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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

Abstract

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.

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Data availability

All the datasets created are reported in this manuscript.

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Funding

Grant from the University of Zagreb, Croatia, project “Significance of pharmacogenetic testing of cytochrome P450 isoenzymes and transmembrane transporters SLCO1B1 and ABCG2 in the efficacy and tolerability of statin therapy.”

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Contributions

IM, IR: study concept and design, original draft preparation; VT: methodology, data curation, software, statistics, writing and editing; TB, LŠ, EB, LG: acquisition, analysis and interpretation of data; NB: conceptualization, methodology, original draft preparation, reviewing and editing, supervision.

Corresponding author

Correspondence to Nada Božina.

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Study was approved by the Ethics committee of the University of Zagreb School of Medicine. All procedures performed in the study were in accordance with the 1964 Declaration of Helsinki and its later amendments.

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The authors declare no competing interests.

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Merćep, I., Radman, I., Trkulja, V. et al. 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. Eur J Clin Pharmacol 78, 227–236 (2022). https://doi.org/10.1007/s00228-021-03233-7

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Keywords

  • Rosuvastatin
  • Myotoxicity
  • Hepatotoxicity
  • Polymorphism
  • ABCG2
  • SLCO1B1