单位：[1]National Research Institute for Family Planning, Beijing, China[2]Beijing Hypertension League Institute, Beijing, China[3]Shanghai Diabetes Institute, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, Shanghai, China[4]Institute for Metabolic Diseases, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital South Campus, Shanghai, China[5]Department of Cardiology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China北京朝阳医院[6]Beijing Key Laboratory of Hypertension, Beijing, China[7]Medical Research Center, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China北京朝阳医院[8]Department of Cardiology, The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China[9]Department of Cardiology, Beijing Friendship Hospital, Capital Medical University, Beijing, China临床科室心血管中心心内科首都医科大学附属北京友谊医院[10]Department of Cardiology, Kailuan General Hospital, Hebei Union University, Tangshan, Hebei, China[11]Department of Hypertension, Fuwai Hospital, Beijing, China[12]State Key Laboratory of Cardiovascular Disease, Beijing, China[13]National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
Hypertension is a major global health burden and a leading risk factor for cardiovascular diseases. Although its heritability has been documented previously, contributing loci identified to date account for only a small fraction of blood pressure (BP) variation, which strongly suggests the existence of undiscovered variants. To identify novel variants, we conducted a three staged genetic study in 21,990 hypertensive cases and normotensive controls. Four single nucleotide polymorphisms (SNPs) at three new genes (L3MBTL4 rs403814, P-meta = 6.128 x 10(-9); LOC729251, and TCEANC) and seven SNPs at five previously reported genes were identified as being significantly associated with hypertension. Through functional analysis, we found that L3MBTL4 is predominantly expressed in vascular smooth muscle cells and up-regulated in spontaneously hypertensive rats. Rats with ubiquitous over-expression of L3MBTL4 exhibited significantly elevated BP, increased thickness of the vascular media layer and cardiac hypertrophy. Mechanistically, L3MBTL4 over-expression could lead to down-regulation of latent transforming growth factor-beta binding protein 1 (LTBP1), and phosphorylation activation of the mitogen-activated protein kinases (MAPK) signaling pathway, which is known to trigger the pathological progression of vascular remodeling and BP elevation. These findings pinpointed L3MBTL4 as a critical contributor to the development and progression of hypertension and uncovers a novel target for therapeutic intervention.
基金：
National Basic Research ProgramNational Basic Research Program of China [2014CB542302]; International S&T Cooperation Program of China [2013DFB30310]; Natural Science Foundation of ChinaNational Natural Science Foundation of China (NSFC) [811170244, 81222001, 81470541]
第一作者单位：[1]National Research Institute for Family Planning, Beijing, China[2]Beijing Hypertension League Institute, Beijing, China
共同第一作者：
通讯作者：
通讯机构：[11]Department of Hypertension, Fuwai Hospital, Beijing, China[12]State Key Laboratory of Cardiovascular Disease, Beijing, China[13]National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
推荐引用方式(GB/T 7714)：
Liu Xin,Hu Cheng,Bao Minghui,et al.Genome Wide Association Study Identifies L3MBTL4 as a Novel Susceptibility Gene for Hypertension[J].SCIENTIFIC REPORTS.2016,6:doi:10.1038/srep30811.
APA：
Liu, Xin,Hu, Cheng,Bao, Minghui,Li, Jing,Liu, Xiaoyan...&Cai, Jun.(2016).Genome Wide Association Study Identifies L3MBTL4 as a Novel Susceptibility Gene for Hypertension.SCIENTIFIC REPORTS,6,
MLA：
Liu, Xin,et al."Genome Wide Association Study Identifies L3MBTL4 as a Novel Susceptibility Gene for Hypertension".SCIENTIFIC REPORTS 6.(2016)
