Association Between Genetic Polymorphisms of Metabolic Enzymes and Azathioprine-Induced Myelosuppression in 1,419 Chinese Patients: A Retrospective Study

Zhao-Yang Chen; Yang-Hui Zhu; Ling-Yan Zhou; Wei-Qiao Shi; Zhou Qin; Bin Wu; Yu Yan; Yu-Wen Pei; Ning-Ning Chao; Rui Zhang; Mi-Ye Wang; Ze-Hao Su; Xiao-Jun Lu; Zhi-Yao He; Ting Xu

doi:10.3389/fphar.2021.672769

Association Between Genetic Polymorphisms of Metabolic Enzymes and Azathioprine-Induced Myelosuppression in 1,419 Chinese Patients: A Retrospective Study

Front Pharmacol. 2021 May 18:12:672769. doi: 10.3389/fphar.2021.672769. eCollection 2021.

Authors

Zhao-Yang Chen¹, Yang-Hui Zhu¹, Ling-Yan Zhou¹, Wei-Qiao Shi¹, Zhou Qin¹, Bin Wu¹, Yu Yan¹, Yu-Wen Pei¹, Ning-Ning Chao², Rui Zhang³, Mi-Ye Wang³, Ze-Hao Su⁴, Xiao-Jun Lu⁵, Zhi-Yao He^{1

6}, Ting Xu^{1

6}

Affiliations

¹ Department of Pharmacy, State Key Laboratory of Biotherapy and Cancer Center, Med-X Center for Informatics, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, China.
² Institute of Respiratory Health, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, China.
³ Department of Information Center, Engineering Research Center of Medical Information Technology of the Education Ministry, West China Hospital, Sichuan University, Chengdu, China.
⁴ Med-X Center for Informatics, West China Hospital, Sichuan University, Chengdu, China.
⁵ Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, China.
⁶ Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, China.

Abstract

The aim of this study was to investigate the correlation between genetic polymorphisms of azathioprine-metabolizing enzymes and adverse reactions of myelosuppression. To this end, a retrospective analysis was performed on 1,419 Chinese patients involving 40 different diseases and 3 genes: ITPA (94C>A), TPMT*3 (T>C), and NUDT15 (415C>T). Strict inclusion and exclusion criteria were established to collect the relative cases, and the correlation between azathioprine and myelosuppression was evaluated by adverse drug reaction criteria. The mutation rates of the three genes were 29.32, 3.73, and 21.92% and grades I to IV myelosuppression occurred in 54 (9.28%) of the 582 patients who took azathioprine. The highest proportion of myelosuppression was observed in 5 of the 6 (83.33%) patients carrying the NUDT15 (415C>T) TT genotype and 12 of the 102 (11.76%) patients carrying the NUDT15 (415C>T) CT genotype. Only the NUDT15 (415C>T) polymorphism was found to be associated with the adverse effects of azathioprine-induced myelosuppression (odds ratio [OR], 51.818; 95% CI, 5.280-508.556; p = 0.001), which suggested that the NUDT15 (415C>T) polymorphism could be an influencing factor of azathioprine-induced myelosuppression in the Chinese population. Epistatic interactions between ITPA (94C>A) and NUDT15 (415C>T) affect the occurrence of myelosuppression. Thus, it is recommended that the genotype of NUDT15 (415C>T) and ITPA (94C>A) be checked before administration, and azathioprine should be avoided in patients carrying a homozygous NUDT15 (415C>T) mutation. This study is the first to investigate the association between genetic polymorphisms of these three azathioprine-metabolizing enzymes and myelosuppression in a large number of cases with a diverse range of diseases.

Keywords: ITPA; NUDT15; TPMT; adverse drug reaction; azathioprine; myelosuppression.