Genome-Wide Gene–Potassium Interaction Analyses on Blood Pressure: The GenSalt Study (Genetic Epidemiology Network of Salt Sensitivity)

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Background—Gene–environmental interaction analysis can identify novel genetic factors for blood pressure (BP). We performed genome-wide analyses to identify genomic loci that interact with potassium to influence BP using single-marker (1 and 2 df joint tests) and gene-based tests among Chinese participants of the GenSalt study (Genetic Epidemiology Network of Salt Sensitivity).Methods and Results—Among 1876 GenSalt participants, the average of 3 urine samples was used to estimate potassium excretion. Nine BP measurements were taken using a random-zero sphygmomanometer. A total of 2.2 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<1.00×104) from GenSalt were evaluated for replication among 775 Chinese participants of the MESA (Multi-ethnic Study of Atherosclerosis). 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 ARL15 rs16882447 on systolic BP (P=2.83×10−9) and RANBP3L rs958929 on pulse pressure (P=1.58×10−8). The 2 df tests confirmed the ARL15 rs16882447 signal for systolic BP (P=1.15×10−9). Genome-wide gene-based analysis identified CC2D2A (P=2.59×10−7) at 4p15.32 and BNC2 (P=4.49×1010) at 9p22.2 for systolic BP, GGNBP1 (P=1.18×108), and LINC00336 (P=1.36×108) at 6p21 for diastolic BP, DAB1 (P=1.05×1013) at 1p32.2, and MIR4466 (P=5.34×108) at 6q25.3 for pulse pressure. The BNC2 (P=3.57×108) gene was also significant for mean arterial pressure.Conclusions—We identified 2 novel BP loci and 6 genes through the examination of single nucleotide polymorphism- and gene-based interactions with potassium.

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