Abstract
AimsGenome-wide association studies (GWAS) have consistently identified an association between coronary artery disease (CAD) and a locus on chromosome 10 containing a single gene, JCAD (formerly KIAA1462). However, little is known about the mechanism by which JCAD could influence the development of atherosclerosis.Methods and resultsVascular function was quantified in subjects with CAD by flow-mediated dilatation (FMD) and vasorelaxation responses in isolated blood vessel segments. The JCAD risk allele identified by GWAS was associated with reduced FMD and reduced endothelial-dependent relaxations. To study the impact of loss of Jcad on atherosclerosis, Jcad−/− mice were crossed to an ApoE−/− background and fed a high-fat diet from 6 to16 weeks of age. Loss of Jcad did not affect blood pressure or heart rate. However, Jcad−/−ApoE−/− mice developed significantly less atherosclerosis in the aortic root and the inner curvature of the aortic arch. En face analysis revealed a striking reduction in pro-inflammatory adhesion molecules at sites of disturbed flow on the endothelial cell layer of Jcad−/− mice. Loss of Jcad lead to a reduced recovery perfusion in response to hind limb ischaemia, a model of altered in vivo flow. Knock down of JCAD using siRNA in primary human aortic endothelial cells significantly reduced the response to acute onset of flow, as evidenced by reduced phosphorylation of NF-КB, eNOS, and Akt.ConclusionThe novel CAD gene JCAD promotes atherosclerotic plaque formation via a role in the endothelial cell shear stress mechanotransduction pathway.
Highlights
Genome-wide association studies (GWAS) have achieved significant progress in identifying, and robustly replicating, common genetic variation that contributes to increased coronary artery disease (CAD) risk.The post-GWAS challenge is to identify the genes that confer the causative association with the CAD locus and discover the biological mechanisms linking these genes to CAD
We have previously identified a locus on chromosome 10 which harbours a single gene, JCAD (Junctional protein associated with Coronary Artery Disease; previously KIAA1462).[1]
This difference was not due to a change in sensitively of the Vascular smooth muscle cells (VSMCs) to nitric oxide, since endothelial cell independent dilation in response to GTN was not different between genotypes (Figure 1B). These in vivo studies were supported by ex vivo organ bath measurements of endothelial cell function in saphenous vein rings harvested at the time of cardiac surgery, revealing a significant decrease in sensitivity to the endothelial cell dependent vasodilator bradykinin in carriers of the JCAD rs2487928 risk allele (Figure 1C), with no difference in the response to the endothelium-independent dilator, sodium nitroprusside (SNP; Figure 1D)
Summary
Genome-wide association studies (GWAS) have achieved significant progress in identifying, and robustly replicating, common genetic variation that contributes to increased coronary artery disease (CAD) risk.The post-GWAS challenge is to identify the genes that confer the causative association with the CAD locus and discover the biological mechanisms linking these genes to CAD. We have previously identified a locus on chromosome 10 which harbours a single gene, JCAD (Junctional protein associated with Coronary Artery Disease; previously KIAA1462).[1] This association has been robustly confirmed in subsequent meta-analyses.[2] Using the STARNET data set, we identified an expression quantitative trait locus between the protective allele of the lead SNP rs2487928 which was associated with decreased expression of JCAD in both atherosclerotic and atherosclerosis free arterial tissue. This indicates that decreased expression of JCAD associated with the rs2487928 allele is protective,[3] leading to the hypothesis that loss of JCAD would result in reduced atherosclerosis burden
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