Selective Genotyping Reveals Association Between the Epithelial Sodium Channel γ-Subunit and Systolic Blood Pressure

Abstract

Abstract-Systolic blood pressure is determined in large part by genes. Six independent studies have reported evidence of linkage between systolic pressure and chromosome 16p12 that incorporates SCNN1G, the gene encoding the ␥-subunit of the epithelial sodium channel. We undertook the first comprehensive association analysis of SCNN1G and systolic pressure. To achieve genetic contrast, we sampled unrelated subjects within the upper (mean: 166 mm Hg; nϭ96) and lower (mean: 98 mm Hg; nϭ94) 10% of the systolic pressure distribution of 2911 subjects from the Victorian Family Heart Study. We examined genotypes and haplotypes related to 26 single nucleotide polymorphisms across SCNN1G and its promoter. Each of 3 single nucleotide polymorphisms (rs13331086, rs11074553, and rs4299163) in introns 5 and 6 showed evidence of association with systolic pressure in logistic regression analyses adjusted for age, sex, and body mass index. Considered as a haplotype block, these single nucleotide polymorphisms were significantly associated with systolic pressure (haplo.score global: Pϭ0.0001). In permutation analyses to account for multiple testing, a result such as this was observed only once in 10 000 permutations. The estimated frequency of 1 haplotype (TGC) was substantially greater in high (13.3%) than low (0.6%) systolic pressure subjects (Pϭ0.0001). Three other haplotypes (TGG, TAC, and GGC) showed associations with high or low systolic pressure consistent with the observed associations of their composite alleles. These findings identify relatively common polymorphisms in the SCNN1G gene that are associated with high systolic blood pressure in the general Australian white population. (Hypertension. 2007;50:672-678.)

Hereditary Determinants of Human Hypertension

“…25 A large north American population-based study analyzed subjects falling within the upper and lower Ϸ5 th %iles of DBP distribution among Ͼ50 000 individuals in a primary care population, to assess the role of genetic variation at 35 loci with known physiological roles in adrenergic or renal regulation of BP. 22 In addition to confirming genotype-on-phenotype associations found previously, they discovered that sex-by-gene interactions ( Figure 2) influence blood pressure.…”

Epithelial Sodium Channel

“…24,44 -47 A recent study 48 examined genotypes and haplotypes related to 26 SNPs across SCNN1G and its promoter in a large cohort (Ͼ2900 people from the Victorian Family Heart Study). By sampling unrelated subjects within the upper (mean 166 mm Hg) and lower (mean 98 mm Hg) 10% of the systolic pressure distribution, a significant genetic contrast was achieved, leading to the identification of relatively common polymorphisms in the SCNN1G gene that are associated with high systolic blood pressure in the general Australian white population.…”

“…By sampling unrelated subjects within the upper (mean 166 mm Hg) and lower (mean 98 mm Hg) 10% of the systolic pressure distribution, a significant genetic contrast was achieved, leading to the identification of relatively common polymorphisms in the SCNN1G gene that are associated with high systolic blood pressure in the general Australian white population. 48 The observation that the ␥-subunit comes out of many independent and large studies as candidate gene participating in determining systolic blood pressure is interesting. Indeed, the ␥-subunit may have a specific role in ENaC activation by a novel mechanism (ie, proteolytic cleavage of its extracellular domain).…”

A “SNP in Time” for SCNN1G to Join the “Highly Likely” List of Genes for Essential Hypertension

“…In the present issue of Hypertension, Harrap and colleagues 3,4 in Melbourne build on their previous association findings for single nucleotide polymorphisms (SNPs) in SCNN1G and BP variation in their Victorian Family Heart Study population. 3,4 As well as these subjects, they now use data from 3 other large cohorts, the Utah Pedigree Study, the Genetic Regulation of Arterial Pressure of Humans in the Community Study, and the Silesian Hypertension Study, to examine 1611 families composed of 8199 individuals.…”

“…3,4 As well as these subjects, they now use data from 3 other large cohorts, the Utah Pedigree Study, the Genetic Regulation of Arterial Pressure of Humans in the Community Study, and the Silesian Hypertension Study, to examine 1611 families composed of 8199 individuals. 5 In their 2007 study, they found that 6 of 26 SCNN1G SNPs were associated with systolic BP (SBP).…”