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 –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 –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.