Genome-Wide Gene-Sodium Interaction Analyses on Blood Pressure: The Genetic Epidemiology Network of Salt-Sensitivity Study.
We performed genome-wide analyses to identify genomic loci that interact with sodium to influence blood pressure (BP) using single-marker-based (1 and 2 df joint tests) and gene-based tests among 1876 Chinese participants of the Genetic Epidemiology Network of Salt-Sensitivity (GenSalt) study. Among GenSalt participants, the average of 3 urine samples was used to estimate sodium excretion. Nine BP measurements were taken using a random zero sphygmomanometer. A total of 2.05 million single-nucleotide polymorphisms were imputed using Affymetrix 6.0 genotype data and the Chinese Han of Beijing and Japanese of Tokyo HapMap reference panel. Promising findings (P<1.00×10(-4)) from GenSalt were evaluated for replication among 775 Chinese participants of the Multi-Ethnic Study of Atherosclerosis (MESA). Single-nucleotide polymorphism and gene-based results were meta-analyzed across the GenSalt and MESA studies to determine genome-wide significance. The 1 df tests identified interactions for UST rs13211840 on diastolic BP (P=3.13×10(-9)). The 2 df tests additionally identified associations for CLGN rs2567241 (P=3.90×10(-12)) and LOC105369882 rs11104632 (P=4.51×10(-8)) with systolic BP. The CLGN variant rs2567241 was also associated with diastolic BP (P=3.11×10(-22)) and mean arterial pressure (P=2.86×10(-15)). Genome-wide gene-based analysis identified MKNK1 (P=6.70×10(-7)), C2orf80 (P<1.00×10(-12)), EPHA6 (P=2.88×10(-7)), SCOC-AS1 (P=4.35×10(-14)), SCOC (P=6.46×10(-11)), CLGN (P=3.68×10(-13)), MGAT4D (P=4.73×10(-11)), ARHGAP42 (P≤1.00×10(-12)), CASP4 (P=1.31×10(-8)), and LINC01478 (P=6.75×10(-10)) that were associated with at least 1 BP phenotype. In summary, we identified 8 novel and 1 previously reported BP loci through the examination of single-nucleotide polymorphism and gene-based interactions with sodium.
From the Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA (C.L., J.H., J.Z., T.N.K.); Department of Medicine, Tulane University School of Medicine, New Orleans, LA (J.H., J.C.); State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center of Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China (D.G., J.C., J.H., S.C.); Department of Epidemiology, Human Genetics and Environmental Sciences, University of Texas School of Public Health, Houston (J.E.H.); Division of Biostatistics, Washington University School of Medicine, St. Louis, MO (D.C.R., C.C.G.); and Division of Prevention and Population Sciences, National Heart, Lung, Blood Institute, Bethesda, MD (C.E.J.).
Changwei
C
Li
From the Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA (C.L., J.H., J.Z., T.N.K.); Department of Medicine, Tulane University School of Medicine, New Orleans, LA (J.H., J.C.); State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center of Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China (D.G., J.C., J.H., S.C.); Department of Epidemiology, Human Genetics and Environmental Sciences, University of Texas School of Public Health, Houston (J.E.H.); Division of Biostatistics, Washington University School of Medicine, St. Louis, MO (D.C.R., C.C.G.); and Division of Prevention and Population Sciences, National Heart, Lung, Blood Institute, Bethesda, MD (C.E.J.).
Jiang
J
He
From the Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA (C.L., J.H., J.Z., T.N.K.); Department of Medicine, Tulane University School of Medicine, New Orleans, LA (J.H., J.C.); State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center of Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China (D.G., J.C., J.H., S.C.); Department of Epidemiology, Human Genetics and Environmental Sciences, University of Texas School of Public Health, Houston (J.E.H.); Division of Biostatistics, Washington University School of Medicine, St. Louis, MO (D.C.R., C.C.G.); and Division of Prevention and Population Sciences, National Heart, Lung, Blood Institute, Bethesda, MD (C.E.J.).
Jing
J
Chen
From the Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA (C.L., J.H., J.Z., T.N.K.); Department of Medicine, Tulane University School of Medicine, New Orleans, LA (J.H., J.C.); State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center of Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China (D.G., J.C., J.H., S.C.); Department of Epidemiology, Human Genetics and Environmental Sciences, University of Texas School of Public Health, Houston (J.E.H.); Division of Biostatistics, Washington University School of Medicine, St. Louis, MO (D.C.R., C.C.G.); and Division of Prevention and Population Sciences, National Heart, Lung, Blood Institute, Bethesda, MD (C.E.J.).
Jinying
J
Zhao
From the Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA (C.L., J.H., J.Z., T.N.K.); Department of Medicine, Tulane University School of Medicine, New Orleans, LA (J.H., J.C.); State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center of Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China (D.G., J.C., J.H., S.C.); Department of Epidemiology, Human Genetics and Environmental Sciences, University of Texas School of Public Health, Houston (J.E.H.); Division of Biostatistics, Washington University School of Medicine, St. Louis, MO (D.C.R., C.C.G.); and Division of Prevention and Population Sciences, National Heart, Lung, Blood Institute, Bethesda, MD (C.E.J.).
Dongfeng
D
Gu
From the Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA (C.L., J.H., J.Z., T.N.K.); Department of Medicine, Tulane University School of Medicine, New Orleans, LA (J.H., J.C.); State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center of Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China (D.G., J.C., J.H., S.C.); Department of Epidemiology, Human Genetics and Environmental Sciences, University of Texas School of Public Health, Houston (J.E.H.); Division of Biostatistics, Washington University School of Medicine, St. Louis, MO (D.C.R., C.C.G.); and Division of Prevention and Population Sciences, National Heart, Lung, Blood Institute, Bethesda, MD (C.E.J.).
James E
JE
Hixson
From the Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA (C.L., J.H., J.Z., T.N.K.); Department of Medicine, Tulane University School of Medicine, New Orleans, LA (J.H., J.C.); State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center of Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China (D.G., J.C., J.H., S.C.); Department of Epidemiology, Human Genetics and Environmental Sciences, University of Texas School of Public Health, Houston (J.E.H.); Division of Biostatistics, Washington University School of Medicine, St. Louis, MO (D.C.R., C.C.G.); and Division of Prevention and Population Sciences, National Heart, Lung, Blood Institute, Bethesda, MD (C.E.J.).
Dabeeru C
DC
Rao
From the Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA (C.L., J.H., J.Z., T.N.K.); Department of Medicine, Tulane University School of Medicine, New Orleans, LA (J.H., J.C.); State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center of Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China (D.G., J.C., J.H., S.C.); Department of Epidemiology, Human Genetics and Environmental Sciences, University of Texas School of Public Health, Houston (J.E.H.); Division of Biostatistics, Washington University School of Medicine, St. Louis, MO (D.C.R., C.C.G.); and Division of Prevention and Population Sciences, National Heart, Lung, Blood Institute, Bethesda, MD (C.E.J.).
Cashell E
CE
Jaquish
From the Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA (C.L., J.H., J.Z., T.N.K.); Department of Medicine, Tulane University School of Medicine, New Orleans, LA (J.H., J.C.); State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center of Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China (D.G., J.C., J.H., S.C.); Department of Epidemiology, Human Genetics and Environmental Sciences, University of Texas School of Public Health, Houston (J.E.H.); Division of Biostatistics, Washington University School of Medicine, St. Louis, MO (D.C.R., C.C.G.); and Division of Prevention and Population Sciences, National Heart, Lung, Blood Institute, Bethesda, MD (C.E.J.).
Charles C
CC
Gu
From the Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA (C.L., J.H., J.Z., T.N.K.); Department of Medicine, Tulane University School of Medicine, New Orleans, LA (J.H., J.C.); State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center of Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China (D.G., J.C., J.H., S.C.); Department of Epidemiology, Human Genetics and Environmental Sciences, University of Texas School of Public Health, Houston (J.E.H.); Division of Biostatistics, Washington University School of Medicine, St. Louis, MO (D.C.R., C.C.G.); and Division of Prevention and Population Sciences, National Heart, Lung, Blood Institute, Bethesda, MD (C.E.J.).
Jichun
J
Chen
From the Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA (C.L., J.H., J.Z., T.N.K.); Department of Medicine, Tulane University School of Medicine, New Orleans, LA (J.H., J.C.); State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center of Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China (D.G., J.C., J.H., S.C.); Department of Epidemiology, Human Genetics and Environmental Sciences, University of Texas School of Public Health, Houston (J.E.H.); Division of Biostatistics, Washington University School of Medicine, St. Louis, MO (D.C.R., C.C.G.); and Division of Prevention and Population Sciences, National Heart, Lung, Blood Institute, Bethesda, MD (C.E.J.).
Jianfeng
J
Huang
From the Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA (C.L., J.H., J.Z., T.N.K.); Department of Medicine, Tulane University School of Medicine, New Orleans, LA (J.H., J.C.); State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center of Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China (D.G., J.C., J.H., S.C.); Department of Epidemiology, Human Genetics and Environmental Sciences, University of Texas School of Public Health, Houston (J.E.H.); Division of Biostatistics, Washington University School of Medicine, St. Louis, MO (D.C.R., C.C.G.); and Division of Prevention and Population Sciences, National Heart, Lung, Blood Institute, Bethesda, MD (C.E.J.).
Shufeng
S
Chen
From the Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA (C.L., J.H., J.Z., T.N.K.); Department of Medicine, Tulane University School of Medicine, New Orleans, LA (J.H., J.C.); State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center of Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China (D.G., J.C., J.H., S.C.); Department of Epidemiology, Human Genetics and Environmental Sciences, University of Texas School of Public Health, Houston (J.E.H.); Division of Biostatistics, Washington University School of Medicine, St. Louis, MO (D.C.R., C.C.G.); and Division of Prevention and Population Sciences, National Heart, Lung, Blood Institute, Bethesda, MD (C.E.J.). tkelly@tulane.edu.
Tanika N
TN
Kelly
D020727:ADP-Ribosylation Factors / Q000235:genetics*; D000328:Adult; D001794:Blood Pressure / Q000502:physiology*; D001795:Blood Pressure Determination / Q000379:methods; D002135:Calcium-Binding Proteins / Q000235:genetics*; D053471:Caspases, Initiator / Q000235:genetics*; D002681:China / Q000453:epidemiology; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D006973:Hypertension / Q000453:epidemiology / Q000235:genetics / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D018832:Molecular Chaperones / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D012965:Sodium Chloride / Q000378:metabolism / Q000494:pharmacology
D002135:Calcium-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D018832:Molecular Chaperones; C087341:calmegin; D012965:Sodium Chloride; C491395:MKNK1 protein, human; D017346:Protein Serine-Threonine Kinases; C093516:CASP4 protein, human; D053471:Caspases, Initiator; C491435:ARL6 protein, human; D020727:ADP-Ribosylation Factors
blood pressure; genes; genome-wide association study; sodium