Common variants in the ATP2B1 gene are associated with susceptibility to hypertension: the Japanese Millennium Genome Project

Abstract

Hypertension is one of the most common complex genetic disorders. We have described previously 38 single nucleotide polymorphisms (SNPs) with suggestive association with hypertension in Japanese individuals. In this study we extend our previous findings by analyzing a large sample of Japanese individuals (n=14 105) for the most associated SNPs. We also conducted replication analyses in Japanese of susceptibility loci for hypertension identified recently from genome-wide association studies of European ancestries. Association analysis revealed significant association of the ATP2B1 rs2070759 polymorphism with hypertension (P=5.3×10(-5); allelic odds ratio: 1.17 [95% CI: 1.09 to 1.26]). Additional SNPs in ATP2B1 were subsequently genotyped, and the most significant association was with rs11105378 (odds ratio: 1.31 [95% CI: 1.21 to 1.42]; P=4.1×10(-11)). Association of rs11105378 with hypertension was cross-validated by replication analysis with the Global Blood Pressure Genetics consortium data set (odds ratio: 1.13 [95% CI: 1.05 to 1.21]; P=5.9×10(-4)). Mean adjusted systolic blood pressure was highly significantly associated with the same SNP in a meta-analysis with individuals of European descent (P=1.4×10(-18)). ATP2B1 mRNA expression levels in umbilical artery smooth muscle cells were found to be significantly different among rs11105378 genotypes. Seven SNPs discovered in published genome-wide association studies were also genotyped in the Japanese population. In the combined analysis with replicated 3 genes, FGF5 rs1458038, CYP17A1, rs1004467, and CSK rs1378942, odds ratio of the highest risk group was 2.27 (95% CI: 1.65 to 3.12; P=4.6×10(-7)) compared with the lower risk group. In summary, this study confirmed common genetic variation in ATP2B1, as well as FGF5, CYP17A1, and CSK, to be associated with blood pressure levels and risk of hypertension.

Figure 1

Ex vivo expression analysis of ATP2B1 mRNA. Graphs depict the log² relative expression levels of the ATP2B1 mRNA in umbilical artery smooth muscle cells obtained by normalizing to GAPDH. Genotype of ATP2B1 rs11105378 of each sample was analyzed by direct sequencing using isolated genomic DNA from umbilical artery smooth muscle cells.

Figure 2

ORs for hypertension according to the number of risk genotypes Number of risk genotype was calculated by the following 4 SNPs: ATP2B1 rs1105378, FGF5 rs1458038, CYP17A1, rs1004467, and CSK rs1378942. Hypertensive subjects were defined as being treated with antihypertensive medication, SBP ≥140 mm Hg, or DBP ≥90 mm Hg; normotensive subjects were defined as all not treated with antihypertensive medication, SBP ≤120 mm Hg, and DBP ≤85 mm Hg. Adjusted OR for hypertension and BP levels were calculated using logistic and linear multiple regression analysis, adjusting for sex, age, age, BMI, and cohort variables. Frequency of hypertension and P values for the hypertension odds are shown in the top of column and the bottom of square, respectively.