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Adverse reaction to thiazides linked to genetics

A small number of patients are genetically predisposed to developing thiazide-induced hyponatremia when they take thiazide diuretics, according to a study just published in the Journal of Clinical Investigation.

Up to 9% of patients taking a thiazide may develop thiazide-induced hyponatremia (TIH), according to researchers.

“The mechanism of TIH is poorly understood. Serum sodium concentration in the thiazide treated general population is virtually unchanged by thiazide therapy, implying that TIH occurs in a susceptible subgroup, but this subgroup cannot be prospectively identified and so TIH is largely unpredictable at the point of thiazide initiation,” James S. Ware, PhD, MRCP, of Imperial College, London, and colleagues wrote. “Pharmacogenetic predeposition to a range of adverse drug effects raises the possibility that TIH might also have genetic causation.”

To understand TIH’s causes better, researchers analyzed genetic and phenotypic characteristics 157 patients from the United Kingdom admitted to the hospital with hyponatremic TIH (serum sodium < 130 mM). The patients were matched with healthy normonatremic thiazide controls from primary care. The researchers also conducted a genome wide association study of 48 of the patients and 2,922 population controls from the British 1958 Cohort.

Ware and colleagues found that the patients with severe TIH had larger amounts of urinary PGE₂ excretion and free water reabsorption, showed an extended phenotype of intravascular volume expansion, and had lower antiduretic hormones, zinc, magnesium and serum chloride.

In the genome analysis, the researchers identified an additional 14 regions connected to TIH. They performed additional studies and resequencing on the SLCO2A1 gene, and found a single nucleotide polymorphism — rs34550074 (p.A396T) — was associated with TIH. The association with this variant, which was linked to increased urinary PGE₂/metabolite excretion, was replicated in a second cohort of patients with TIH.

“We suggest therefore that, in individuals carrying the SLCO2A1 A396T variant, the combination of thiazide-specific effects on free water generation, and the increase in collecting duct water permeability from reduced SLCO2A1 activity, combine to produce thiazide-induced hyponatremia.,” Ware and colleagues wrote.

Researchers noted that their study is the most detailed and biggest phenotypic description of patients with TIH ever, and sets the stage for potential treatment options.

“In the future, we may be able to personalize the treatment of patients with hypertension; we may be able to predict who is at high risk of experiencing this side effect of thiazide tablets and either choose alternative antihypertensive medication or focus additional safety blood test monitoring in those at particularly high risk,” Mark Glover, MB, BChir, PhD, of the University of Nottingham in England, said in a press release. – by Janel Miller

Disclosure: The researchers report no relevant financial disclosures.