Department of Physiology, University of Melbourne, Melbourne, Victoria, Australia.
Hypertension. 2011 Dec;58(6):1073-8. doi: 10.1161/HYPERTENSIONAHA.111.176370. Epub 2011 Oct 17.
Variants in the gene encoding the γ-subunit of the epithelial sodium channel (SCNN1G) are associated with both Mendelian and quantitative effects on blood pressure. Here, in 4 cohorts of 1611 white European families composed of a total of 8199 individuals, we undertook staged testing of candidate single-nucleotide polymorphisms for SCNN1G (supplemented with imputation based on data from the 1000 Genomes Project) followed by a meta-analysis in all of the families of the strongest candidate. We also examined relationships between the genotypes and relevant intermediate renal phenotypes, as well as expression of SCNN1G in human kidneys. We found that an intronic single-nucleotide polymorphism of SCNN1G (rs13331086) was significantly associated with age-, sex-, and body mass index-adjusted blood pressure in each of the 4 populations (P<0.05). In an inverse variance-weighted meta-analysis of this single-nucleotide polymorphism in all 4 of the populations, each additional minor allele copy was associated with a 1-mm Hg increase in systolic blood pressure and 0.52-mm Hg increase in diastolic blood pressure (SE=0.33, P=0.002 for systolic blood pressure; SE=0.21, P=0.011 for diastolic blood pressure). The same allele was also associated with higher 12-hour overnight urinary potassium excretion (P=0.04), consistent with increased epithelial sodium channel activity. Renal samples from hypertensive subjects showed a nonsignificant (P=0.07) 1.7-fold higher expression of SCNN1G compared with normotensive controls. These data provide genetic and phenotypic evidence in support of a role for a common genetic variant of SCNN1G in blood pressure determination.
γ-亚基上皮钠通道（SCNN1G）基因变异与孟德尔遗传和血压的定量效应均有关。在此，我们对来自 4 个白人欧洲家系队列（共包含 1611 个家系，总计 8199 人）的候选单核苷酸多态性进行了分阶段测试，测试内容包括 SCNN1G 的候选单核苷酸多态性（补充了基于 1000 基因组计划数据的推断），随后对所有家系中最强候选单核苷酸多态性进行了荟萃分析。我们还研究了基因型与相关中间肾脏表型之间的关系，以及 SCNN1G 在人类肾脏中的表达情况。我们发现，SCNN1G 的内含子单核苷酸多态性（rs13331086）与 4 个人群的年龄、性别和体重指数校正后的血压均显著相关（P<0.05）。在对 4 个人群中该单核苷酸多态性的逆方差加权荟萃分析中，每个额外的次要等位基因拷贝与收缩压增加 1mmHg 和舒张压增加 0.52mmHg 相关（收缩压的 SE=0.33，P=0.002；舒张压的 SE=0.21，P=0.011）。同一等位基因也与较高的 12 小时夜间尿钾排泄量相关（P=0.04），这与上皮钠通道活性增加一致。与血压正常的对照者相比，高血压患者的肾脏样本中 SCNN1G 的表达量（P=0.07）升高了 1.7 倍，但差异无统计学意义。这些数据为 SCNN1G 的常见遗传变异在血压确定中的作用提供了遗传和表型证据。
