This week, my choice for Paper of the Week is one in which the mechanism by which a heart disease risk variant, initially observed in GWAS, has been determined. The paper is by Pu, Xiao et al. and published in the American Journal of Human Genetics 92:366-374.
ADAMTS7 encodes a metalloprotease which cleaves protein in order to activate them. One of its substrates is COMP, known as thrombospondin-5, which is known to be made by vascular smooth muscle cells (VSMC) and inhibit their migration. The authors noted that ADAMTS7 accumulated in smooth muscle cells in both carotid and coronary atherosclerotic plaques. The relevant genetic variant here is rs3825807, calling for a nonsynonymous A to G, leading to a substitution at amino acid 214, Ser to Pro, in the prodomain of the ADAMTS7 protease. VSMCs harboring the G/G genotype for rs3825807 had attenuated migratory ability, while conditioned media of VSMCs of the G/G genotype contained less of the cleaved form of COMP.
The authors write that "the results of our study indicate that rs3825807 has an effect on ADAMTS7 maturation, thrombospondin-5 cleavage, and VSMC migration, with the variant associated with protection from atherosclerosis and CAD (coronary artery disease) rendering a reduction in ADAMTS7 function." I find this a noteworthy study because it takes a GWAS hit for CAD risk and informs us as to how that allele can lead to plaque formation and atherosclerosis.