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Transporter Genes and statin-induced Hepatotoxicity

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Abstract

Purpose

Hepatotoxicity has emerged as a major cause of statin treatment interruption. Although organic anion-transporting polypeptide 1B1 (SLCO1B1), multidrug resistance protein 1 (ABCB1), and breast cancer resistance protein (ABCG2) have been identified as transporters of statins, knowledge of their role in statin-associated hepatotoxicity remains limited. Therefore, we aimed to conduct a comprehensive analysis to elucidate the association between hepatotoxicity and SLCO1B1, ABCB1, and ABCG2 polymorphisms.

Methods

This study retrospectively analyzed prospectively collected samples. We selected 10 single nucleotide polymorphisms (SNPs) of SLCO1B1, 9 SNPs of ABCB1, and 12 SNPs of ABCG2. We developed two models for multivariable analyses (Model I: clinical factors only; Model II: both clinical and genetic factors), and the attributable risk (%) of variables in Model II was determined.

Results

Among 851 patients, 66 (7.8%) developed hepatotoxicity. In Model I, lipophilic statins, atrial fibrillation (Afib), and diabetes mellitus showed a significant association with hepatotoxicity. In Model II, lipophilic statins and Afib, SLCO1B1 rs11045818 A allele, SLCO1B1 rs4149035 T allele, and ABCG2 rs2622629 TT genotype were associated with higher hepatotoxicity risk. Among them, the SLCO1B1 rs11045818 A allele exhibited the highest attributable risk (93.2%). The area under the receiver operating characteristic curve in Model I was 0.62 (95% CI: 0.55–0.69), and it was increased to 0.71 in Model II (95% CI: 0.64–0.77).

Conclusion

This study investigated the correlation between hepatotoxicity and polymorphisms of transporter genes in patients taking statins. The findings could help improve personalized treatments for patients receiving statin therapy.

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Data Availability

The datasets analyzed during the current study are presented as a supplementary file.

Code Availability

Not applicable.

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Funding

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (grant number: NRF-2023R1A2C1007463).

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Author notes

  1. Seo-A Choi and Jung Sun Kim contributed equally to this work.

Authors and Affiliations

  1. College of Pharmacy and Graduate School of Pharmaceutical Sciences, Ewha Womans University, Seoul, 03760, Korea

    Seo-A Choi, Jung Sun Kim, Yoon-A Park, Da Hoon Lee, Minju Park & Hye Sun Gwak

  2. School of Pharmacy, Sungkyunkwan University, Suwon, 16419, Korea

    Jeong Yee

  3. Department of Neurology, Ewha Womans University Mokdong Hospital, Ewha Womans University College of Medicine, Seoul, 07985, Korea

    Yoonkyung Chang

  4. Department of Neurology, Ewha Womans University Seoul Hospital, Ewha Womans University College of Medicine, Seoul, 07804, Korea

    Tae-** Song

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  1. Seo-A Choi
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Contributions

All the authors have made substantial contributions to the conception of the study. SAC, JSK, TJS, and HSG contributed to designing the study. YC and TJS contributed to material preparation and YAP, DHL, MP and JY contributed to data collection. SAC and JSK performed data analysis and interpretation. SAC and JSK contributed to the drafting of the manuscript. TJS and HSG contributed to the critical revision of the manuscript. All authors approved the final manuscript.

Corresponding authors

Correspondence to Tae-** Song or Hye Sun Gwak.

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Ethics Approval

The study was conducted in accordance with the Declaration of Helsinki, and the protocol was approved by the Ethics Committee of Ewha Womans University Seoul Hospital and Ewha Womans University Mokdong Hospital (IRB number: 2020-11-014 and 2021-02-026, respectively).

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All authors approved the final manuscript and the submission to this journal.

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Written informed consent was obtained from all patients.

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The authors declare no competing interests.

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Choi, SA., Kim, J.S., Park, YA. et al. Transporter Genes and statin-induced Hepatotoxicity. Cardiovasc Drugs Ther (2024). https://doi.org/10.1007/s10557-024-07580-2

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