Genetic variation at ADAMTS7 and severity of coronary artery disease

Abstract

BackgroundGenome-wide association studies have identified ADAMTS7 as a risk locus for coronary artery disease and myocardial infarction. Functional studies suggest that ADAMTS7 might promote cellular processes in atherosclerosis. We sought to examine whether carriers of a loss-of-function genetic variant exhibit favourable characteristics on plaque histology, angiographic coronary artery disease severity, and cardiovascular outcomes. MethodsThe single-nucleotide polymorphism rs3825807 was used as a marker for ADAMTS7. Human coronary atherosclerotic plaques (n=50) were genotyped, and characterised with immunohistochemical analysis. Burden of angiographic coronary artery disease was assessed by angiographic severity scores in two independent population-based cohorts—the Southampton Atherosclerosis Study (SAS, n=1359) in the UK, and the prospective Emory Genebank study (Emory GB, n=2684) in the USA. Follow-up data were collected in Emory GB over a median of 7 years. FindingsHuman coronary atherosclerotic plaques with the loss-of-function G allele exhibited thinner fibrous cap (p=0·017) and lower percentage area of α-actin (smooth muscle cell marker) in the intima (p=0·029). After adjustment for age and sex, the G allele was associated with less coronary artery disease in both SAS (odds ratio 0·82, 95% CI 0·67–0·99), and Emory GB (0·84, 0·74–0·95). Angiographic burden was further characterised with the Gensini Score (GS) and Sullivan Extent Score (SES). ADAMTS genotypes were associated with all of the angiographic severity scores in both SAS (GS p=0·026, SES p=0·029) and Emory GB (GS p<0·0001, SES p<0·0001). Outcome analysis showed lower incidence of revascularisation for G allele carriers (hazard ratio 0·77, 95% CI 0·60–0·98), but not all cause mortality (1·12, 0·92–1·35). InterpretationCarriers of the ADAMTS7 loss-of-function allele G had reduced atherosclerotic plaque progression, as demonstrated by thinner cap and smooth muscle migration. In addition there was less severe angiographic coronary artery disease in the SAS and Emory GB cohorts, as well as lower incidence of revascularisation procedure, further supporting the role of this protease in promoting atherosclerosis. FundingNone.