Mutations in the Na-Cl Cotransporter Reduce Blood Pressure in Humans

低钙尿 血压 内科学 内分泌学 吉特尔曼综合征 医学 外显率 低钾血症 人口 远曲小管 肾功能 低镁血症 遗传学 生物 化学 肾单位 表型 基因 有机化学 环境卫生
作者
Dinna N. Cruz,David B. Simon,Carol Nelson‐Williams,Anita Farhi,Karin E. Finberg,Laura Burleson,John R. Gill,Richard P. Lifton
出处
期刊:Hypertension [Lippincott Williams & Wilkins]
卷期号:37 (6): 1458-1464 被引量:156
标识
DOI:10.1161/01.hyp.37.6.1458
摘要

The relationship between salt homeostasis and blood pressure has remained difficult to establish from epidemiological studies of the general population. Recently, mendelian forms of hypertension have demonstrated that mutations that increase renal salt balance lead to higher blood pressure, suggesting that mutations that decrease the net salt balance might have the converse effect. Gitelman's syndrome, caused by loss of function mutations in the Na-Cl cotransporter of the distal convoluted tubule (NCCT), features inherited hypokalemic alkalosis with so-called "normal" blood pressure. We hypothesized that the mild salt wasting of Gitelman's syndrome results in reduced blood pressure and protection from hypertension. We have formally addressed this question through the study of 199 members of a large Amish kindred with Gitelman's syndrome. Through genetic testing, family members were identified as inheriting 0 (n=60), 1 (n=113), or 2 (n=26) mutations in NCCT, permitting an unbiased assessment of the clinical consequences of inheriting these mutations by comparison of the phenotypes of relatives with contrasting genotypes. The results demonstrate high penetrance of hypokalemic alkalosis, hypomagnesemia, and hypocalciuria in patients inheriting 2 mutant NCCT alleles. In addition, the NCCT genotype was a significant predictor of blood pressure, with homozygous mutant family members having significantly lower age- and gender-adjusted systolic and diastolic blood pressures than those of their wild-type relatives. Moreover, both homozygote and heterozygote subjects had significantly higher 24-hour urinary Na(+) than did wild-type subjects, reflecting a self-selected higher salt intake. Finally, heterozygous children, but not adults, had significantly lower blood pressures than those of the wild-type relatives. These findings provide formal demonstration that inherited mutations that impair renal salt handling lower blood pressure in humans.
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