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.