title: The epithelial sodium channel γ-subunit gene and blood pressure: family based association, renal gene expression, and physiological analyses.
abstract: Variants in the gene encoding the γ-subunit of the epithelial sodium channel (SCNN1G) are associated with both Mendelian and quantitative effects on blood pressure. Here, in 4 cohorts of 1611 white European families composed of a total of 8199 individuals, we undertook staged testing of candidate single-nucleotide polymorphisms for SCNN1G (supplemented with imputation based on data from the 1000 Genomes Project) followed by a meta-analysis in all of the families of the strongest candidate. We also examined relationships between the genotypes and relevant intermediate renal phenotypes, as well as expression of SCNN1G in human kidneys. We found that an intronic single-nucleotide polymorphism of SCNN1G (rs13331086) was significantly associated with age-, sex-, and body mass index-adjusted blood pressure in each of the 4 populations (P<0.05). In an inverse variance-weighted meta-analysis of this single-nucleotide polymorphism in all 4 of the populations, each additional minor allele copy was associated with a 1-mm Hg increase in systolic blood pressure and 0.52-mm Hg increase in diastolic blood pressure (SE=0.33, P=0.002 for systolic blood pressure; SE=0.21, P=0.011 for diastolic blood pressure). The same allele was also associated with higher 12-hour overnight urinary potassium excretion (P=0.04), consistent with increased epithelial sodium channel activity. Renal samples from hypertensive subjects showed a nonsignificant (P=0.07) 1.7-fold higher expression of SCNN1G compared with normotensive controls. These data provide genetic and phenotypic evidence in support of a role for a common genetic variant of SCNN1G in blood pressure determination.
authors: Department of Physiology, University of Melbourne, Melbourne, Victoria, Australia. cara.busst@inserm.fr
authors: Cara J
authors: CJ
authors: Büsst
authors: Lisa D S
authors: LD
authors: Bloomer
authors: Katrina J
authors: KJ
authors: Scurrah
authors: Justine A
authors: JA
authors: Ellis
authors: Timothy A
authors: TA
authors: Barnes
authors: Fadi J
authors: FJ
authors: Charchar
authors: Peter
authors: P
authors: Braund
authors: Paul N
authors: PN
authors: Hopkins
authors: Nilesh J
authors: NJ
authors: Samani
authors: Steven C
authors: SC
authors: Hunt
authors: Maciej
authors: M
authors: Tomaszewski
authors: Stephen B
authors: SB
authors: Harrap
mesh_terms: D000293:Adolescent; D000328:Adult; D001794:Blood Pressure / Q000235:genetics*; D015331:Cohort Studies; D053503:Epithelial Sodium Channels / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D005060:Europe / Q000453:epidemiology / Q000208:ethnology; D005260:Female; D018628:Gene Dosage; D015870:Gene Expression; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D006973:Hypertension / Q000453:epidemiology / Q000235:genetics; D007438:Introns / Q000235:genetics; D007668:Kidney / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D011044:Poland / Q000453:epidemiology; D020641:Polymorphism, Single Nucleotide; D011188:Potassium / Q000652:urine*; D040641:Quantitative Trait Loci; D012333:RNA, Messenger / Q000096:biosynthesis; D012964:Sodium / Q000378:metabolism; D014589:Utah / Q000453:epidemiology; D044465:White People / Q000235:genetics; D055815:Young Adult
chemical_list: D053503:Epithelial Sodium Channels; D012333:RNA, Messenger; C507052:SCNN1G protein, human; D012964:Sodium; D011188:Potassium