Aims: Azathioprine (AZA) is commonly used to treat autoimmune diseases, but its applications have been limited due to significant adverse effects, particularly leukopenia. The aim of this study was to investigate the associations of NUDT15, TPMT, and inosine triphosphatase (ITPA) polymorphisms with AZA-induced toxicity. Materials and Methods: A total of 86 Chinese patients with autoimmune diseases were recruited, and the NUDT15*2-*6, TPMT*3C, and ITPA rs7270101 genotypes of these patients were characterized by Sanger sequencing. Sociodemographic data and clinical records over a period of 6 months were also collected. Results: The TPMT*3C and NUDT15*3 genotypes were significantly associated with AZA-induced leukopenia (p = 0.007 and 4.475 × 10^-6, respectively). The p-value for the correlation between ITPA rs7270101 and leukopenia was 0.059. In addition, NUDT15*3 was significantly associated with gastrointestinal effects, erythropenia, hypochromia, and thrombocytopenia [p = 0.002, 1.109 × 10^-5, 1.653 × 10^-7, and 9.110 × 10^-6, respectively; allelic odds ratio (95% confidence interval): 5.714 (1.56-20.95), 9.333 (2.96-29.47), 13.18 (4.15-41.87), and 20.13 (3.40-119.18), respectively]. The TPMT*3C genotypes were also significantly associated with gastrointestinal discomfort [p = 0.028, 12.08 (0.71-204.49)], alopecia [p = 2.864 × 10^-4, 33 (1.80-606.47)], and hypochromia [p = 0.045, 10.33 (0.61-173.66)]. Conclusion: This study demonstrated that NUDT15*3 and TPMT*3C are both highly predictive genetic markers for AZA-induced toxicity in Chinese populations with rheumatic diseases.

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