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

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.

Automated summary

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.