Association of a sodium channel alpha subunit promoter variant with blood pressure.

The SCNNIA gene, which is located on human chromosome 12p13.3, encodes the alpha subunit of the amiloride-sensitive epithelial sodium channel, and mutations in SCNNIA can result in pseudohypoaldosteronism type I. It was postulated that genetic variations in SCNN1A could lead to an increased risk of hypertension. Sequence variations in SCNN1A were identified, and the association between these polymorphisms and BP was examined in a large cohort (n = 3898) representing the general population in Japan. Four polymorphisms in the promoter region, three polymorphisms in the exonic region, and one polymorphism in the first intron were identified. Because association studies with one-half of the study population indicated that the A(2139)G polymorphism, among others, significantly affected BP, this polymorphism was studied in the entire study population. Multiple logistic analyses indicated that the odds ratio for hypertension with the GA+GG genotype was 1.31 (P = 0.0154) in the total population and 1.77 (P = 0.0035) among subjects <60 yr of age. A significantly higher frequency of proteinuria was also observed among subjects with the GA+GG genotype. A transient transfection assay using MDCK cells indicated that the promoter activity of the G(2139) allele was higher than that of the A(2139) allele. Therefore, possession of the SCNN1A G(2139) allele significantly increased the risk of hypertension. A lower level of SCNN1A subunit expression among subjects with the AA genotype might lead to lower levels of sodium reabsorption in the kidney and might provide protection against the development of hypertension.