title: Genetic and Functional Evidence Supports LPAR1 as a Susceptibility Gene for Hypertension.
abstract: Essential hypertension is a complex disease affected by genetic and environmental factors and serves as a major risk factor for cardiovascular diseases. Serum lysophosphatidic acid correlates with an elevated blood pressure in rats, and lysophosphatidic acid interacts with 6 subtypes of receptors. In this study, we assessed the genetic association of lysophosphatidic acid receptors with essential hypertension by genotyping 28 single-nucleotide polymorphisms from genes encoding for lysophosphatidic acid receptors, LPAR1, LPAR2, LPAR3, LPAR4, LPAR5, and LPAR6 and their flanking sequences, in 3 Han Chinese cohorts consisting of 2630 patients and 3171 controls in total. We identified a single-nucleotide polymorphism, rs531003 in the 3'-flanking genomic region of LPAR1, associated with hypertension (the Bonferroni corrected P=1.09×10(-5), odds ratio [95% confidence interval]=1.23 [1.13-1.33]). The risk allele C of rs531003 is associated with the increased expression of LPAR1 and the susceptibility of hypertension, particularly in those with a shortage of sleep (P=4.73×10(-5), odds ratio [95% confidence interval]=1.75 [1.34-2.28]). We further demonstrated that blood pressure elevation caused by sleep deprivation and phenylephrine-induced vasoconstriction was both diminished in LPAR1-deficient mice. Together, we show that LPAR1 is a novel susceptibility gene for human essential hypertension and that stress, such as shortage of sleep, increases the susceptibility of patients with risk allele to essential hypertension.
authors.affiliation: From the Department of Human Population Genetics, Institute of Molecular Medicine, Peking University, Beijing, PR China (K.X., Y.L., G.Y.Z., X.L.T.); Department of Physiology and Pathophysiology, School of Basic Medical Sciences (L.M., H.L.) and Department of Cardiology, Beijing Chaoyang Hospital (F.J.), Capital Medical University, Beijing, PR China; State Key Laboratory of Cardiovascular Diseases (F.W., X.C.) and Department of Cardiology (A.D.), Fuwai Hospital and Cardiovascular Institute, Chinese Academy of Medical Sciences and Peking Union Medical College, National Center for Cardiovascular Diseases, Beijing, PR China; Cardiovascular Department, PLA General Hospital, Beijing, PR China (Z.S., Y.C.); and Molecular and Cellular Neuroscience Department, Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, CA (J.C.).
authors.forename: Ke
authors.initials: K
authors.lastname: Xu
authors.affiliation: From the Department of Human Population Genetics, Institute of Molecular Medicine, Peking University, Beijing, PR China (K.X., Y.L., G.Y.Z., X.L.T.); Department of Physiology and Pathophysiology, School of Basic Medical Sciences (L.M., H.L.) and Department of Cardiology, Beijing Chaoyang Hospital (F.J.), Capital Medical University, Beijing, PR China; State Key Laboratory of Cardiovascular Diseases (F.W., X.C.) and Department of Cardiology (A.D.), Fuwai Hospital and Cardiovascular Institute, Chinese Academy of Medical Sciences and Peking Union Medical College, National Center for Cardiovascular Diseases, Beijing, PR China; Cardiovascular Department, PLA General Hospital, Beijing, PR China (Z.S., Y.C.); and Molecular and Cellular Neuroscience Department, Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, CA (J.C.).
authors.forename: Lu
authors.initials: L
authors.lastname: Ma
authors.affiliation: From the Department of Human Population Genetics, Institute of Molecular Medicine, Peking University, Beijing, PR China (K.X., Y.L., G.Y.Z., X.L.T.); Department of Physiology and Pathophysiology, School of Basic Medical Sciences (L.M., H.L.) and Department of Cardiology, Beijing Chaoyang Hospital (F.J.), Capital Medical University, Beijing, PR China; State Key Laboratory of Cardiovascular Diseases (F.W., X.C.) and Department of Cardiology (A.D.), Fuwai Hospital and Cardiovascular Institute, Chinese Academy of Medical Sciences and Peking Union Medical College, National Center for Cardiovascular Diseases, Beijing, PR China; Cardiovascular Department, PLA General Hospital, Beijing, PR China (Z.S., Y.C.); and Molecular and Cellular Neuroscience Department, Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, CA (J.C.).
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
authors.affiliation: From the Department of Human Population Genetics, Institute of Molecular Medicine, Peking University, Beijing, PR China (K.X., Y.L., G.Y.Z., X.L.T.); Department of Physiology and Pathophysiology, School of Basic Medical Sciences (L.M., H.L.) and Department of Cardiology, Beijing Chaoyang Hospital (F.J.), Capital Medical University, Beijing, PR China; State Key Laboratory of Cardiovascular Diseases (F.W., X.C.) and Department of Cardiology (A.D.), Fuwai Hospital and Cardiovascular Institute, Chinese Academy of Medical Sciences and Peking Union Medical College, National Center for Cardiovascular Diseases, Beijing, PR China; Cardiovascular Department, PLA General Hospital, Beijing, PR China (Z.S., Y.C.); and Molecular and Cellular Neuroscience Department, Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, CA (J.C.).
authors.forename: Fang
authors.initials: F
authors.lastname: Wang
authors.affiliation: From the Department of Human Population Genetics, Institute of Molecular Medicine, Peking University, Beijing, PR China (K.X., Y.L., G.Y.Z., X.L.T.); Department of Physiology and Pathophysiology, School of Basic Medical Sciences (L.M., H.L.) and Department of Cardiology, Beijing Chaoyang Hospital (F.J.), Capital Medical University, Beijing, PR China; State Key Laboratory of Cardiovascular Diseases (F.W., X.C.) and Department of Cardiology (A.D.), Fuwai Hospital and Cardiovascular Institute, Chinese Academy of Medical Sciences and Peking Union Medical College, National Center for Cardiovascular Diseases, Beijing, PR China; Cardiovascular Department, PLA General Hospital, Beijing, PR China (Z.S., Y.C.); and Molecular and Cellular Neuroscience Department, Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, CA (J.C.).
authors.forename: Gu-Yan
authors.initials: GY
authors.lastname: Zheng
authors.affiliation: From the Department of Human Population Genetics, Institute of Molecular Medicine, Peking University, Beijing, PR China (K.X., Y.L., G.Y.Z., X.L.T.); Department of Physiology and Pathophysiology, School of Basic Medical Sciences (L.M., H.L.) and Department of Cardiology, Beijing Chaoyang Hospital (F.J.), Capital Medical University, Beijing, PR China; State Key Laboratory of Cardiovascular Diseases (F.W., X.C.) and Department of Cardiology (A.D.), Fuwai Hospital and Cardiovascular Institute, Chinese Academy of Medical Sciences and Peking Union Medical College, National Center for Cardiovascular Diseases, Beijing, PR China; Cardiovascular Department, PLA General Hospital, Beijing, PR China (Z.S., Y.C.); and Molecular and Cellular Neuroscience Department, Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, CA (J.C.).
authors.forename: Zhijun
authors.initials: Z
authors.lastname: Sun
authors.affiliation: From the Department of Human Population Genetics, Institute of Molecular Medicine, Peking University, Beijing, PR China (K.X., Y.L., G.Y.Z., X.L.T.); Department of Physiology and Pathophysiology, School of Basic Medical Sciences (L.M., H.L.) and Department of Cardiology, Beijing Chaoyang Hospital (F.J.), Capital Medical University, Beijing, PR China; State Key Laboratory of Cardiovascular Diseases (F.W., X.C.) and Department of Cardiology (A.D.), Fuwai Hospital and Cardiovascular Institute, Chinese Academy of Medical Sciences and Peking Union Medical College, National Center for Cardiovascular Diseases, Beijing, PR China; Cardiovascular Department, PLA General Hospital, Beijing, PR China (Z.S., Y.C.); and Molecular and Cellular Neuroscience Department, Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, CA (J.C.).
authors.forename: Feng
authors.initials: F
authors.lastname: Jiang
authors.affiliation: From the Department of Human Population Genetics, Institute of Molecular Medicine, Peking University, Beijing, PR China (K.X., Y.L., G.Y.Z., X.L.T.); Department of Physiology and Pathophysiology, School of Basic Medical Sciences (L.M., H.L.) and Department of Cardiology, Beijing Chaoyang Hospital (F.J.), Capital Medical University, Beijing, PR China; State Key Laboratory of Cardiovascular Diseases (F.W., X.C.) and Department of Cardiology (A.D.), Fuwai Hospital and Cardiovascular Institute, Chinese Academy of Medical Sciences and Peking Union Medical College, National Center for Cardiovascular Diseases, Beijing, PR China; Cardiovascular Department, PLA General Hospital, Beijing, PR China (Z.S., Y.C.); and Molecular and Cellular Neuroscience Department, Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, CA (J.C.).
authors.forename: Yundai
authors.initials: Y
authors.lastname: Chen
authors.affiliation: From the Department of Human Population Genetics, Institute of Molecular Medicine, Peking University, Beijing, PR China (K.X., Y.L., G.Y.Z., X.L.T.); Department of Physiology and Pathophysiology, School of Basic Medical Sciences (L.M., H.L.) and Department of Cardiology, Beijing Chaoyang Hospital (F.J.), Capital Medical University, Beijing, PR China; State Key Laboratory of Cardiovascular Diseases (F.W., X.C.) and Department of Cardiology (A.D.), Fuwai Hospital and Cardiovascular Institute, Chinese Academy of Medical Sciences and Peking Union Medical College, National Center for Cardiovascular Diseases, Beijing, PR China; Cardiovascular Department, PLA General Hospital, Beijing, PR China (Z.S., Y.C.); and Molecular and Cellular Neuroscience Department, Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, CA (J.C.).
authors.forename: Huirong
authors.initials: H
authors.lastname: Liu
authors.affiliation: From the Department of Human Population Genetics, Institute of Molecular Medicine, Peking University, Beijing, PR China (K.X., Y.L., G.Y.Z., X.L.T.); Department of Physiology and Pathophysiology, School of Basic Medical Sciences (L.M., H.L.) and Department of Cardiology, Beijing Chaoyang Hospital (F.J.), Capital Medical University, Beijing, PR China; State Key Laboratory of Cardiovascular Diseases (F.W., X.C.) and Department of Cardiology (A.D.), Fuwai Hospital and Cardiovascular Institute, Chinese Academy of Medical Sciences and Peking Union Medical College, National Center for Cardiovascular Diseases, Beijing, PR China; Cardiovascular Department, PLA General Hospital, Beijing, PR China (Z.S., Y.C.); and Molecular and Cellular Neuroscience Department, Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, CA (J.C.).
authors.forename: Aimin
authors.initials: A
authors.lastname: Dang
authors.affiliation: From the Department of Human Population Genetics, Institute of Molecular Medicine, Peking University, Beijing, PR China (K.X., Y.L., G.Y.Z., X.L.T.); Department of Physiology and Pathophysiology, School of Basic Medical Sciences (L.M., H.L.) and Department of Cardiology, Beijing Chaoyang Hospital (F.J.), Capital Medical University, Beijing, PR China; State Key Laboratory of Cardiovascular Diseases (F.W., X.C.) and Department of Cardiology (A.D.), Fuwai Hospital and Cardiovascular Institute, Chinese Academy of Medical Sciences and Peking Union Medical College, National Center for Cardiovascular Diseases, Beijing, PR China; Cardiovascular Department, PLA General Hospital, Beijing, PR China (Z.S., Y.C.); and Molecular and Cellular Neuroscience Department, Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, CA (J.C.).
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
authors.affiliation: From the Department of Human Population Genetics, Institute of Molecular Medicine, Peking University, Beijing, PR China (K.X., Y.L., G.Y.Z., X.L.T.); Department of Physiology and Pathophysiology, School of Basic Medical Sciences (L.M., H.L.) and Department of Cardiology, Beijing Chaoyang Hospital (F.J.), Capital Medical University, Beijing, PR China; State Key Laboratory of Cardiovascular Diseases (F.W., X.C.) and Department of Cardiology (A.D.), Fuwai Hospital and Cardiovascular Institute, Chinese Academy of Medical Sciences and Peking Union Medical College, National Center for Cardiovascular Diseases, Beijing, PR China; Cardiovascular Department, PLA General Hospital, Beijing, PR China (Z.S., Y.C.); and Molecular and Cellular Neuroscience Department, Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, CA (J.C.).
authors.forename: Jerold
authors.initials: J
authors.lastname: Chun
authors.affiliation: From the Department of Human Population Genetics, Institute of Molecular Medicine, Peking University, Beijing, PR China (K.X., Y.L., G.Y.Z., X.L.T.); Department of Physiology and Pathophysiology, School of Basic Medical Sciences (L.M., H.L.) and Department of Cardiology, Beijing Chaoyang Hospital (F.J.), Capital Medical University, Beijing, PR China; State Key Laboratory of Cardiovascular Diseases (F.W., X.C.) and Department of Cardiology (A.D.), Fuwai Hospital and Cardiovascular Institute, Chinese Academy of Medical Sciences and Peking Union Medical College, National Center for Cardiovascular Diseases, Beijing, PR China; Cardiovascular Department, PLA General Hospital, Beijing, PR China (Z.S., Y.C.); and Molecular and Cellular Neuroscience Department, Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, CA (J.C.). tianxiaoli@pku.edu.cn.
authors.forename: Xiao-Li
authors.initials: XL
authors.lastname: Tian
mesh_terms: D000368:Aged; D000483:Alleles; D000818:Animals; D044466:Asian People / Q000235:genetics; D001794:Blood Pressure / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D006973:Hypertension / Q000235:genetics*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D049368:Receptors, Lysophosphatidic Acid / Q000235:genetics*; D012892:Sleep Deprivation / Q000235:genetics
chemical_list: D049368:Receptors, Lysophosphatidic Acid
keywords: Chinese; hypertension; lysophosphatidic acid receptor; single nucleotide polymorphism; sleep deprivation; susceptibility