Association of sodium channel γ-subunit promoter variant with blood pressure

The SCNNIG gene, located on human chromosome 16p12, encodes the gamma subunit of the amiloride-sensitive epithelial sodium channel, and mutations in SCNNIG can result in Liddle's syndrome or pseudohypoaldosteronism type I. We identified sequence variations in the promoter region of SCNNIG and examined the association between this polymorphism and blood pressure in a large cohort (n=4075) representing the general population in Japan. We found T(-1290)C, T(-501)G, G(-173)A, and G(-104)T polymorphisms in the promoter region of SCNNIG and confirmed the existence of T387C and T474C polymorphisms in exon 3 and the C1947G polymorphism in exon 13. Because the genotypes of the T(-1290)C, T(-501)G, G(-104)T, and T474C polymorphisms were in tight linkage disequilibrium, we selected the T474C and G(-173)A polymorphisms for an association study. The G(-173)A polymorphism of SCNNIG had a significant effect on systolic pressure (P=0.0050) and Pulse pressure (P=0.0050). The AA genotype was associated with an I I mm Hg drop in systolic pressure and an 8 nim Hg drop in pulse pressure and with a higher prevalence of hypotension (P=0.0195). A transient transfection assay using MDCK cells and human renal epithelial cells indicated that the promoter activity of the G(-173) allele was higher than that of the A(-173) allele. Although the effects of the A(-173) allele were recessive and although the AA genotype was found in just 0.7% of our study population, we observed that this variation of human SCNNIG had significant effects on blood pressure.