Genetic Determinants of Thiazide-Induced Hyperuricemia, Hyperglycemia, and Urinary Electrolyte Disturbances - A Genome-Wide Evaluation of the UK Biobank.

Asiimwe, Innocent G ORCID: 0000-0002-1196-1822, Walker, Lauren ORCID: 0000-0002-3827-4387, Sofat, Reecha, Jorgensen, Andrea L ORCID: 0000-0002-6977-9337, Pirmohamed, Munir ORCID: 0000-0002-7534-7266 and Multimorbidity Mechanism and Therapeutic Research Collaborative , (2024) Genetic Determinants of Thiazide-Induced Hyperuricemia, Hyperglycemia, and Urinary Electrolyte Disturbances - A Genome-Wide Evaluation of the UK Biobank. Clinical pharmacology and therapeutics.

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Abstract

Thiazide diuretics, widely used in hypertension, cause a variety of adverse reactions, including hyperglycemia, hyperuricemia, and electrolyte abnormalities. In this study, we aimed to identify genetic variants that interact with thiazide-use to increase the risk of these adverse reactions. Using UK Biobank data, we first performed genomewide variance quantitative trait locus (vQTL) analysis of ~ 6.2 million SNPs on 95,493 unrelated hypertensive White British participants (24,313 on self-reported bendroflumethiazide treatment at recruitment) for 2 blood (glucose and urate) and 2 urine (potassium and sodium) biomarkers. Second, we conducted direct gene-environment interaction (GEI) tests on the significant (P < 2.5 × 10^-9 ) vQTLs, included a second UK Biobank cohort comprising 13,647 unrelated hypertensive White British participants (3,478 on thiazides other than bendroflumethiazide) and set significance at P = 0.05 divided by the number of vQTL SNPs tested for GEIs. The vQTL analysis identified eight statistically significant SNPs for blood glucose (5 SNPs) and serum urate (3 SNPs), with none being identified for the urinary biomarkers. Two of the SNPs (1 glucose SNP: CDKAL1 intron rs35612982, GEI P = 6.24 × 10^-3 ; and 1 serum urate SNP: SLC2A9 intron rs938564, GEI P = 4.51 × 10^-4 ) demonstrated significant GEI effects in the first, but not the second, cohort. Both genes are biologically plausible candidates, with the SLC2A9-mediated interaction having been previously reported. In conclusion, we used a two-stage approach to detect two biologically plausible genetic loci that can interact with thiazides to increase the risk of thiazide-associated biochemical abnormalities. Understanding how environmental exposures (including medications such as thiazides) and genetics interact, is an important step toward precision medicine and improved patient outcomes.

Item Type:	Article
Uncontrolled Keywords:	Multimorbidity Mechanism and Therapeutic Research Collaborative (MMTRC)
Divisions:	Faculty of Health and Life Sciences Faculty of Health and Life Sciences > Institute of Population Health Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology
Depositing User:	Symplectic Admin
Date Deposited:	12 Apr 2024 10:04
Last Modified:	12 Apr 2024 12:38
DOI:	10.1002/cpt.3229
Open Access URL:	https://doi.org/10.1002/cpt.3229
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3180302