机构：[1]Department of Human Population Genetics, Institute of Molecular Medicine, Peking University, Beijing, China[2]Beijing Anzhen Hospital, Capital Medical University, China首都医科大学附属安贞医院[3]Department of Cardiology, Beijing Anzhen Hospital, Capital Medical University, China临床科室心脏内科中心首都医科大学附属安贞医院[4]Department of Cardiology, Beijing Chaoyang Hospital, Capital Medical University, China内科系统(本部)心脏中心（本部）北京朝阳医院[5]Beijing Institute of Heart, Lung, and Blood Vessel Disease, China首都医科大学附属安贞医院[6]Department of Internal Medicine, Gene Therapy Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China华中科技大学同济医学院附属同济医院[7]Department of Cardiology, The General Hospital of Chinese People’s Liberation Army, Beijing, China[8]Cardiovascular Medicine Center, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China[9]State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing[10]Department of Cardiology, The First Affiliated Hospital of Nanjing Medical University, China内科系统心血管内科江苏省人民医院[11]Department of Internal Medicine, Hospital of Peking University, Beijing, China[12]Department of Cardiology, The Second Affiliated Hospital of Harbin Medical University, China[13]Department of Cardiology, The First Affiliated Hospital of Zhengzhou University, China[14]Cardiovascular Department, Ningbo First Hospital, Ningbo University, China[15]Institut fur Integrative und Experimentelle Genomik, Universitat zu Lubeck, Germany[16]German Research Centre for Cardiovascular Research, Partner Site Hamburg/Lubeck/Kiel[17]Deutsches Herzzentrum Munchen, Technische Universitat Munchen, Germany[18]German Centre for Cardiovascular Research, Partner Site Munich Heart Alliance[19]Department of Human Population Genetics, Human Aging Research Institute and School of Life Science, Nanchang University, China[20]Institute of Medical Systems Biology, Guangdong Medical University, Dongguan, China[21]School of Public Health, Guangdong Medical University, Dongguan, China
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 21828 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=3.51x10(-11)), rs17165136 (THSD7A [thrombospondin type 1 domain-containing 7A]; odds ratio 1.28; 95% CI, 1.21-1.35; P<1.00x10(-25)), and rs852787 (DAB1 [disabled-1]; odds ratio, 1.29; 95% CI, 1.21-1.38; P=2.02x10(-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.
基金：
This study was supported by grants from the National Basic Research Program of the Chinese Ministry of Science and Technology (973 Grants 2013CB530700 and 2007CB512103) and the National Natural Science Foundation of China (81630034 and 81130003) to X.-L. Tian.
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外文
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出版当年[2017]版：
大类|1 区医学
小类|2 区血液学2 区外周血管病
最新[2023]版：
大类|1 区医学
小类|2 区血液学2 区外周血管病
第一作者：
第一作者机构：[1]Department of Human Population Genetics, Institute of Molecular Medicine, Peking University, Beijing, China[2]Beijing Anzhen Hospital, Capital Medical University, China[5]Beijing Institute of Heart, Lung, and Blood Vessel Disease, China
共同第一作者：
通讯作者：
通讯机构：[1]Department of Human Population Genetics, Institute of Molecular Medicine, Peking University, Beijing, China[19]Department of Human Population Genetics, Human Aging Research Institute and School of Life Science, Nanchang University, China[*1]Human Population Genetics, Human Aging Research Institute and School of Life Science, Nanchang University, A217 Life Science Bldg, 999 Xuefu Rd, Honggutan New District, Nanchang City, Jiangxi Province 330031, China.
推荐引用方式(GB/T 7714)：
Yang Li,Dao Wen Wang,Yundai Chen,et al.Genome-Wide Association and Functional Studies Identify SCML4 and THSD7A as Novel Susceptibility Genes for Coronary Artery Disease[J].ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY.2018,38(4):964-975.doi:10.1161/ATVBAHA.117.310594.
APA：
Yang Li,Dao Wen Wang,Yundai Chen,Can Chen,Jian Guo...&Xiao-Li Tian.(2018).Genome-Wide Association and Functional Studies Identify SCML4 and THSD7A as Novel Susceptibility Genes for Coronary Artery Disease.ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY,38,(4)
MLA：
Yang Li,et al."Genome-Wide Association and Functional Studies Identify SCML4 and THSD7A as Novel Susceptibility Genes for Coronary Artery Disease".ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY 38..4(2018):964-975
医学