Kelly Tanika N, Li Changwei, Hixson James E, Gu Dongfeng, Rao Dabeeru C, Huang Jianfeng, Rice Treva K, Chen Jichun, Cao Jie, Li Jianxin, Anderson Christopher E, He Jiang
Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, New Orleans, Louisiana, USA.
Department of Epidemiology and Biostatistics, College of Public Health, University of Georgia at Athens, Athens, Georgia, USA.
Am J Hypertens. 2017 May 1;30(5):495-501. doi: 10.1093/ajh/hpx004.
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.
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.
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).
This study presents of the first evidence of a contribution of rare RAAS variants to BP salt-sensitivity. Clinical Trial RegistryTrial Number: NCT00721721.
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）进行了重测序研究，以在盐敏感性遗传流行病学网络（GenSalt）研究的参与者中鉴定与BP盐敏感性相关的罕见变异。
GenSalt研究在1906名参与者中进行，这些参与者先进行了为期7天的低钠饮食（51.3 mmol钠/天），随后进行了为期7天的高钠饮食研究（307.8 mmol钠/天）。从GenSalt参与者中选择了300名盐敏感性最高和300名盐抵抗性最高的参与者进行重测序研究。使用基于毛细管的测序方法对7个RAAS基因进行重测序。使用传统的负担测试来检验罕见变异与BP盐敏感性的关联。采用单标记分析来检验低频和常见变异的关联。
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变异的携带者盐敏感性的优势比高1.55倍[95%置信区间（CI）：1.15，2.10]（P = 0.004），在Bonferroni校正后这一发现具有显著性。还鉴定出APLN基因与盐敏感性存在名义上的关联，罕见的APLN变异使盐敏感性的优势比高2.22倍（95% CI：1.05，6.58）（P = 0.03）。在Bonferroni校正后，单标记分析未鉴定出变异与BP盐敏感性的关联。鉴定出一个低频错义RENBP变异存在名义上的关联。rs78377269的每个次要等位基因使盐敏感性的优势比增加2.21倍（95% CI：1.10，4.42）（P = 0.03）。
本研究首次提供了罕见RAAS变异对BP盐敏感性有贡献的证据。临床试验注册编号：NCT00721721。
