title: Salt sensitivity of blood pressure is associated with polymorphisms in the sodium-bicarbonate cotransporter.
abstract: Previous studies have demonstrated that single nucleotide polymorphisms (SNPs) of the sodium-bicarbonate co-transporter gene (SLC4A5) are associated with hypertension. We tested the hypothesis that SNPs in SLC4A5 are associated with salt sensitivity of blood pressure in 185 whites consuming an isocaloric constant diet with a randomized order of 7 days of low Na(+) (10 mmol/d) and 7 days of high Na(+) (300 mmol/d) intake. Salt sensitivity was defined as a ≥ 7-mm Hg increase in mean arterial pressure during a randomized transition between high and low Na(+) diet. A total of 35 polymorphisms in 17 candidate genes were assayed, 25 of which were tested for association. Association analyses with salt sensitivity revealed 3 variants that associated with salt sensitivity, 2 in SLC4A5 (P<0.001) and 1 in GRK4 (P=0.020). Of these, 2 SNPs in SLC4A5 (rs7571842 and rs10177833) demonstrated highly significant results and large effects sizes, using logistic regression. These 2 SNPs had P values of 1.0 × 10(-4) and 3.1 × 10(-4) with odds ratios of 0.221 and 0.221 in unadjusted regression models, respectively, with the G allele at both sites conferring protection. These SNPs remained significant after adjusting for body mass index and age (P=8.9 × 10(-5) and 2.6 × 10(-4) and odds ratios 0.210 and 0.286, respectively). Furthermore, the association of these SNPs with salt sensitivity was replicated in a second hypertensive population. Meta-analysis demonstrated significant associations of both SNPs with salt sensitivity (rs7571842 [P=1.2 × 10(-5)]; rs1017783 [P=1.1 × 10(-4)]). In conclusion, SLC4A5 variants are strongly associated with salt sensitivity of blood pressure in 2 separate white populations.
authors.affiliation: Department of Medicine, University of Virginia Health System, Charlottesville, VA 22908-1414, USA. rmc4c@virginia.edu
authors.forename: Robert M
authors.initials: RM
authors.lastname: Carey
authors.forename: Cynthia D
authors.initials: CD
authors.lastname: Schoeffel
authors.forename: John J
authors.initials: JJ
authors.lastname: Gildea
authors.forename: John E
authors.initials: JE
authors.lastname: Jones
authors.forename: Helen E
authors.initials: HE
authors.lastname: McGrath
authors.forename: Lindsay N
authors.initials: LN
authors.lastname: Gordon
authors.forename: Min Jeong
authors.initials: MJ
authors.lastname: Park
authors.forename: Rafal S
authors.initials: RS
authors.lastname: Sobota
authors.forename: Patricia C
authors.initials: PC
authors.lastname: Underwood
authors.forename: Jonathan
authors.initials: J
authors.lastname: Williams
authors.forename: Bei
authors.initials: B
authors.lastname: Sun
authors.forename: Benjamin
authors.initials: B
authors.lastname: Raby
authors.forename: Jessica
authors.initials: J
authors.lastname: Lasky-Su
authors.forename: Paul N
authors.initials: PN
authors.lastname: Hopkins
authors.forename: Gail K
authors.initials: GK
authors.lastname: Adler
authors.forename: Scott M
authors.initials: SM
authors.lastname: Williams
authors.forename: Pedro A
authors.initials: PA
authors.lastname: Jose
authors.forename: Robin A
authors.initials: RA
authors.lastname: Felder
mesh_terms: D000328:Adult; D000450:Aldosterone / Q000097:blood; D001794:Blood Pressure / Q000235:genetics* / Q000502:physiology; D015992:Body Mass Index; D004032:Diet; D004305:Dose-Response Relationship, Drug; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D006973:Hypertension / Q000209:etiology / Q000235:genetics* / Q000503:physiopathology; D016015:Logistic Models; D008297:Male; D015201:Meta-Analysis as Topic; D008875:Middle Aged; D016017:Odds Ratio; D017063:Outcome Assessment, Health Care; D020641:Polymorphism, Single Nucleotide; D012083:Renin / Q000097:blood; D017673:Sodium Chloride, Dietary / Q000008:administration & dosage / Q000009:adverse effects; D027982:Sodium-Bicarbonate Symporters / Q000235:genetics*
chemical_list: C422023:SLC4A5 protein, human; D017673:Sodium Chloride, Dietary; D027982:Sodium-Bicarbonate Symporters; D000450:Aldosterone; D012083:Renin