Phenotypic and pharmacogenetic evaluation of patients with thiazide-induced hyponatremia.
Channavajjhala, Sarath K
Schuster, Victor L
The Journal of clinical investigation
The American Society for Clinical Investigations
MetadataShow full item record
Ware, J. S., Wain, L. V., Channavajjhala, S. K., Jackson, V. E., Edwards, E., Lu, R., Siew, K., et al. (2017). Phenotypic and pharmacogenetic evaluation of patients with thiazide-induced hyponatremia.. The Journal of clinical investigation, 127 (9), 3367-3374. https://doi.org/10.1172/jci89812
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.
Nephrons, Humans, Hyponatremia, Water, Prostaglandins, Dinoprostone, Organic Anion Transporters, Cohort Studies, Pharmacogenetics, Phenotype, Polymorphism, Single Nucleotide, Aged, Aged, 80 and over, Middle Aged, Female, Male, Thiazides, Sodium Chloride Symporter Inhibitors, Aquaporin 1, Aquaporin 2, Genome-Wide Association Study, United Kingdom
This work was supported by an Academy of Medical Sciences grant for clinical lecturers (to JSW and MG), British Heart Foundation grant PG/09/089 (to KMO), the National Institute for Health Research (NIHR) Royal Brompton Cardiovascular Biomedical Research Unit (to JSW and SC), the Fondation Leducq (to JSW and SC), and the British Heart Foundation (to JSW and SC). MDT holds a Medical Research Council Senior Clinical Fellowship (G0902313). This work was supported by the Medical Research Council (grant numbers G510364 and G1000861). This research used the ALICE and SPECTRE High Performance Computing Facilities at the University of Leicester.
External DOI: https://doi.org/10.1172/jci89812
This record's URL: https://www.repository.cam.ac.uk/handle/1810/296352
Attribution 4.0 International
Licence URL: http://creativecommons.org/licenses/by/4.0/
Recommended or similar items
The following licence files are associated with this item: