermountain Heart Collaborative Study. Cleveland GB=Cleveland Clinic GeneBank. MI-GEN=Myocardial Infarction Genetics Consortium. GerMI FS=German Myocardial Infarction Family Study. *We used Genetic Power Calculator to estimate the non-centrality parameter for the given asymmetric case-control sample size, and then determined the effective (symmetric) case-control sample size that returns the same non-centrality parameter.
Figure 3
Figure 3. Association of rs514659 at the 9q34.2 ABO locus with myocardial infarction in patients with angiographic CAD (myocardial infarction versus no myocardial infarction)
Forest plot for the association of rs514659 with myocardial infarction in each individual study and overall in meta-analysis of all eight studies: PennCath, MedStar, WTCC, OHGS, CADomics, ADVANCE, and Cleveland GB 1 and 2. CAD=coronary artery disease. WTCCC=Wellcome Trust Case-Control Consortium. OHGS=Ottawa Heart Genomics Study. CADomics=Coronary Artery Disease and genomics. ADVANCE=Atherosclerotic Disease VAscular functioN and genetiC Epidemiology study. GB=GeneBank. *We used Genetic Power Calculator to estimate the non-centrality parameter for the given asymmetric case-control sample size, and then determined the effective (symmetric) case-control sample size that returns the same non-centrality parameter.
Figure 4
Figure 4. Association between the 9q34.2 ABO locus and myocardial infarction in patients with angiographic CAD
(A) Recombination rate, linkage disequilibrium (in r2; colour coding of the squares correspond to strength of linkage disequilibrium), and p values for SNPs in the ABO region based on meta-analysis data from all eight studies. (B) Selected SNPs and haplotype blocks at the ABO locus. The top imputed SNP, rs514659, shown in the red box. The top genotyped SNP, rs612169, is shown in the black box; the rs612169A allele fully tags the allele of blood group O. Top SNPs for myocardial infarction in patients with angiographic CAD, including rs514659 and rs612169, lie in intron 1 of ABO and are all in tight linkage disequilibrium with the inferred blood group O allele. The rs8176672A allele tags blood group B whereas the rs8176704A allele tags blood group A1. Additional symbols mark rs651007 (*) and rs579459 (†). The rs651007 SNP tags (r2=0·88) rs507666, which was the top SNP in GWAS of circulating concentrations of LDL-cholesterol and ICAM-1. The rs579459 SNP was a top SNP in GWAS of circulating levels of E-selectin and P-selectin., These SNPs are in moderate linkage disequilibrium with rs514659 (r2=0·53 for rs651007, r2=0·36 for rs579459) and had modest associations with AngCADMI+ (p=0·053 for rs651007, p=0·001 for rs579459). CAD=coronary artery disease. AngCADMI+=angiographic CAD with myocardial infarction. AngCADMI–=angiographic CAD without myocardial infarction. ICAM-1=Inter-cellular adhesion molecule 1).
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References

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