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Previous research suggests that concurrent use of omeprazole with fluconazole, a potent cytochrome P450 (CYP) 2C19\/3A4 inhibitor,\u00a0may increase the risk of myopathy. However, the contribution of genetic polymorphisms in CYP enzymes remains unclear.<\/jats:p><\/jats:sec><jats:sec><jats:title>Aims<\/jats:title><jats:p>This study leveraged electronic health record (EHR) and biobank data to validate an interaction between omeprazole and fluconazole and to explore drug\u2013gene interactions (DGIs) between omeprazole and polymorphisms in CYP enzymes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Materials and Methods<\/jats:title><jats:p>A nested case\u2013control design with incidence\u2010density matching was used. Cases were defined as patients who developed myopathy during ongoing omeprazole therapy. For each case, up to four controls were selected from patients who had not developed myopathy by the time the case was diagnosed. Conditional logistic regression models, adjusting for relevant covariates, evaluated (i) the association between concomitant fluconazole use and myopathy and (ii) genotype\u2010stratified myopathy risk.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Among 902 cases and 3608 controls, the combined use of omeprazole and fluconazole was linked to an increased risk of myopathy (adjusted odds ratio [AOR]\u2009=\u20091.75, 95% confidence interval [CI]: 1.17\u20132.63, <jats:italic>p<\/jats:italic>\u2009=\u20090.007). In the DGI analysis, which included 862 cases and 3448 controls, individuals classified as CYP2C19 poor metabolizers paired with CYP3A4 extensive metabolizers showed a significantly higher myopathy risk (AOR\u2009=\u20091.62, 95% CI: 1.03\u20132.55, <jats:italic>p<\/jats:italic>\u2009=\u20090.036); those with CYP2C19 poor metabolizer\/CYP3A4 intermediate metabolizer had an even greater risk (AOR\u2009=\u20094.77, 95% CI: 1.74\u201313.1, <jats:italic>p<\/jats:italic>\u2009=\u20090.002).<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>These findings not only confirm previously reported drug\u2013drug interactions (DDIs) between omeprazole and fluconazole but also reveal the emerging clinical implications of DGIs.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>By integrating EHR and genetic data, the study showcases how informatics tools can translate DDI findings into DGI hypotheses, effectively bridging genetic insights and clinical outcomes.<\/jats:p><\/jats:sec>","DOI":"10.1002\/phar.70058","type":"journal-article","created":{"date-parts":[[2025,9,8]],"date-time":"2025-09-08T09:55:33Z","timestamp":1757325333000},"page":"654-666","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Association of Omeprazole\u2010Related Myopathy With Drug\u2013Drug and Drug\u2013Gene Interactions Involving <scp>CYP2C19<\/scp> and <scp>CYP3A4<\/scp>: A Nested Case\u2013Control Study"],"prefix":"10.1002","volume":"45","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8240-1198","authenticated-orcid":false,"given":"Eugene","family":"Jeong","sequence":"first","affiliation":[{"name":"Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt\u2010Ingram Cancer Center Vanderbilt University School of Medicine  Nashville Tennessee 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