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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; Kinnear, Sue; Shrine, Nick; Jalland, Mahli; Henry, Amanda P.; Clayton, Jenny; O’Shaughnessy, Kevin M.; Tobin, Martin D.; Schuster, Victor; Cook, Stuart; Hall, Ian P.; Glover, Mark

Authors

James S. Ware

Louise V. Wain

Sarath K. Channavajjhala

Victoria E. Jackson

Elizabeth Edwards

Run Lu

Keith Siew

Wenjing Jia

Sue Kinnear

Nick Shrine

Mahli Jalland

Amanda P. Henry

Jenny Clayton

Kevin M. O’Shaughnessy

Martin D. Tobin

Victor Schuster

Stuart Cook

Ian P. Hall

Mark Glover



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.

Journal Article Type Article
Publication Date Aug 7, 2017
Journal Journal of Clinical Investigation
Print ISSN 0021-9738
Electronic ISSN 1558-8238
Publisher American Society for Clinical Investigation
Peer Reviewed Peer Reviewed
Volume 127
Issue 9
Pages 3367-3374
APA6 Citation 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
DOI https://doi.org/10.1172/JCI89812
Publisher URL https://www.jci.org/articles/view/89812
Copyright Statement Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0

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Copyright Statement
Copyright information regarding this work can be found at the following address: http://creativecommons.org/licenses/by/4.0





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