Identification of 108 SNPs in TSC, WNK1, and WNK4 and their association with hypertension in a Japanese general population

The deletion of thiazide-sensitive Na-Cl cotransporter (TSC, SLC12A3) causes Gitelman's syndrome characterized by low blood pressure, while deletions of the WNK1 (PRKWNK1) and WNK4 (PRKWINK4) genes cause familial hypertension known as pseudohypoaldosteronism type II. Recent studies have revealed that cell surface expression of TSC is regulated by WNK1 and WNK4. We hypothesized that molecular variations in TSC, WNK1, and WNK4 could lead to all increased morbidity of hypertension. We identified 52, 35, and 21 polymorphisms in Japanese hypertensives by sequencing the entire coding regions of TSC, WNK1 and WNK4, respectively. Twenty-one representative polymorphisms were genotyped in 1,818 Japanese individuals (771 Subjects with hypertension and 1,047 controls) randomly sampled in Suita city. The results indicated that the systolic blood pressure in men with the CT+TT genotype in WNK4 C14717T was 3.1 mmHg, higher than those with the CC genotype (p =0.042) after adjustment with confounding factors such as age, BMI, hyperlipidemia, diabetes mellitus, antihypertensive drug use, smoking, and drinking. Multivariate logistic regression analysis (with adjustment for the same parameters) in men revealed that the odds ratio for the presence of hypertension of the CT+TT genotype in C14717T to the CC genotype was 1.62 (p = 0.010, 95% confidence interval, 1.12-2.33). Association of TSC and WNK1 with hypertension was not observed. In conclusion, Our Study Suggests the possible involvement or WNK4 in essential hypertension in a Japanese general population.