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Genetic Polymorphisms of SLCO1B1, CYP2E1 and UGT1A1 and Susceptibility to Anti-Tuberculosis Drug-Induced Hepatotoxicity: A Chinese Population-Based Prospective Case–Control Study

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Abstract

Background

Drug transporters and drug-metabolizing enzymes have been linked to drug-induced hepatotoxicity. Solute carrier organic anion transporter family member 1B1 (SLCO1B1), cytochrome P450 2E1 (CYP2E1), and UDP glucuronosyltransferase 1A1 (UGT1A1) were selected as candidate genes to explore their association with susceptibility to anti-tuberculosis drug-induced hepatotoxicity (ATDH).

Methods

Thirty-four tag single nucleotide polymorphisms (tagSNPs) in SLCO1B1, CYP2E1, and UGT1A1 with 10-kb expansion up- and down-stream were genotyped in 461 patients with ATDH and 466 patients without ATDH in a prospective 1:1 matched case–control study. The frequencies and distributions of genotypes and haplotypes were compared between the groups using three genetic models (dominant, recessive, and additive) to identify associations with susceptibility to ATDH.

Results

Patients with the rs4149034 G/A, rs1564370 G/C, and rs2900478 T/A genotypes of SLCO1B1 had a significantly lower risk of ATDH, while those carrying the rs2417957 T/T and rs4149063 T/T genotypes had an increased risk. The rs4148323 A/A genotype of UGT1A1 was found to significantly reduce the risk of ATDH. Haplotype analysis showed the TGTG, TTTC, and GTTC haplotypes of SLCO1B1 were associated with an increased ATDH risk, whereas the GACC haplotype was related to a reduced risk. The ATG haplotype of UGT1A1 reduced the risk of ATDH. Moreover, treatment outcomes in tuberculosis patients were further affected by genetic variants of SLCO1B1.

Conclusions

Genetic polymorphisms of SLCO1B1 and UGT1A1 were found to be associated with susceptibility to ATDH. Molecular identification of susceptibility genes provides a theoretical foundation for predicting the likelihood of ATDH and predicting treatment outcomes in tuberculosis patients.

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Acknowledgements

We specially acknowledge the technical assistance from Genesky Biotechnologies Inc. Shanghai, China. We also thank Medjaden Bioscience Limited for assisting in the preparation of this manuscript.

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Author notes

  1. Qin Sun and Hai-peng Liu contributed equally to this manuscript.

Authors and Affiliations

  1. Clinic and Research Center of Tuberculosis, Shanghai Key Laboratory of Tuberculosis, Shanghai Pulmonary Hospital, Tongji University School of Medicine, No. 507 Zhengmin Road, Yangpu District, Shanghai, 200433, China

    Qin Sun, Hai-peng Liu, Rui-juan Zheng, Peng Wang, Zhi-bin Liu, Wei Sha & He-ping Xiao

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  1. Qin Sun
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  2. Hai-peng Liu
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Corresponding author

Correspondence to Wei Sha.

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Funding

This study was supported by the National Nature Science Foundation of China (no. 81400006), the Shanghai Pujiang Program (no. 16PJD041), and the National Science and Technology Major Program (no. 2014ZX09507008).

Conflict of interest

The authors declare no conflict of interest.

Ethics approval

The present study was approved by the Ethics Committees of both Tongji University School of Medicine and Shanghai Pulmonary Hospital.

Informed consent

Written informed consent was received from patients.

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Sun, Q., Liu, Hp., Zheng, Rj. et al. Genetic Polymorphisms of SLCO1B1, CYP2E1 and UGT1A1 and Susceptibility to Anti-Tuberculosis Drug-Induced Hepatotoxicity: A Chinese Population-Based Prospective Case–Control Study. Clin Drug Investig 37, 1125–1136 (2017). https://doi.org/10.1007/s40261-017-0572-6

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