Mutations in the Na-Cl cotransporter reduce blood pressure in humans
Mutations in the Na-Cl cotransporter reduce blood pressure in humans
复制标题
DOI：
10.1161/01.hyp.37.6.1458
复制
发表时间：
2001-06-01
期刊：
影响因子：
8.3
通讯作者：
Lifton, RP
中科院分区：
文献类型：
--
作者：
Cruz, DN;Simon, DB;Lifton, RP
盐平衡和血压之间的关系仍然很难从普通人群的流行病学研究中建立起来。最近，孟德尔式高血压已经证明，增加肾盐平衡的突变导致血压升高，这表明减少净盐平衡的突变可能具有匡威的效果。Gitelman综合征是由远端曲小管（NCCT）的钠-氯协同转运蛋白功能缺失突变引起的，其特征是遗传性低钾血症伴所谓的“正常”血压。我们假设Gitelman综合征的轻度盐耗导致血压降低和对高血压的保护。我们已经正式解决了这个问题，通过研究的199名成员的一个大型阿米什家族与Gitelman综合征。通过基因检测，家族成员被鉴定为遗传NCCT中的0（n=60）、1（n=113）或2（n=26）个突变，允许通过比较具有对比基因型的亲属的表型来无偏倚地评估遗传这些突变的临床后果。结果表明，在遗传了2个突变NCCT等位基因的患者中，低钾血症、低镁血症和低钙尿症的发生率较高。此外，NCCT基因型是血压的重要预测因子，纯合子突变家族成员的年龄和性别调整收缩压和舒张压显著低于其野生型亲属。此外，纯合子和杂合子受试者的24小时尿Na+显著高于野生型受试者，反映了自我选择的较高盐摄入量。最后，杂合子儿童（而非成人）的血压明显低于野生型亲属。这些发现提供了正式的证据，即损害肾盐处理的遗传突变降低了人类的血压。
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.