Ware James S, Wain Louise V, Channavajjhala Sarath K, Jackson Victoria E, Edwards Elizabeth, Lu Run, Siew Keith, Jia Wenjing, Shrine Nick, Kinnear Sue, Jalland Mahli, Henry Amanda P, Clayton Jenny, O'Shaughnessy Kevin M, Tobin Martin D, Schuster Victor L, Cook Stuart, Hall Ian P, Glover Mark
NIHR Biomedical Research Unit in Cardiovascular Disease at Royal Brompton & Harefield, NHS Foundation Trust and Imperial College London, London, United Kingdom.
National Heart and Lung Institute, Imperial College London, London, United Kingdom.
J Clin Invest. 2017 Sep 1;127(9):3367-3374. doi: 10.1172/JCI89812. Epub 2017 Aug 7.
Thiazide diuretics are among the most widely used treatments for hypertension, but thiazide-induced hyponatremia (TIH), a clinically significant adverse effect, is poorly understood. Here, we have studied the phenotypic and genetic characteristics of patients hospitalized with TIH. In a cohort of 109 TIH patients, those with severe TIH displayed an extended phenotype of intravascular volume expansion, increased free water reabsorption, urinary prostaglandin E2 excretion, and reduced excretion of serum chloride, magnesium, zinc, and antidiuretic hormone. GWAS in a separate cohort of 48 TIH patients and 2,922 controls from the 1958 British birth cohort identified an additional 14 regions associated with TIH. We identified a suggestive association with a variant in SLCO2A1, which encodes a prostaglandin transporter in the distal nephron. Resequencing of SLCO2A1 revealed a nonsynonymous variant, rs34550074 (p.A396T), and association with this SNP was replicated in a second cohort of TIH cases. TIH patients with the p.A396T variant demonstrated increased urinary excretion of prostaglandin E2 and metabolites. Moreover, the SLCO2A1 phospho-mimic p.A396E showed loss of transporter function in vitro. These findings indicate that the phenotype of TIH involves a more extensive metabolic derangement than previously recognized. We propose one mechanism underlying TIH development in a subgroup of patients in which SLCO2A1 regulation is altered.
噻嗪类利尿剂是治疗高血压最常用的药物之一，但噻嗪类药物引起的低钠血症（TIH）这一具有临床意义的不良反应却鲜为人知。在此，我们研究了因TIH住院患者的表型和遗传特征。在109例TIH患者队列中，严重TIH患者表现出血管内容量扩张、自由水重吸收增加、尿前列腺素E2排泄增加以及血清氯、镁、锌和抗利尿激素排泄减少的扩展表型。在来自1958年英国出生队列的48例TIH患者和2922例对照的独立队列中进行的全基因组关联研究（GWAS）确定了另外14个与TIH相关的区域。我们发现与SLCO2A1中的一个变体存在提示性关联，该变体在远端肾单位中编码一种前列腺素转运蛋白。对SLCO2A1进行重测序发现了一个非同义变体rs34550074（p.A396T），并且在第二个TIH病例队列中复制了与该单核苷酸多态性（SNP）的关联。携带p.A396T变体的TIH患者表现出尿前列腺素E2及其代谢产物排泄增加。此外，SLCO2A1磷酸化模拟物p.A396E在体外显示出转运蛋白功能丧失。这些发现表明，TIH的表型涉及比以前认识到的更广泛的代谢紊乱。我们提出了在一部分SLCO2A1调节改变的患者中TIH发生的一种潜在机制。
