背景:罕见变异在血压(BP)盐敏感性中的作用尚不清楚。我们对肾素-血管紧张素-醛固酮系统(RAAS)进行了重新测序研究,以确定盐敏感性遗传流行病学网络(GenSalt)研究参与者中与BP盐敏感性相关的罕见变异。
方法:GenSalt研究对1,906名参与者进行了为期7天的低钠(51.3mmol钠/天),随后进行了为期7天的高钠喂养研究(307.8mmol钠/天)。选择了300名对盐最敏感的和300名对盐最耐盐的参与者进行重新测序研究。使用基于毛细管的测序方法对七个RAAS基因进行重测序。使用传统的负荷测试测试了罕见的变体与BP盐敏感性的关联。采用单标记分析来测试低频和常见变体的关联。
结果:聚合罕见变异分析显示RAAS途径与BP盐敏感性相关。与非携带者相比,罕见RAAS变体的携带者的盐敏感性几率高1.55倍[95%置信区间(CI):1.15,2.10](P=0.004),Bonferroni校正后的重要发现。还确定了APLN基因与盐敏感性的名义关联,与罕见的APLN变体相比,盐敏感性的几率提高了2.22倍(95%CI:1.05,6.58)(P=0.03)。在Bonferroni调整后,单标记分析未鉴定出变体BP盐敏感性关联。低频的标称关联,鉴定了错义RENBP变体。rs78377269的每个次要等位基因赋予2.21倍(95%CI:1.10,4.42)增加盐敏感性的几率(P=0.03)。
结论:本研究提供了罕见RAAS变异对BP盐敏感性有贡献的第一个证据。临床试验注册试验编号:NCT00721721。
BACKGROUND: 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.
METHODS: 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.
RESULTS: 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 (P = 0.004), a finding which was significant after Bonferroni correction. A nominal association of the APLN gene with salt-sensitivity was also identified, with rare APLN variants conferring a 2.22-fold (95% CI: 1.05, 6.58) higher odds of salt-sensitivity (P = 0.03). Single-marker analyses did not identify variant-BP salt-sensitivity associations after Bonferroni adjustment. A nominal association of a low-frequency, missense RENBP variant was identified. Each minor allele of rs78377269 conferred a 2.21-fold (95% CI: 1.10, 4.42) increased odds of salt-sensitivity (P = 0.03).
CONCLUSIONS: This study presents of the first evidence of a contribution of rare RAAS variants to BP salt-sensitivity. Clinical
Trial RegistryTrial Number: NCT00721721.