4.7 Article

Association of genetic variants in TPMT, ITPA, and NUDT15 with azathioprine-induced myelosuppression in southwest china patients with autoimmune hepatitis

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SCIENTIFIC REPORTS
卷 11, 期 1, 页码 -

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NATURE PORTFOLIO
DOI: 10.1038/s41598-021-87095-0

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  1. Science and Technology Agency of Sichuan Province [2019YFS0287]

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The study confirmed that NUDT15 variants are potential independent risk predictors for AZA-induced leukopenia and neutropenia, while TPMT*3C and ITPA variants are not significantly associated with myelosuppression. Additionally, BMI may be a crucial non-genetic factor that affects the concentration of AZA metabolites and myelosuppression.
This study aimed to investigate the influence of TPMT*3C, ITPA, NUDT15, and 6-thioguanine nucleotides (6-TGN) on azathioprine (AZA)-induced myelosuppression in Southwest China patients with autoimmune hepatitis (AIH). A total of 113 Chinese patients with AIH receiving AZA maintenance treatment were evaluated. The relevant clinical data of the patients were collected from the hospital information system. Genotyping of TPMT*3C(rs1142345), ITPA (rs1127354) and NUDT15(rs116855232) was conducted using a TaqMan double fluorescent probe. The concentration of 6-TGN was determined using UPLC-MS/MS. Among AIH patients treated with AZA, 40 (35.4%) exhibited different degrees of myelosuppression. The NUDT15 variant was associated with leukopenia (P=8.26 x 10(-7); OR=7.5; 95% CI 3.08-18.3) and neutropenia (P=3.54 x 10(-6); OR=8.05; 95% CI 2.96-21.9); however, no significant association with myelosuppression was observed for TPMT*3C and ITPA variants (P>0.05). There was no significant difference in 6-TGN concentration between AIH patients with or without myelosuppression (P=0.556), nor was there a significant difference between patients with variant alleles of TPMT*3C, ITPA, or NUDT15 and wild-type patients (P>0.05). Interestingly, it was found that patients with a lower BMI had higher adjusted 6-TGN levels and a higher incidence of myelosuppression (P=0.026 and 0.003). This study confirmed that NUDT15 variants are a potential independent risk predictor for AZA-induced leukopenia and neutropenia. BMI may be a crucial non-genetic factor that affects the concentration of AZA metabolites and myelosuppression. In addition, the 6-TGN concentration in red blood cells does not reflect the toxicity of AZA treatment, and new biomarkers for AZA therapeutic drug monitoring need further research.

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