Genome-Wide Gene–Potassium Interaction Analyses on Blood Pressure

Abstract

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 <1.00×10 − 4 ) 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 =4.49×10 − 10 ) at 9p22.2 for systolic BP, GGNBP1 ( P =1.18×10 − 8 ), and LINC00336 ( P =1.36×10 − 8 ) at 6p21 for diastolic BP, DAB1 ( P =1.05×10 − 13 ) at 1p32.2, and MIR4466 ( P =5.34×10 − 8 ) at 6q25.3 for pulse pressure. The BNC2 ( P =3.57×10 − 8 ) 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.