title: Genome-wide linkage and regional association study of blood pressure response to the cold pressor test in Han Chinese: the genetic epidemiology network of salt sensitivity study.
abstract: BACKGROUND
  Blood pressure (BP) response to cold pressor test (CPT) is associated with increased risk of cardiovascular disease. We performed a genome-wide linkage scan and regional association analysis to identify genetic determinants of BP response to CPT.
  
  
  RESULTS
  A total of 1961 Chinese participants completed the CPT. Multipoint quantitative trait linkage analysis was performed, followed by single-marker and gene-based analyses of variants in promising linkage regions (logarithm of odds ≥2). A suggestive linkage signal was identified for systolic BP response to CPT at 20p13 to 20p12.3, with a maximum multipoint logarithm of odds score of 2.37. On the basis of regional association analysis with 1351 single nucleotide polymorphisms in the linkage region, we found that marker rs2326373 at 20p13 was significantly associated with mean arterial pressure responses to CPT (P=8.8×10(-6)) after false discovery rate adjustment for multiple comparisons. A similar trend was also observed for systolic BP response (P=0.03) and diastolic BP response (P=4.6×10(-5)). Results of gene-based analyses showed that variants in genes MCM8 and SLC23A2 were associated with systolic BP response to CPT (P=4.0×10(-5) and 2.7×10(-4), respectively), and variants in genes MCM8 and STK35 were associated with mean arterial pressure response to CPT (P=1.5×10(-5) and 5.0×10(-5), respectively).
  
  
  CONCLUSIONS
  Within a suggestive linkage region on chromosome 20, we identified a novel variant associated with BP responses to CPT. We also found gene-based associations of MCM8, SLC23A2, and STK35 in this region. Additional work is warranted to confirm these findings.
  
  
  BACKGROUND
  http://www.clinicaltrials.gov; Unique identifier: NCT00721721.
authors.affiliation: From the Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA (X.Y., J.H., J.C., T.N.K.); State Key Laboratory of Cardiovascular Disease, Department of Epidemiology and Population Genetics, Fuwai Hospital, National Center of Cardiovascular Diseases (X.Y., D.G., J.H., J.C., X.W.) and National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences (D.L.), Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Department of Medicine, Tulane University School of Medicine, New Orleans, LA (J.H., J.C.); Department of Epidemiology, University of Texas School of Public Health, Houston (J.E.H., L.C.S.); Division of Biostatistics, Washington University School of Medicine, St. Louis, MO (D.C.R., T.K.R.); Institute of Basic Medicine, Shandong Academy of Medical Sciences, Shandong, China (F.L.); Department of Cardiology, First Affiliated Hospital of Medical College of Xi'an Jiaotong University, Shaanxi, China (J.M.); and Division of Prevention and Population Sciences, National Heart, Lung, and Blood Institute, Bethesda, MD (C.E.J.).
authors.forename: Xueli
authors.initials: X
authors.lastname: Yang
authors.affiliation: From the Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA (X.Y., J.H., J.C., T.N.K.); State Key Laboratory of Cardiovascular Disease, Department of Epidemiology and Population Genetics, Fuwai Hospital, National Center of Cardiovascular Diseases (X.Y., D.G., J.H., J.C., X.W.) and National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences (D.L.), Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Department of Medicine, Tulane University School of Medicine, New Orleans, LA (J.H., J.C.); Department of Epidemiology, University of Texas School of Public Health, Houston (J.E.H., L.C.S.); Division of Biostatistics, Washington University School of Medicine, St. Louis, MO (D.C.R., T.K.R.); Institute of Basic Medicine, Shandong Academy of Medical Sciences, Shandong, China (F.L.); Department of Cardiology, First Affiliated Hospital of Medical College of Xi'an Jiaotong University, Shaanxi, China (J.M.); and Division of Prevention and Population Sciences, National Heart, Lung, and Blood Institute, Bethesda, MD (C.E.J.). gudongfeng@vip.sina.com tkelly@tulane.edu.
authors.forename: Dongfeng
authors.initials: D
authors.lastname: Gu
authors.affiliation: From the Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA (X.Y., J.H., J.C., T.N.K.); State Key Laboratory of Cardiovascular Disease, Department of Epidemiology and Population Genetics, Fuwai Hospital, National Center of Cardiovascular Diseases (X.Y., D.G., J.H., J.C., X.W.) and National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences (D.L.), Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Department of Medicine, Tulane University School of Medicine, New Orleans, LA (J.H., J.C.); Department of Epidemiology, University of Texas School of Public Health, Houston (J.E.H., L.C.S.); Division of Biostatistics, Washington University School of Medicine, St. Louis, MO (D.C.R., T.K.R.); Institute of Basic Medicine, Shandong Academy of Medical Sciences, Shandong, China (F.L.); Department of Cardiology, First Affiliated Hospital of Medical College of Xi'an Jiaotong University, Shaanxi, China (J.M.); and Division of Prevention and Population Sciences, National Heart, Lung, and Blood Institute, Bethesda, MD (C.E.J.).
authors.forename: Jiang
authors.initials: J
authors.lastname: He
authors.affiliation: From the Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA (X.Y., J.H., J.C., T.N.K.); State Key Laboratory of Cardiovascular Disease, Department of Epidemiology and Population Genetics, Fuwai Hospital, National Center of Cardiovascular Diseases (X.Y., D.G., J.H., J.C., X.W.) and National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences (D.L.), Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Department of Medicine, Tulane University School of Medicine, New Orleans, LA (J.H., J.C.); Department of Epidemiology, University of Texas School of Public Health, Houston (J.E.H., L.C.S.); Division of Biostatistics, Washington University School of Medicine, St. Louis, MO (D.C.R., T.K.R.); Institute of Basic Medicine, Shandong Academy of Medical Sciences, Shandong, China (F.L.); Department of Cardiology, First Affiliated Hospital of Medical College of Xi'an Jiaotong University, Shaanxi, China (J.M.); and Division of Prevention and Population Sciences, National Heart, Lung, and Blood Institute, Bethesda, MD (C.E.J.).
authors.forename: James E
authors.initials: JE
authors.lastname: Hixson
authors.affiliation: From the Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA (X.Y., J.H., J.C., T.N.K.); State Key Laboratory of Cardiovascular Disease, Department of Epidemiology and Population Genetics, Fuwai Hospital, National Center of Cardiovascular Diseases (X.Y., D.G., J.H., J.C., X.W.) and National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences (D.L.), Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Department of Medicine, Tulane University School of Medicine, New Orleans, LA (J.H., J.C.); Department of Epidemiology, University of Texas School of Public Health, Houston (J.E.H., L.C.S.); Division of Biostatistics, Washington University School of Medicine, St. Louis, MO (D.C.R., T.K.R.); Institute of Basic Medicine, Shandong Academy of Medical Sciences, Shandong, China (F.L.); Department of Cardiology, First Affiliated Hospital of Medical College of Xi'an Jiaotong University, Shaanxi, China (J.M.); and Division of Prevention and Population Sciences, National Heart, Lung, and Blood Institute, Bethesda, MD (C.E.J.).
authors.forename: Dabeeru C
authors.initials: DC
authors.lastname: Rao
authors.affiliation: From the Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA (X.Y., J.H., J.C., T.N.K.); State Key Laboratory of Cardiovascular Disease, Department of Epidemiology and Population Genetics, Fuwai Hospital, National Center of Cardiovascular Diseases (X.Y., D.G., J.H., J.C., X.W.) and National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences (D.L.), Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Department of Medicine, Tulane University School of Medicine, New Orleans, LA (J.H., J.C.); Department of Epidemiology, University of Texas School of Public Health, Houston (J.E.H., L.C.S.); Division of Biostatistics, Washington University School of Medicine, St. Louis, MO (D.C.R., T.K.R.); Institute of Basic Medicine, Shandong Academy of Medical Sciences, Shandong, China (F.L.); Department of Cardiology, First Affiliated Hospital of Medical College of Xi'an Jiaotong University, Shaanxi, China (J.M.); and Division of Prevention and Population Sciences, National Heart, Lung, and Blood Institute, Bethesda, MD (C.E.J.).
authors.forename: Fanghong
authors.initials: F
authors.lastname: Lu
authors.affiliation: From the Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA (X.Y., J.H., J.C., T.N.K.); State Key Laboratory of Cardiovascular Disease, Department of Epidemiology and Population Genetics, Fuwai Hospital, National Center of Cardiovascular Diseases (X.Y., D.G., J.H., J.C., X.W.) and National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences (D.L.), Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Department of Medicine, Tulane University School of Medicine, New Orleans, LA (J.H., J.C.); Department of Epidemiology, University of Texas School of Public Health, Houston (J.E.H., L.C.S.); Division of Biostatistics, Washington University School of Medicine, St. Louis, MO (D.C.R., T.K.R.); Institute of Basic Medicine, Shandong Academy of Medical Sciences, Shandong, China (F.L.); Department of Cardiology, First Affiliated Hospital of Medical College of Xi'an Jiaotong University, Shaanxi, China (J.M.); and Division of Prevention and Population Sciences, National Heart, Lung, and Blood Institute, Bethesda, MD (C.E.J.).
authors.forename: Jianjun
authors.initials: J
authors.lastname: Mu
authors.affiliation: From the Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA (X.Y., J.H., J.C., T.N.K.); State Key Laboratory of Cardiovascular Disease, Department of Epidemiology and Population Genetics, Fuwai Hospital, National Center of Cardiovascular Diseases (X.Y., D.G., J.H., J.C., X.W.) and National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences (D.L.), Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Department of Medicine, Tulane University School of Medicine, New Orleans, LA (J.H., J.C.); Department of Epidemiology, University of Texas School of Public Health, Houston (J.E.H., L.C.S.); Division of Biostatistics, Washington University School of Medicine, St. Louis, MO (D.C.R., T.K.R.); Institute of Basic Medicine, Shandong Academy of Medical Sciences, Shandong, China (F.L.); Department of Cardiology, First Affiliated Hospital of Medical College of Xi'an Jiaotong University, Shaanxi, China (J.M.); and Division of Prevention and Population Sciences, National Heart, Lung, and Blood Institute, Bethesda, MD (C.E.J.).
authors.forename: Cashell E
authors.initials: CE
authors.lastname: Jaquish
authors.affiliation: From the Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA (X.Y., J.H., J.C., T.N.K.); State Key Laboratory of Cardiovascular Disease, Department of Epidemiology and Population Genetics, Fuwai Hospital, National Center of Cardiovascular Diseases (X.Y., D.G., J.H., J.C., X.W.) and National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences (D.L.), Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Department of Medicine, Tulane University School of Medicine, New Orleans, LA (J.H., J.C.); Department of Epidemiology, University of Texas School of Public Health, Houston (J.E.H., L.C.S.); Division of Biostatistics, Washington University School of Medicine, St. Louis, MO (D.C.R., T.K.R.); Institute of Basic Medicine, Shandong Academy of Medical Sciences, Shandong, China (F.L.); Department of Cardiology, First Affiliated Hospital of Medical College of Xi'an Jiaotong University, Shaanxi, China (J.M.); and Division of Prevention and Population Sciences, National Heart, Lung, and Blood Institute, Bethesda, MD (C.E.J.).
authors.forename: Jing
authors.initials: J
authors.lastname: Chen
authors.affiliation: From the Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA (X.Y., J.H., J.C., T.N.K.); State Key Laboratory of Cardiovascular Disease, Department of Epidemiology and Population Genetics, Fuwai Hospital, National Center of Cardiovascular Diseases (X.Y., D.G., J.H., J.C., X.W.) and National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences (D.L.), Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Department of Medicine, Tulane University School of Medicine, New Orleans, LA (J.H., J.C.); Department of Epidemiology, University of Texas School of Public Health, Houston (J.E.H., L.C.S.); Division of Biostatistics, Washington University School of Medicine, St. Louis, MO (D.C.R., T.K.R.); Institute of Basic Medicine, Shandong Academy of Medical Sciences, Shandong, China (F.L.); Department of Cardiology, First Affiliated Hospital of Medical College of Xi'an Jiaotong University, Shaanxi, China (J.M.); and Division of Prevention and Population Sciences, National Heart, Lung, and Blood Institute, Bethesda, MD (C.E.J.).
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Huang
authors.affiliation: From the Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA (X.Y., J.H., J.C., T.N.K.); State Key Laboratory of Cardiovascular Disease, Department of Epidemiology and Population Genetics, Fuwai Hospital, National Center of Cardiovascular Diseases (X.Y., D.G., J.H., J.C., X.W.) and National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences (D.L.), Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Department of Medicine, Tulane University School of Medicine, New Orleans, LA (J.H., J.C.); Department of Epidemiology, University of Texas School of Public Health, Houston (J.E.H., L.C.S.); Division of Biostatistics, Washington University School of Medicine, St. Louis, MO (D.C.R., T.K.R.); Institute of Basic Medicine, Shandong Academy of Medical Sciences, Shandong, China (F.L.); Department of Cardiology, First Affiliated Hospital of Medical College of Xi'an Jiaotong University, Shaanxi, China (J.M.); and Division of Prevention and Population Sciences, National Heart, Lung, and Blood Institute, Bethesda, MD (C.E.J.).
authors.forename: Lawrence C
authors.initials: LC
authors.lastname: Shimmin
authors.affiliation: From the Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA (X.Y., J.H., J.C., T.N.K.); State Key Laboratory of Cardiovascular Disease, Department of Epidemiology and Population Genetics, Fuwai Hospital, National Center of Cardiovascular Diseases (X.Y., D.G., J.H., J.C., X.W.) and National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences (D.L.), Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Department of Medicine, Tulane University School of Medicine, New Orleans, LA (J.H., J.C.); Department of Epidemiology, University of Texas School of Public Health, Houston (J.E.H., L.C.S.); Division of Biostatistics, Washington University School of Medicine, St. Louis, MO (D.C.R., T.K.R.); Institute of Basic Medicine, Shandong Academy of Medical Sciences, Shandong, China (F.L.); Department of Cardiology, First Affiliated Hospital of Medical College of Xi'an Jiaotong University, Shaanxi, China (J.M.); and Division of Prevention and Population Sciences, National Heart, Lung, and Blood Institute, Bethesda, MD (C.E.J.).
authors.forename: Treva K
authors.initials: TK
authors.lastname: Rice
authors.affiliation: From the Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA (X.Y., J.H., J.C., T.N.K.); State Key Laboratory of Cardiovascular Disease, Department of Epidemiology and Population Genetics, Fuwai Hospital, National Center of Cardiovascular Diseases (X.Y., D.G., J.H., J.C., X.W.) and National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences (D.L.), Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Department of Medicine, Tulane University School of Medicine, New Orleans, LA (J.H., J.C.); Department of Epidemiology, University of Texas School of Public Health, Houston (J.E.H., L.C.S.); Division of Biostatistics, Washington University School of Medicine, St. Louis, MO (D.C.R., T.K.R.); Institute of Basic Medicine, Shandong Academy of Medical Sciences, Shandong, China (F.L.); Department of Cardiology, First Affiliated Hospital of Medical College of Xi'an Jiaotong University, Shaanxi, China (J.M.); and Division of Prevention and Population Sciences, National Heart, Lung, and Blood Institute, Bethesda, MD (C.E.J.).
authors.forename: Jichun
authors.initials: J
authors.lastname: Chen
authors.affiliation: From the Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA (X.Y., J.H., J.C., T.N.K.); State Key Laboratory of Cardiovascular Disease, Department of Epidemiology and Population Genetics, Fuwai Hospital, National Center of Cardiovascular Diseases (X.Y., D.G., J.H., J.C., X.W.) and National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences (D.L.), Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Department of Medicine, Tulane University School of Medicine, New Orleans, LA (J.H., J.C.); Department of Epidemiology, University of Texas School of Public Health, Houston (J.E.H., L.C.S.); Division of Biostatistics, Washington University School of Medicine, St. Louis, MO (D.C.R., T.K.R.); Institute of Basic Medicine, Shandong Academy of Medical Sciences, Shandong, China (F.L.); Department of Cardiology, First Affiliated Hospital of Medical College of Xi'an Jiaotong University, Shaanxi, China (J.M.); and Division of Prevention and Population Sciences, National Heart, Lung, and Blood Institute, Bethesda, MD (C.E.J.).
authors.forename: Xigui
authors.initials: X
authors.lastname: Wu
authors.affiliation: From the Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA (X.Y., J.H., J.C., T.N.K.); State Key Laboratory of Cardiovascular Disease, Department of Epidemiology and Population Genetics, Fuwai Hospital, National Center of Cardiovascular Diseases (X.Y., D.G., J.H., J.C., X.W.) and National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences (D.L.), Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Department of Medicine, Tulane University School of Medicine, New Orleans, LA (J.H., J.C.); Department of Epidemiology, University of Texas School of Public Health, Houston (J.E.H., L.C.S.); Division of Biostatistics, Washington University School of Medicine, St. Louis, MO (D.C.R., T.K.R.); Institute of Basic Medicine, Shandong Academy of Medical Sciences, Shandong, China (F.L.); Department of Cardiology, First Affiliated Hospital of Medical College of Xi'an Jiaotong University, Shaanxi, China (J.M.); and Division of Prevention and Population Sciences, National Heart, Lung, and Blood Institute, Bethesda, MD (C.E.J.).
authors.forename: Depei
authors.initials: D
authors.lastname: Liu
authors.affiliation: From the Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA (X.Y., J.H., J.C., T.N.K.); State Key Laboratory of Cardiovascular Disease, Department of Epidemiology and Population Genetics, Fuwai Hospital, National Center of Cardiovascular Diseases (X.Y., D.G., J.H., J.C., X.W.) and National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences (D.L.), Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China; Department of Medicine, Tulane University School of Medicine, New Orleans, LA (J.H., J.C.); Department of Epidemiology, University of Texas School of Public Health, Houston (J.E.H., L.C.S.); Division of Biostatistics, Washington University School of Medicine, St. Louis, MO (D.C.R., T.K.R.); Institute of Basic Medicine, Shandong Academy of Medical Sciences, Shandong, China (F.L.); Department of Cardiology, First Affiliated Hospital of Medical College of Xi'an Jiaotong University, Shaanxi, China (J.M.); and Division of Prevention and Population Sciences, National Heart, Lung, and Blood Institute, Bethesda, MD (C.E.J.). gudongfeng@vip.sina.com tkelly@tulane.edu.
authors.forename: Tanika N
authors.initials: TN
authors.lastname: Kelly
mesh_terms: D000293:Adolescent; D000328:Adult; D044466:Asian People / Q000235:genetics*; D001794:Blood Pressure / Q000187:drug effects*; D002681:China; D002874:Chromosome Mapping; D002890:Chromosomes, Human, Pair 20; D003080:Cold Temperature; D003710:Demography; D005260:Female; D008040:Genetic Linkage; D055106:Genome-Wide Association Study; D006801:Humans; D006973:Hypertension / Q000453:epidemiology / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D064110:Minichromosome Maintenance Proteins / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D011494:Protein Kinases / Q000235:genetics; D017346:Protein Serine-Threonine Kinases; D012982:Sodium, Dietary / Q000494:pharmacology*; D060347:Sodium-Coupled Vitamin C Transporters / Q000235:genetics; D055815:Young Adult
chemical_list: D009687:Nuclear Proteins; C555163:SLC23A2 protein, human; D012982:Sodium, Dietary; D060347:Sodium-Coupled Vitamin C Transporters; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; C470368:STK35 protein, human; C471623:MCM8 protein, human; D064110:Minichromosome Maintenance Proteins
keywords: blood pressure; genetic association studies; linkage mapping