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Phenotypic and pharmacogenetic evaluation of patients with thiazide-induced hyponatremia
James S. Ware, … , Ian P. Hall, Mark Glover
James S. Ware, … , Ian P. Hall, Mark Glover
Published August 7, 2017
Citation Information: J Clin Invest. 2017;127(9):3367-3374. https://doi.org/10.1172/JCI89812.
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Research Article Nephrology Therapeutics

Phenotypic and pharmacogenetic evaluation of patients with thiazide-induced hyponatremia

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Abstract

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.

Authors

James S. Ware, Louise V. Wain, Sarath K. Channavajjhala, Victoria E. Jackson, Elizabeth Edwards, Run Lu, Keith Siew, Wenjing Jia, Nick Shrine, Sue Kinnear, Mahli Jalland, Amanda P. Henry, Jenny Clayton, Kevin M. O’Shaughnessy, Martin D. Tobin, Victor L. Schuster, Stuart Cook, Ian P. Hall, Mark Glover

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Figure 4

Hypothesis for the role of SLCO2A1 in contributing to TIH in individuals carrying the SLCO2A1 A396T variant.

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Hypothesis for the role of SLCO2A1 in contributing to TIH in individuals...
(A) Under low ADH conditions, apical PGT in the renal collecting duct scavenges PGE2 from the lumen, resulting in AQP2 internalization and minimal osmotic water reabsorption. (B) With reduced or absent apical PGT, PGE2 reaching the lumen is able to stimulate apical EP4 receptors, resulting in insertion of AQP2 and osmotic water reabsorption.
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