title: Genome Wide Association Study Identifies L3MBTL4 as a Novel Susceptibility Gene for Hypertension.
abstract: 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, Pmeta = 6.128 × 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-β 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.
authors.affiliation: National Research Institute for Family Planning, Beijing, China.|Beijing Hypertension League Institute, Beijing, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Liu
authors.affiliation: Shanghai Diabetes Institute, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.|Institute for Metabolic Diseases, Shanghai Jiao Tong University Affiliated Sixth People's Hospital South Campus, Shanghai, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Hu
authors.affiliation: Department of Cardiology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China.
authors.forename: Minghui
authors.initials: M
authors.lastname: Bao
authors.affiliation: Department of Cardiology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China.|Beijing Key Laboratory of Hypertension, Beijing, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: Medical Research Center, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Cardiology, The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China.
authors.forename: Xuerui
authors.initials: X
authors.lastname: Tan
authors.affiliation: Department of Cardiology, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Cardiology, The First Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China.
authors.forename: Yequn
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Cardiology, Kailuan General Hospital, Hebei Union University, Tangshan, Hebei, China.
authors.forename: Shouling
authors.initials: S
authors.lastname: Wu
authors.affiliation: Department of Cardiology, Kailuan General Hospital, Hebei Union University, Tangshan, Hebei, China.
authors.forename: Shuohua
authors.initials: S
authors.lastname: Chen
authors.affiliation: Shanghai Diabetes Institute, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Zhang
authors.affiliation: Shanghai Diabetes Institute, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Jiang
authors.affiliation: Shanghai Diabetes Institute, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
authors.forename: Weiping
authors.initials: W
authors.lastname: Jia
authors.affiliation: National Research Institute for Family Planning, Beijing, China.|Beijing Hypertension League Institute, Beijing, China.
authors.forename: Xingyu
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Cardiology, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China.
authors.forename: Xinchun
authors.initials: X
authors.lastname: Yang
authors.affiliation: Department of Hypertension, Fuwai Hospital, Beijing, China.|State Key Laboratory of Cardiovascular Disease, Beijing, China.|National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Cai
mesh_terms: D000368:Aged; D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study / Q000379:methods*; D006801:Humans; D006973:Hypertension / Q000235:genetics*; D053779:Latent TGF-beta Binding Proteins / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008297:Male; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D010766:Phosphorylation; D020641:Polymorphism, Single Nucleotide; D051381:Rats; D011918:Rats, Inbred SHR; D015854:Up-Regulation
chemical_list: D004268:DNA-Binding Proteins; C000627189:L3MBTL4 protein, human; C000627190:L3mbtl4 protein, rat; C509032:LTBP1 protein, human; D053779:Latent TGF-beta Binding Proteins