Genome-Wide Association and Functional Studies Identify SCML4 and THSD7A as Novel Susceptibility Genes for Coronary Artery Disease

Objective— The genetic contribution to coronary artery disease (CAD) remains largely unclear. We combined genetic screening with functional characterizations to identify novel loci and candidate genes for CAD. Approach and Results— We performed genome-wide screening followed by multicenter validation in 8 cohorts consisting of 21 828 participants of Han ethnicity and identified 3 novel intragenic SNPs (single nucleotide polymorphisms), rs9486729 (SCML4 [Scm polycomb group protein-like 4]; odds ratio, 1.25; 95% CI, 1.17–1.34;P =3.51×10−11 ), rs17165136 (THSD7A [thrombospondin type 1 domain-containing 7A]; odds ratio 1.28; 95% CI, 1.21–1.35;P <1.00×10−25 ), and rs852787 (DAB1 [disabled-1]; odds ratio, 1.29; 95% CI, 1.21–1.38;P =2.02×10−14 ), associated with CAD with genome-wide significance. The risk allele of rs9486729 and protective allele of rs17165136 were associated with the decreased expression of their host genes,SCML4 andTHSD7A , respectively, whereas rs852787 did not have transcriptional effects on any gene. Knockdown ofSCML4 activated endothelial cells by increasing the expression ofIL-6 ,E-selectin , andICAM and weakened their antiapoptotic activity, whereas the knockdown ofTHSD7A had little effect on these endothelial cell functions but attenuated monocyte adhesion via decreasing the expression ofICAM ,L-selectin , andITGB2 . We further showed that inhibiting the expression ofSCML4 exacerbated endothelial dysfunction and vascular remodeling in a rat model with partial carotid ligation.Conclusions— We identify 3 novel loci associated with CAD and show that 2 genes,SCML4 andTHSD7A , make functional contributions to atherosclerosis. How rs852787 and its host geneDAB1 are linked to CAD needs further studies.