Loss of function polymorphisms in SLCO1B1 (c.521T>C, rs4149056) and ABCG2 (c.421C>A, rs2231142) genes are associated with adverse events of rosuvastatin: a case-control study.

Autor: Merćep I; Department of Internal Medicine, University Hospital Centre Zagreb, University of Zagreb School of Medicine, Zagreb, Croatia., Radman I; University Department of Ophthalmology, University Hospital Centre Sestre Milosrdnice, Zagreb, Croatia., Trkulja V; Department of Pharmacology, University of Zagreb School of Medicine, Zagreb, Croatia., Božina T; Department of Medical Chemistry, Biochemistry and Clinical Chemistry, School of Medicine, University of Zagreb, Zagreb, Croatia., Šimičević L; Division of Pharmacogenomics and Therapy Individualization, Department of Laboratory Diagnostics, University Hospital Centre Zagreb, Zagreb, Croatia., Budimir E; University of Zagreb School of Medicine, Zagreb, Croatia., Ganoci L; Division of Pharmacogenomics and Therapy Individualization, Department of Laboratory Diagnostics, University Hospital Centre Zagreb, Zagreb, Croatia., Božina N; Department of Pharmacology, University of Zagreb School of Medicine, Zagreb, Croatia. nada.bozina@mef.hr.; Division of Pharmacogenomics and Therapy Individualization, Department of Laboratory Diagnostics, University Hospital Centre Zagreb, Zagreb, Croatia. nada.bozina@mef.hr.
Jazyk: angličtina
Zdroj: European journal of clinical pharmacology [Eur J Clin Pharmacol] 2022 Feb; Vol. 78 (2), pp. 227-236. Date of Electronic Publication: 2021 Oct 19.
DOI: 10.1007/s00228-021-03233-7
Abstrakt: Purpose: The study aims to evaluate relationship between polymorphisms associated with a reduced function of two transporter proteins resulting in increased exposure to rosuvastatin - organic anion transporter 1B1 (OATP1B1) (SLCO1B1 c.521T>C) and ATP binding cassette subfamily G member 2 (ABCG2) (ABCG2 c.421C>A) and occurrence of rosuvastatin related myotoxicity/hepatotoxicity.
Methods: In a case-control study, cases (rosuvastatin treated patients developing myotoxicity or hepatotoxicity) and controls (concurrent rosuvastatin treated patients free of adverse events) were prospectively recruited over a 2 year period in a single tertiary center specialized in treatment of metabolic disorders. Subjects were evaluated for clinical, comorbidity, and comedication characteristics and for genotype predicted metabolizing phenotypes regarding cytochrome P450 enzymes CYP2C9 and CYP2C19. Standard regression analysis and analysis in matched sets of cases and controls (optimal full matching) were undertaken by fitting frequentist and Bayesian models (covariates/matching variables: age, sex, diabetes, liver/renal disease, hypertension, CYP2C9 and C19 phenotype, use of CYP or transporter inhibitors, non evaluated transporter genotype).
Results: A total of 88 cases (81 with myotoxicity, 6 with hepatotoxicity, 1 with both) and 129 controls were recruited. Odds of variant SLCO1B1 c.521T>C allele were 2.2-2.5 times higher in cases than in controls (OR = 2.45, 95% CI 1.34-4.48; Bayesian OR = 2.59, 95% CrI 1.42-4.90 in regression analysis; OR = 2.20, 1.10-4.42; Bayesian OR = 2.26, 1.28-4.41 in matched analysis). Odds of variant ABCG2 c.421C>A allele were 2.1-2.3 times higher in cases than in controls (OR = 2.24, 1.04-4.83; Bayesian OR = 2.35, 1.09-4.31 in regression analysis; OR = 2.10, 0.83-5.31; Bayesian OR = 2.17, 1.07-4.35 in matched analysis).
Conclusion: Loss of function polymorphisms in SLCO1B1 c.521T>C and ABCG2 c.421C>A genes are associated with the presence of rosuvastatin related myotoxicity and/or hepatotoxicity.
(© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)
Databáze: MEDLINE
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