Examination of the TPMT and NUDT15*3 Variants to Predict the Response to Thiopurines in an Italian Cohort of Patients with Inflammatory Bowel Disease

Thiopurines are employed in inflammatory bowel diseases (IBDs; Crohn's disease, CD; ulcerative colitis, UC) to induce remission, prevent relapse, and reduce the steroid dosage, although they can sometimes be ineffective and present side effects. Genetic variations in the <i>TPMT</i> and <i>NUDT15</i> genes are well recognized to influence the therapeutic response, despite notable regional differences in their frequencies across various ethnic populations. Herein, the risk haplotypes TPMT*3A, *3B, *3C, and the variant NUDT15*3 were examined in a retrospective cohort of 383 Italian IBD patients who received azathioprine or 6-mercaptopurine. <i>TPMT</i> and <i>NUDT15</i> genotyping was performed by Sanger sequencing and TaqMan allelic discrimination, respectively. Allelic and genotype frequencies and genotype-phenotype correlations in non-responder and intolerant patients were assessed in comparison to responders. In total, 17% of patients did not respond to treatment, while 20% experienced adverse events, with leukopenia found in 13% of patients. TPMT haplotypes were found in 3.1% of patients, and 1.6% had the NUDT15*3 variant. CD patients with leukopenia had a higher frequency of the <i>TPMT</i> risk haplotype (40% vs. 4%, <i>p</i> = 0.024). Although additional validation through larger prospective studies or meta-analyses is needed, our findings support the importance of <i>TPMT</i> gene-variant assessment for forecasting azathioprine-related leukopenia in Italian IBD patients.