Sodium Bicarbonate Cotransporter Polymorphisms Are Associated With Baseline and 10-Year Follow-Up Blood Pressures

Abstract

Abstract-The NaHCO 3 cotransporter gene (SLC4A5) on chromosome 2 encodes a protein that transports sodium and bicarbonate across the cell membrane and regulates cellular pH. The National Heart, Lung, and Blood Institute Family Blood Pressure Program found linkage of blood pressure-related traits to the chromosomal region containing SLC4A5 and phenotype associations with single nucleotide polymorphisms (SNPs) in this gene. However, the results were inconsistent over various phenotypes and SNPs. Nevertheless, the evidence was strong enough to propose this gene as a blood pressure-related gene. To extend these findings, SLC4A5 SNPs were genotyped in an independent set of 96 Utah pedigrees of 1040 adult subjects at baseline, 760 of whom were followed longitudinally for 10 years. After adjusting for age, gender, body mass index, and polygenic correlations within pedigrees, SNP hcv1137534 was significantly associated with both systolic blood pressure and diastolic blood pressure (DBP) at baseline (unadjusted Pϭ0.009 and Pϭ0.043; respectively) and at 10-year follow-up (Pϭ0.008 and Pϭ0.007; respectively). In secondary tests of association of baseline-stressed blood pressure, hcv1137534 was borderline or significantly associated with DBP change during an isometric handgrip test (Pϭ0.054), DBP change from supine to standing (Pϭ0.020), and DBP change after a 50°tilt (Pϭ0.034). There was no evidence for compensation of abnormal SLC4A5 sodium transport by genotype-specific differences in sodium-lithium countertransport, lithium-potassium cotransport, altered plasma sodium, chloride, or CO 2 levels. Therefore, in these Utah pedigrees, the SLC4A5 gene was significantly associated with blood pressure and persisted after 10 years of follow-up. These results additionally confirm the involvement of SLC4A5 with blood pressure control, although the mechanism is still unclear.

Deficient acid handling with distal RTA in the NBCe2 knockout mouse

“…shown that mutations in the SLC4A5 gene are associated with hypertension (2,7,18). Targeted disruption of NBCe2 in mice also results in hypertension (15) or neurological dysfunction (20).…”

Modular structure of sodium-coupled bicarbonate transporters

“…Apically expressed NBCe2 in choroid plexus epithelia (Praetorius and Nielson, 2004) operates with a 1:3 stoichiometry (Millar and Brown, 2008), secreting HCO 3 -into the cerebrospinal fluid. Polymorphisms in the SLC4A5 gene locus have been genetically linked to hypertension (Barkley et al, 2004;Hunt et al, 2006), although none of the associated genetic changes alter the predicted NBCe2 peptide sequence. Alignment is based on a manually adjusted version of a sequence alignment that was originally generated by ClustalW (http://www.ebi.ac.uk/ Tools/clustalw2/index.html) using GenBank protein accession numbers for NBCe1-…”

The sodium-bicarbonate cotransporter NBCe2 (slc4a5) expressed in human renal proximal tubules shows increased apical expression under high-salt conditions

“…(36) A locus in chromosome 2 (2p14-2p13.1) (27,28) contains the SLC4A5 gene, which has been linked to increased blood pressure (BP). (6,29) SLC4A5 encodes the electrogenic sodium bicarbonate cotransporter 4 (NBCe2, formerly known as NBC4) (30), which has been significantly associated with high BP and/or SS (4,5,19,32,33). A related sodium bicarbonate cotransporter, NBCe1, encoded by SLC4A4, is located in the human renal proximal tubule (RPT) (21), medullary thick ascending limb (mTAL), and collecting duct (7).…”