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Abstract
Purpose Genome-wide association studies have identified ADAMTS7 as a risk locus for coronary artery disease (CAD) and myocardial infarction (MI). Functional studies suggest ADAMTS7 may promote cellular processes in atherosclerosis. We studied if risk variant carriers exhibit a greater burden of angiographic CAD.
Methods We genotyped ADAMTS7 in the Southampton Atherosclerosis Study (SAS, n = 1359), and replicated in the Emory Genebank (Emory GB, n = 2684). Angiographic CAD was phenotyped as presence of >50% stenosis in epicardial vessel and semi-quantitative scores including the Gensini Score (GS), Sullivan Extent Score (SES) and the Duke Severity Index (DSI); and ex-vivo immunohistochemical analysis of human coronary plaques (n = 48).
Results We confirmed an association between ADAMTS7 genotype and presence of CAD under an additive genotype model in SAS (p = 0.05) and Emory GB (p = 0.017), but found no associations with MI in the presence of CAD. ADAMTS genotypes were associated with all of the angiographic severity scores in SAS (GS p = 0.017, SES p = 0.045, DSI p = 0.029), and independently replicated in Emory GB (GS p < 0.001, SES p < 0.001, DSI p = 0.001). Meta-analysis demonstrated that homozygous carriers of the risk allele had greater odds of multi-vessel disease [OR 1.36 (95% CI 1.13–1.63)] and proximal stenoses [OR 1.41 (95% CI 1.15–1.72)], compared to non-risk allele carriers. Additionally, the risk genotype was associated with greater fibrous cap thickness (p = 0.013) and% area of α-actin (smooth muscle cell marker) in the intima (p = 0.029).
Conclusions The ADAMTS7 risk variant is associated with multiple angiographic measures of CAD burden and plaque remodelling, further supporting the role of this protease in promoting atherosclerosis.
Associations between ADAMTS7 rs3825807 genotype and mean angiographic severity scorings in a) Emory Genebank; and b) Southampton Atherosclerosis Study. Error bars represent SEM
- ADAMTS7
- genetics
- Coronary artery disease
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