Phenotypic and pharmacogenetic evaluation of patients with thiazide-induced hyponatremia
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 10...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
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American Society for Clinical Investigation
2017
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| Online Access: | https://eprints.nottingham.ac.uk/44729/ |
| _version_ | 1848796985639829504 |
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| author | 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 Cook, Stuart Hall, Ian P. Glover, Mark |
| author_facet | 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 Cook, Stuart Hall, Ian P. Glover, Mark |
| author_sort | Ware, James S. |
| building | Nottingham Research Data Repository |
| collection | Online Access |
| description | 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. |
| first_indexed | 2025-11-14T19:56:41Z |
| format | Article |
| id | nottingham-44729 |
| institution | University of Nottingham Malaysia Campus |
| institution_category | Local University |
| last_indexed | 2025-11-14T19:56:41Z |
| publishDate | 2017 |
| publisher | American Society for Clinical Investigation |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | nottingham-447292020-05-04T18:59:46Z https://eprints.nottingham.ac.uk/44729/ 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 Cook, Stuart Hall, Ian P. Glover, Mark 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. American Society for Clinical Investigation 2017-08-07 Article PeerReviewed 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, Cook, Stuart, Hall, Ian P. and Glover, Mark (2017) Phenotypic and pharmacogenetic evaluation of patients with thiazide-induced hyponatremia. Journal of Clinical Investigation, 127 (9). pp. 3367-3374. ISSN 1558-8238 https://www.jci.org/articles/view/89812 doi:10.1172/JCI89812 doi:10.1172/JCI89812 |
| spellingShingle | 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 Cook, Stuart Hall, Ian P. Glover, Mark Phenotypic and pharmacogenetic evaluation of patients with thiazide-induced hyponatremia |
| title | Phenotypic and pharmacogenetic evaluation of patients with thiazide-induced hyponatremia |
| title_full | Phenotypic and pharmacogenetic evaluation of patients with thiazide-induced hyponatremia |
| title_fullStr | Phenotypic and pharmacogenetic evaluation of patients with thiazide-induced hyponatremia |
| title_full_unstemmed | Phenotypic and pharmacogenetic evaluation of patients with thiazide-induced hyponatremia |
| title_short | Phenotypic and pharmacogenetic evaluation of patients with thiazide-induced hyponatremia |
| title_sort | phenotypic and pharmacogenetic evaluation of patients with thiazide-induced hyponatremia |
| url | https://eprints.nottingham.ac.uk/44729/ https://eprints.nottingham.ac.uk/44729/ https://eprints.nottingham.ac.uk/44729/ |