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In this study, we aimed to identify genetic variants that interact with thiazide\u2010use to increase the risk of these adverse reactions. Using UK Biobank data, we first performed genomewide variance quantitative trait locus (vQTL) analysis of ~\u20096.2 million SNPs on 95,493 unrelated hypertensive White British participants (24,313 on self\u2010reported bendroflumethiazide treatment at recruitment) for 2 blood (glucose and urate) and 2 urine (potassium and sodium) biomarkers. Second, we conducted direct gene\u2013environment interaction (GEI) tests on the significant (<jats:italic>P<\/jats:italic>\u2009&lt;\u20092.5\u2009\u00d7\u200910<jats:sup>\u22129<\/jats:sup>) 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 <jats:italic>P<\/jats:italic>\u2009=\u20090.05 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: <jats:italic>CDKAL1<\/jats:italic> intron rs35612982, GEI <jats:italic>P<\/jats:italic>\u2009=\u20096.24\u2009\u00d7\u200910<jats:sup>\u22123<\/jats:sup>; and 1 serum urate SNP: <jats:italic>SLC2A9<\/jats:italic> intron rs938564, GEI <jats:italic>P<\/jats:italic>\u2009=\u20094.51\u2009\u00d7\u200910<jats:sup>\u22124<\/jats:sup>) demonstrated significant GEI effects in the first, but not the second, cohort. Both genes are biologically plausible candidates, with the <jats:italic>SLC2A9<\/jats:italic>\u2010mediated interaction having been previously reported. In conclusion, we used a two\u2010stage approach to detect two biologically plausible genetic loci that can interact with thiazides to increase the risk of thiazide\u2010associated 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.<\/jats:p>","DOI":"10.1002\/cpt.3229","type":"journal-article","created":{"date-parts":[[2024,3,1]],"date-time":"2024-03-01T07:24:11Z","timestamp":1709277851000},"page":"1408-1417","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Genetic Determinants of Thiazide\u2010Induced Hyperuricemia, Hyperglycemia, and Urinary Electrolyte Disturbances \u2013 A Genome\u2010Wide Evaluation of the <scp>UK<\/scp> Biobank"],"prefix":"10.1002","volume":"115","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1196-1822","authenticated-orcid":false,"given":"Innocent G.","family":"Asiimwe","sequence":"first","affiliation":[{"name":"Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology University of Liverpool  Liverpool UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1354-0826","authenticated-orcid":false,"given":"Lauren","family":"Walker","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology University of Liverpool  Liverpool UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0242-6115","authenticated-orcid":false,"given":"Reecha","family":"Sofat","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology University of Liverpool  Liverpool UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6977-9337","authenticated-orcid":false,"given":"Andrea L.","family":"Jorgensen","sequence":"additional","affiliation":[{"name":"Department of Health Data Science, Institute of Population Health Sciences University of Liverpool  Liverpool UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7534-7266","authenticated-orcid":false,"given":"Munir","family":"Pirmohamed","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Therapeutics, Institute of Systems, Molecular and Integrative Biology University of Liverpool  Liverpool UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"the Multimorbidity Mechanism and Therapeutic Research Collaborative (MMTRC)","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,2,29]]},"reference":[{"key":"e_1_2_10_1_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(20)30925-9"},{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41569-021-00559-8"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.115.018912"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(08)60655-8"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1093\/eurheartj\/ehy339"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1001\/jama.1958.02990020025004"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11906-018-0826-6"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1097\/HJH.0000000000000447"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcp.14109"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.2352"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1755-5922.2010.00180.x"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1002\/pdi.1808"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1186\/1741-7015-11-83"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-020-00757-z"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkac1010"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-psych-010213-115100"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1136\/annrheumdis-2011-201186"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.3899\/jrheum.191005"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.aaw3538"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1010478"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-018-0579-z"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pmed.1001779"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pmed.1003344"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pmed.1001885"},{"key":"e_1_2_10_25_1","unstructured":"Fry D. 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