Yang Li1, Han Yan2, Jian Guo2, Yingchun Han1, Cuifang Zhang2, Xiuying Liu3, Jie Du1, Xiao-Li Tian2,4. 1. Vascular Biology Laboratory, Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart, Lung & Blood Vessel Disease, Beijing, China. 2. Department of Human Population Genetics, Institute of Molecular Medicine, Peking University, No. 5 Yiheyuan Road, Beijing, China. 3. Center for Molecular Systems Biology, Key Laboratory of Genetic Network Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China. 4. Department of Human Population Genetics, A217 Life Science Building, Human Aging Research Institute and School of Life Science, Jiangxi Key Laboratory of Human Aging, Nanchang University, 999 Xuefu Road, Honggutan New District, Nanchang City, Jiangxi Province 330031, China.
Abstract
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. Published on behalf of the European Society of Cardiology. All rights reserved.
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 CADpatients 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. Published on behalf of the European Society of Cardiology. All rights reserved.
Authors: Hugo Fernandes; Alessandra Zonnari; Ricardo Abreu; Sezin Aday; Marta Barão; Inês Albino; Miguel Lino; Ana Branco; Cátia Seabra; Tânia Barata; Ermelindo C Leal; José Guilherme Tralhão; Lino Gonçalves; Alwin de Jong; Hendrika A B Peters; Margreet R de Vries; Paula da Costa Martins; Paul H A Quax; Lino Ferreira Journal: Mol Ther Nucleic Acids Date: 2022-03-19 Impact factor: 10.183