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…

By M. Reilly, Mingyao Li, Jing He, Jane F. Ferguson, I. Stylianou, N. Mehta, M. Burnett, J. Devaney, C. Knouff, J. Thompson and 22 more. 2011

531 citations recorded by the source corpus.

Summary 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.

Subfields: Genetics, Hematology, Molecular Biology

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Citations in the corpus

• A Disintegrin and Metalloproteinase (ADAM) and ADAM with Thrombospondin Motifs (ADAMTS) Family in Vascular Biology and Disease (2019, background): “Ser214Pro substitution in the ADAMTS-7 propeptide that could be associated with coronary artery disease [156].”
• A genome-wide association study in Europeans and South Asians identifies five new loci for coronary artery disease (2011, unknown): “Note added in proof: Since this manuscript was submitted ADAMTS7 (ref”
• Association between plasma ADAMTS-7 levels and severity of disease in patients with stable obstructive coronary artery disease (2016, background): “Importantly, ADAMTS-7 was reported to be a novel locus associated with human CAD but not acute myocardial infarction (AMI) in 3 recent genomewide association studies (GWAS).([3,4,5]) MMPs and ADAMTSs act not only in the plaque rupture stage but also in the initial stages of atherosclerosis.”
• A comprehensive 1000 Genomes-based genome-wide association meta-analysis of coronary artery disease (2015, unknown): “We confirmed that ABO is particularly associated with risk of myocardial infarction 50 , suggesting that this locus may specifically increase the risk of plaque rupture and/or thrombosis.”
• Biochemistry and physiological functions of ADAMTS7 metalloprotease (2013, background): “In addition, proteases cleave α2-MG at the bait region, resulting in an engulfment of the protease and formation of an irreversible complex (Figure5) [26].”
• Association between plasma ADAMTS-7 levels and ventricular remodeling in patients with acute myocardial infarction (2015, unknown): “Nevertheless, a study showed an association between the ADAMTS-7 locus and angiographic coronary artery disease [15].”
• ADAMTS proteins in human disorders (2018, unknown): “, rs1994016 [70] and rs4380028 [71] are located in intron 8 and 7.”
• A review on coronary artery disease, its risk factors, and therapeutics (2019, background): “Some of these genes are SORT1, MIA3, WDR12, PCSK9, CDKN2A, CDKN2B, MRAS, ANRIL, PHACTRI1, PTPN11, ATXN2, CXCL12, SL5A3, SH2BS, LDLR, KCNE2, and MRPS6 (Reilly et al., 2011).”
• Upregulation of ADAMTS-7 and downregulation of COMP are associated with aortic aneurysm (2017, unknown): “Various ADAMTS family members are highly expressed in human carotid lesions and advanced coronary atherosclerotic plaques, including ADAMTS‐1, ‐4, ‐5, ‐7 and ‐8 (5-9).”