Resequencing Study Identifies Rare Renin–Angiotensin–Aldosterone System Variants Associated With Blood Pressure Salt-Sensitivity: The GenSalt Study

<span class="paragraphSection"><div class="boxTitle">Abstract</div><div class="boxTitle">BACKGROUND</div>The role of rare variants in blood pressure (BP) salt-sensitivity is unknown. We conducted a resequencing study of the renin–angiotensin–aldosterone system (RAAS) to identify rare variants associated with BP salt-sensitivity among participants of the Genetic Epidemiology Network of Salt-Sensitivity (GenSalt) study.<div class="boxTitle">METHODS</div>The GenSalt study was conducted among 1,906 participants who underwent a 7-day low-sodium (51.3 mmol sodium/day) followed by a 7-day high-sodium feeding study (307.8 mmol sodium/day). The 300 most salt-sensitive and 300 most salt-resistant GenSalt participants were selected for the resequencing study. Seven RAAS genes were resequenced using capillary-based sequencing methods. Rare variants were tested for association with BP salt-sensitivity using traditional burden tests. Single-marker analyses were employed to test associations of low-frequency and common variants.<div class="boxTitle">RESULTS</div>Aggregate rare variant analysis revealed an association of the RAAS pathway with BP salt-sensitivity. Carriers of rare RAAS variants had a 1.55-fold [95% confidence interval (CI): 1.15, 2.10] higher odds of salt-sensitivity compared to noncarriers (<span style="font-style:italic;">P</span> = 0.004), a finding which was significant after Bonferroni correction. A nominal association of the <span style="font-style:italic;">APLN</span> gene with salt-sensitivity was also identified, with rare <span style="font-style:italic;">APLN</span> variants conferring a 2.22-fold (95% CI: 1.05, 6.58) higher odds of salt-sensitivity (<span style="font-style:italic;">P</span> = 0.03). Single-marker analyses did not identify variant-BP salt-sensitivity associations after Bonferroni adjustment. A nominal association of a low-frequency, missense <span style="font-style:italic;">RENBP</span> variant was identified. Each minor allele of rs78377269 conferred a 2.21-fold (95% CI: 1.10, 4.42) increased odds of salt-sensitivity (<span style="font-style:italic;">P</span> = 0.03).<div class="boxTitle">CONCLUSIONS</div>This study presents of the first evidence of a contribution of rare RAAS variants to BP salt-sensitivity.<span style="font-style:italic;">Clinical Trial RegistryTrial Number:</span> NCT00721721</span>

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