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.

中文翻译：

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噻嗪类低钠血症患者的表型和药物遗传学评价

噻嗪类利尿剂是最广泛使用的高血压治疗方法之一，但是对噻嗪类引起的低钠血症（TIH）（一种临床上显着的不良反应）知之甚少。在这里，我们研究了TIH住院患者的表型和遗传特征。在109名TIH患者队列中，患有严重TIH的患者表现出血管内体积扩展的扩展表型，游离水重吸收增加，尿中前列腺素E ₂排泄，血清氯，镁，锌和抗利尿激素排泄减少。来自1958年英国出生队列的48名TIH患者和2,922名对照的另一个队列中的GWAS确定了另外14个与TIH相关的区域。我们发现与SLCO2A1中的变体存在暗示性关联，其在远端肾单位中编码前列腺素转运蛋白。对SLCO2A1的重新测序揭示了一个非同义的变体rs34550074（p.A396T），并且在第二批TIH病例中复制了与此SNP的关联。具有p.A396T变体的TIH患者表现出前列腺素E ₂和代谢产物的尿排泄增加。此外，SLCO2A1磷酸模拟p.A396E在体外显示转运蛋白功能丧失。这些发现表明，TIH的表型涉及比以前公认的更广泛的代谢紊乱。我们提出了SLH2A1调节改变的患者亚组TIH发育的基础机制。