NUDT15 Haplotypes and Diplotypes Predict Thiopurine-Induced Leukopenia and the Influence of Prolonged Exposure to Azathioprine on Hematologic Indices in Patients with Inflammatory Bowel Diseases

Abstract

Background. NUDT15 gene polymorphisms have been identified to predispose Asian patients with an inflammatory bowel disease (IBD) to thiopurine-induced leukopenia. This study predicted the influence of NUDT15 haplotypes and diplotypes on azathioprine (AZA)-induced leukopenia as well as the long-term influence of AZA on hematologic parameters in IBD. Methods. 194 IBD patients were tested for NUDT15 genotypes. We collected clinical data of 80 patients with AZA treatment including adverse events, dosage, white blood cell (WBC) count, platelet (PLT) count, and mean corpuscular volume (MCV) after AZA initiation. Patients without adverse events and drug withdrawal were followed up for at least one year. The relationship between NUDT15 haplotypes and diplotypes and leukopenia was analyzed. Results. The haplotypes NUDT15 c.415C > T and c.36_37insGGAGTC as well as the diplotypes NUDT15 ${}^{\ast }$ 1/ ${}^{\ast }$ 2, ${}^{\ast }$ 3/ ${}^{\ast }$ 3, and ${}^{\ast }$ 3/ ${}^{\ast }$ 5 were significantly associated with AZA-induced leukopenia. Only one patient with NUDT15 c.52G > A experienced leukopenia. NUDT15 ${}^{\ast }$ 1/ ${}^{\ast }$ 3 was not associated with leukopenia. After AZA initiation, the WBC count showed a downward trend in both wild types and mutants. The mean of WBC count in the mutant group at 1st month after AZA initiation was lower than that in the wild-type group ( $P=0.006$ ). The MCV increased gradually in mutant cases ( $P=0.039$ ), and the differences were obvious at 6th and 12th months compared with the baseline ( $P=0.014\mathrm{a}\mathrm{n}\mathrm{d}P=0.042$ , respectively). The PLT count showed a decreasing trend in the mutant group, but there was no difference until 11 months after initiating treatment ( $P=0.023$ ). The final dose of AZA in the NUDT15 mutant group was significantly lower than that in the wild-type group ( $P=0.006$ ). Conclusion. NUDT15 polymorphisms may be an appropriate predictor of AZA abnormal hematologic indices in IBD patients. It is necessary for IBD patients to monitor hematological indices and optimize AZA therapy.