Phenotypic and pharmacogenetic evaluation of patients with thiazide-induced hyponatremia

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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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.

Original languageEnglish (US)
Pages (from-to)3367-3374
Number of pages8
JournalJournal of Clinical Investigation
Volume127
Issue number9
DOIs
StatePublished - Sep 1 2017

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Thiazides
Hyponatremia
Pharmacogenetics
Dinoprostone
Sodium Chloride Symporter Inhibitors
Phenotype
Magnesium Chloride
Genome-Wide Association Study
Nephrons
Vasopressins
Prostaglandins
Single Nucleotide Polymorphism
Parturition
Hypertension

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Ware, J. S., Wain, L. V., Channavajjhala, S. K., Jackson, V. E., Edwards, E., Lu, R., ... Glover, M. (2017). Phenotypic and pharmacogenetic evaluation of patients with thiazide-induced hyponatremia. Journal of Clinical Investigation, 127(9), 3367-3374. https://doi.org/10.1172/JCI89812

Phenotypic and pharmacogenetic evaluation of patients with thiazide-induced hyponatremia. / 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.

In: Journal of Clinical Investigation, Vol. 127, No. 9, 01.09.2017, p. 3367-3374.

Research output: Contribution to journalArticle

Ware, JS, Wain, LV, Channavajjhala, SK, Jackson, VE, Edwards, E, Lu, R, Siew, K, Jia, W, Shrine, N, Kinnear, S, Jalland, M, Henry, AP, Clayton, J, O'Shaughnessy, KM, Tobin, MD, Schuster, VL, Cook, S, Hall, IP & Glover, M 2017, 'Phenotypic and pharmacogenetic evaluation of patients with thiazide-induced hyponatremia', Journal of Clinical Investigation, vol. 127, no. 9, pp. 3367-3374. https://doi.org/10.1172/JCI89812
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. / Phenotypic and pharmacogenetic evaluation of patients with thiazide-induced hyponatremia. In: Journal of Clinical Investigation. 2017 ; Vol. 127, No. 9. pp. 3367-3374.
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AU - Jackson, Victoria E.

AU - Edwards, Elizabeth

AU - Lu, Run

AU - Siew, Keith

AU - Jia, Wenjing

AU - Shrine, Nick

AU - Kinnear, Sue

AU - Jalland, Mahli

AU - Henry, Amanda P.

AU - Clayton, Jenny

AU - O'Shaughnessy, Kevin M.

AU - Tobin, Martin D.

AU - Schuster, Victor L.

AU - Cook, Stuart

AU - Hall, Ian P.

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