Genome-Wide Association and Functional Studies Identify
SCML4
and
THSD7A
as Novel Susceptibility Genes for Coronary Artery Disease
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Published:2018-04
Issue:4
Volume:38
Page:964-975
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ISSN:1079-5642
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Container-title:Arteriosclerosis, Thrombosis, and Vascular Biology
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language:en
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Short-container-title:ATVB
Author:
Li Yang1, Wang Dao Wen1, Chen Yundai1, Chen Can1, Guo Jian1, Zhang Shu1, Sun Zhijun1, Ding Hu1, Yao Yan1, Zhou Lei1, Xu Ke1, Song Chun1, Yang Fan1, Zhao Bin1, Yan Han1, Wang Wen-Jing1, Wu Chong1, Lu Xiangfeng1, Yang Xueli1, Dong Jie1, Zheng Guyan1, Tian Shuhan1, Cui Yanjun1, Jin Lijuan1, Liu Gangqiong1, Cui Hanbin1, Wang Shenghuang1, Jiang Feng1, Wang Changhua1, Erdmann Jeanette1, Zeng Linyao1, Huang Shian1, Zhong Jianfeng1, Ma Yuehua1, Chen Wenjiang1, Sun Jianli1, Lei Wei1, Chen Shenghan1, Rao Shaoqi1, Gu Dongfeng1, Schunkert Heribert1, Tian Xiao-Li1
Affiliation:
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...
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.
Publisher
Ovid Technologies (Wolters Kluwer Health)
Subject
Cardiology and Cardiovascular Medicine
Cited by
38 articles.
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