Down-regulated RGS5 by genetic variants impairs endothelial cell function and contributes to coronary artery disease.
AIMS
Genetic contribution to coronary artery disease (CAD) remains largely unillustrated. Although transcriptomic profiles have identified dozens of genes that are differentially expressed in normal and atherosclerotic vessels, whether those genes are genetically associated with CAD remains to be determined. Here, we combined genetic association studies, transcriptome profiles and in vitro and in vivo functional experiments to identify novel susceptibility genes for CAD.


METHODS AND RESULTS
Through an integrative analysis of transcriptome profiles with genome-wide association studies for CAD, we obtained 18 candidate genes and selected one representative single nucleotide polymorphism (SNP) for each gene for multi-centred validations. We identified an intragenic SNP, rs1056515 in RGS5 gene (odds ratio = 1.17, 95% confidence interval =1.10-1.24, P = 3.72 × 10-8) associated with CAD at genome-wide significance. Rare genetic variants in linkage disequilibrium with rs1056515 were identified in CAD patients leading to a decreased expression of RGS5. The decreased expression was also observed in atherosclerotic vessels and endothelial cells treated by various cardiovascular risk factors. Through siRNA knockdown and adenoviral overexpression, we further showed that RGS5 regulated endothelial inflammation, vascular remodelling, as well as canonical NF-κB signalling activation. Moreover, CXCL12, a specific downstream target of the non-canonical NF-κB pathway, was strongly affected by RGS5. However, the p100 processing, a well-documented marker for non-canonical NF-κB pathway activation, was not altered, suggesting an existence of a novel mechanism by which RGS5 regulates CXCL12.


CONCLUSIONS
We identified RGS5 as a novel susceptibility gene for CAD and showed that the decreased expression of RGS5 impaired endothelial cell function and functionally contributed to atherosclerosis through a variety of molecular mechanisms. How RGS5 regulates the expression of CXCL12 needs further studies.
['Li|Yang|Y|', 'Yan|Han|H|', 'Guo|Jian|J|', 'Han|Yingchun|Y|', 'Zhang|Cuifang|C|', 'Liu|Xiuying|X|', 'Du|Jie|J|', 'Tian|Xiao-Li|XL|']
D000328:Adult D000368:Aged D000818:Animals D016893:Carotid Stenosis D016022:Case-Control Studies D054377:Chemokine CXCL12 D003324:Coronary Artery Disease D004195:Disease Models, Animal D015536:Down-Regulation D042783:Endothelial Cells D005260:Female D020869:Gene Expression Profiling D020022:Genetic Predisposition to Disease D055106:Genome-Wide Association Study D057809:HEK293 Cells D006801:Humans D008297:Male D008810:Mice, Inbred C57BL D008875:Middle Aged D016328:NF-kappa B D010641:Phenotype D020641:Polymorphism, Single Nucleotide D020710:RGS Proteins D000074084:THP-1 Cells D059467:Transcriptome
RGS5 Genetic variants Coronary artery disease Atherosclerosis Endothelial cell activation