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

Abstract

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 (PRKWNK4) 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 an 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 of WNK4 in essential hypertension in a Japanese general population.

SLC12A3 (Solute Carrier Family 12 Member [Sodium/Chloride] 3) Polymorphisms Are Associated With End-Stage Renal Disease in Diabetic Nephropathy

“…Although overall frequencies of four SNPs (g.34372 GϾA [Arg913Gln], g.39143 GϾA, g.39240 CϾT, and g.41727 CϾT), which had been previously reported to be associated with diabetic nephropathy, in our control group (5, 7, 13, and 6%, respectively) were similar to those of Japanese (8,9,12, and 8%, respectively), there were significant differences in the nephropathy group between two studies (12 vs. 3%, 13 vs. 4%, 15 vs. 7%, and 12 vs. 3%, respectively) (6). In addition, the frequency of haplotype 4 in block 2 in the control group (5.4%) was also similar to that of Japanese (6.0%, haplotype 7 ϩ haplotype 9), whereas it was different in the nephropathy group between two studies (11.9 vs 0.9%) (6).…”

“…Among the identified 52 polymorphisms in the SLC12A3 gene, as determined by sequencing of 48 Japanese DNA samples (12), we selected four SNPs (g.34372 GϾA [Arg913Gln], g.39143 GϾA, g.39240 CϾT, and g.41727 CϾT) that had been previously reported to be associated with diabetic nephropathy (6). We also selected an additional seven common SNPs based on frequency (frequency Ͼ0.05 in regulatory region, frequency Ͼ0.1 in introns) and linkage disequilibrium (LD) status (12). Two SNPs were in the promoter region, three in exons, and six in introns (Fig.…”

Association of Sixty-One Non-Synonymous Polymorphisms in Forty-One Hypertension Candidate Genes with Blood Pressure Variation and Hypertension

“…Systolic and diastolic blood pressure (SBP/DBP) values were taken as the mean of 2 measurements recorded by well-trained doctors using a mercury sphygmomanometer. Hypertension was defined as a mean SBP of ≥ 140 mmHg, a mean DBP of ≥ 90 mmHg, or current use of antihypertensive medication (20,21). Diabetes was defined as fasting plasma glucose levels ≥ 7.0 mmol/l (126 mg/dl), non-fasting plasma glucose levels ≥ 11.1 mmol/l (200 mg/dl), HbA1c ≥ 6.5%, or current use of antidiabetic medication.…”

Genetic basis of hypertension for the development of tailored medicine

“…Kokubo et al 10 and our group 11 have reported a positive association between the TSC gene (SLC12A3) and a predisposition to hypertension. Matayoshi et al 12 showed that the C1784T polymorphism of SLC12A3 was significantly associated with the antihypertensive effect of diuretics.…”