Genome-Wide Gene-Sodium Interaction Analyses on Blood Pressure: The Genetic Epidemiology Network of Salt-Sensitivity Study

Hypertension. 2016 Aug;68(2):348-55. doi: 10.1161/HYPERTENSIONAHA.115.06765. Epub 2016 Jun 6.

Abstract

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.

Keywords: blood pressure; genes; genome-wide association study; sodium.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • ADP-Ribosylation Factors / genetics*
  • Adult
  • Blood Pressure / physiology*
  • Blood Pressure Determination / methods
  • Calcium-Binding Proteins / genetics*
  • Caspases, Initiator / genetics*
  • China / epidemiology
  • Female
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Humans
  • Hypertension* / epidemiology
  • Hypertension* / genetics
  • Hypertension* / metabolism
  • Intracellular Signaling Peptides and Proteins / genetics*
  • Male
  • Middle Aged
  • Molecular Chaperones / genetics*
  • Polymorphism, Single Nucleotide
  • Protein-Serine-Threonine Kinases / genetics*
  • Sodium Chloride* / metabolism
  • Sodium Chloride* / pharmacology

Substances

  • Calcium-Binding Proteins
  • Intracellular Signaling Peptides and Proteins
  • Molecular Chaperones
  • calmegin
  • Sodium Chloride
  • MKNK1 protein, human
  • Protein-Serine-Threonine Kinases
  • CASP4 protein, human
  • Caspases, Initiator
  • ARL6 protein, human
  • ADP-Ribosylation Factors