Abstract
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 × 10–7; OR = 7.5; 95% CI 3.08–18.3) and neutropenia (P = 3.54 × 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.
Highlights
This study aimed to investigate the influence of Thiopurine methyltransferase (TPMT)*3C, Inosine triphosphate pyrophosphatase (ITPA), NUDT15, and 6-thioguanine nucleotides (6-TGN) on azathioprine (AZA)-induced myelosuppression in Southwest China patients with autoimmune hepatitis (AIH)
ITPA catalyses the hydrolysis of inosine triphosphate (ITP) into inosine monophosphate (IMP) and protects cells from DNA damage induced by accumulated non-canonical nucleotides
The most recent Clinical Pharmacogenetics Implementation Consortium (CPIC) publication includes dosing guidelines based on TPMT and NUDT15 metabolizer status[22], they mainly apply to AZA treatment in ALL and inflammatory bowel disease (IBD) patients
Summary
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). 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). A 2014 study on thiopurinerelated leukopenia in patients with inflammatory bowel disease (IBD) found that the NUDT15 c.415C>T gene mutation is closely related to AZA-induced leukopenia[11]. There has not been a comprehensive assessment of the relationship between AZA toxicity and genetic variants of TPMT*3C T>C, ITPA 94C>A, and NUDT15 c.415C>T in patients with AIH in Southwest China
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