Yang Li1, Dao Wen Wang1, Yundai Chen1, Can Chen1, Jian Guo1, Shu Zhang1, Zhijun Sun1, Hu Ding1, Yan Yao1, Lei Zhou1, Ke Xu1, Chun Song1, Fan Yang1, Bin Zhao1, Han Yan1, Wen-Jing Wang1, Chong Wu1, Xiangfeng Lu1, Xueli Yang1, Jie Dong1, Guyan Zheng1, Shuhan Tian1, Yanjun Cui1, Lijuan Jin1, Gangqiong Liu1, Hanbin Cui1, Shenghuang Wang1, Feng Jiang1, Changhua Wang1, Jeanette Erdmann1, Linyao Zeng1, Shian Huang1, Jianfeng Zhong1, Yuehua Ma1, Wenjiang Chen1, Jianli Sun1, Wei Lei1, Shenghan Chen1, Shaoqi Rao1, Dongfeng Gu1, Heribert Schunkert1, Xiao-Li Tian2. 1. From the Department of Human Population Genetics, Institute of Molecular Medicine, Peking University, Beijing, China (Y.L., J.G., K.X., C.S., F.Y., B.Z., H.Y., W.-J.W., C.W., J.D., G.Z., X.-L.T.); Beijing Anzhen Hospital (Y.L.), Department of Cardiology, Beijing Anzhen Hospital (Y.Y., C.W.), and Department of Cardiology, Beijing Chaoyang Hospital (F.J.), Capital Medical University, China; Beijing Institute of Heart, Lung, and Blood Vessel Disease, China (Y.L.); Department of Internal Medicine, Gene Therapy Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (D.W.W., H.D., S.T.); Department of Cardiology, The General Hospital of Chinese People's Liberation Army, Beijing, China (Y.C., Z.S.); Cardiovascular Medicine Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China (C.C., S.H., J.Z., Y.M., W.C., J.S., W.L.); State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing (S.Z., X.L., X.Y., D.G.); Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, China (L.Z.); Department of Internal Medicine, Hospital of Peking University, Beijing, China (Y.C.); Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, China (L.J.); Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, China (G.L.); Cardiovascular Department, Ningbo First Hospital, Ningbo University, China (H.C., S.W.); Institut für Integrative und Experimentelle Genomik, Universität zu Lübeck, Germany (J.E.); German Research Centre for Cardiovascular Research, Partner Site Hamburg/Lübeck/Kiel (J.E.); Deutsches Herzzentrum München, Technische Universität München, Germany (L.Z., H.S.); German Centre for Cardiovascular Research, Partner Site Munich Heart Alliance (L.Z., H.S.); Department of Human Population Genetics, Human Aging Research Institute and School of Life Science, Nanchang University, China (S.C., X.-L.T.); and Institute of Medical Systems Biology (S.R.) and School of Public Health (S.R.), Guangdong Medical University, Dongguan, China. 2. From the Department of Human Population Genetics, Institute of Molecular Medicine, Peking University, Beijing, China (Y.L., J.G., K.X., C.S., F.Y., B.Z., H.Y., W.-J.W., C.W., J.D., G.Z., X.-L.T.); Beijing Anzhen Hospital (Y.L.), Department of Cardiology, Beijing Anzhen Hospital (Y.Y., C.W.), and Department of Cardiology, Beijing Chaoyang Hospital (F.J.), Capital Medical University, China; Beijing Institute of Heart, Lung, and Blood Vessel Disease, China (Y.L.); Department of Internal Medicine, Gene Therapy Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China (D.W.W., H.D., S.T.); Department of Cardiology, The General Hospital of Chinese People's Liberation Army, Beijing, China (Y.C., Z.S.); Cardiovascular Medicine Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China (C.C., S.H., J.Z., Y.M., W.C., J.S., W.L.); State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing (S.Z., X.L., X.Y., D.G.); Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, China (L.Z.); Department of Internal Medicine, Hospital of Peking University, Beijing, China (Y.C.); Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, China (L.J.); Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, China (G.L.); Cardiovascular Department, Ningbo First Hospital, Ningbo University, China (H.C., S.W.); Institut für Integrative und Experimentelle Genomik, Universität zu Lübeck, Germany (J.E.); German Research Centre for Cardiovascular Research, Partner Site Hamburg/Lübeck/Kiel (J.E.); Deutsches Herzzentrum München, Technische Universität München, Germany (L.Z., H.S.); German Centre for Cardiovascular Research, Partner Site Munich Heart Alliance (L.Z., H.S.); Department of Human Population Genetics, Human Aging Research Institute and School of Life Science, Nanchang University, China (S.C., X.-L.T.); and Institute of Medical Systems Biology (S.R.) and School of Public Health (S.R.), Guangdong Medical University, Dongguan, China. tianxiaoli@ncu.edu.cn.
Abstract
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 and THSD7A, respectively, whereas rs852787 did not have transcriptional effects on any gene. Knockdown of SCML4 activated endothelial cells by increasing the expression of IL-6, E-selectin, and ICAM and weakened their antiapoptotic activity, whereas the knockdown of THSD7A had little effect on these endothelial cell functions but attenuated monocyte adhesion via decreasing the expression of ICAM, L-selectin, and ITGB2. We further showed that inhibiting the expression of SCML4 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 and THSD7A, make functional contributions to atherosclerosis. How rs852787 and its host gene DAB1 are linked to CAD needs further studies.
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 and THSD7A, respectively, whereas rs852787 did not have transcriptional effects on any gene. Knockdown of SCML4 activated endothelial cells by increasing the expression of IL-6, E-selectin, and ICAM and weakened their antiapoptotic activity, whereas the knockdown of THSD7A had little effect on these endothelial cell functions but attenuated monocyte adhesion via decreasing the expression of ICAM, L-selectin, and ITGB2. We further showed that inhibiting the expression of SCML4 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 and THSD7A, make functional contributions to atherosclerosis. How rs852787 and its host gene DAB1 are linked to CAD needs further studies.
Authors: Martin Söderholm; Annie Pedersen; Erik Lorentzen; Tara M Stanne; Steve Bevan; Maja Olsson; John W Cole; Israel Fernandez-Cadenas; Graeme J Hankey; Jordi Jimenez-Conde; Katarina Jood; Jin-Moo Lee; Robin Lemmens; Christopher Levi; Braxton D Mitchell; Bo Norrving; Kristiina Rannikmäe; Natalia S Rost; Jonathan Rosand; Peter M Rothwell; Rodney Scott; Daniel Strbian; Jonathan W Sturm; Cathie Sudlow; Matthew Traylor; Vincent Thijs; Turgut Tatlisumak; Daniel Woo; Bradford B Worrall; Jane M Maguire; Arne Lindgren; Christina Jern Journal: Neurology Date: 2019-02-22 Impact factor: 11.800
Authors: Jennifer R Dungan; Xue Qin; Melissa Hurdle; Carol S Haynes; Elizabeth R Hauser; William E Kraus Journal: Front Genet Date: 2021-06-01 Impact factor: 4.599