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.