A candidate locus in the renalase gene and susceptibility to blood pressure responses to the dietary salt

Abstract

Background: High dietary salt confers a risk of elevating blood pressure (BP) and the development of hypertension. BP to salt intake may be determined in part by individual genetic predisposition. Identifying these genetic underpinnings will enhance our understanding of the biological mechanisms of BP regulation. This study aims to assess the genetic association with salt sensitivity of BP (SSBP) within two well-phenotyped multinational cohorts. Methods: A total of 720 white participants from the HyperPATH consortium program were selected and genotyped using a multiethnic genotyping array. Individuals consumed two study diets containing high (>200 mEq/day) and low (<10 mEq/day) sodium content, after which SSBP, aldosterone, and plasma renin activity (PRA) were assessed in a controlled inpatient research setting. Results: A top signal (rs10887801; beta = 4.57, P = 5.03E − 07) at the renalase gene (RNLS) region was significantly associated with SSBP. We also identified seven single nucleotide variants with linkage disequilibrium to the top signal at this region that comprised a significant haplotype (TCTTAGTT, P = 0.00081). Homozygous carriers of the T-risk allele of the key single nucleotide variant had higher SSBP (P ≤ 0.00001) and lower PRA (P = 0.0076) compared with the nonrisk allele. Conclusion: We identified significant associations between genetic variants of the RNLS gene and BP responses to dietary salt intervention and PRA that suggest susceptibility to volume-driven hypertension. These findings may contribute to a better understanding of the genetic mechanisms underlying BP regulation, support the role of RNLS in the pathogenesis of SSBP, and identify individuals who may be at risk from excess dietary salt intake.