Frequency of thiopurine methyltransferase variants and exploratory predictors of azathioprine-induced leukopenia in Saudi patients with inflammatory bowel disease

Background: Azathioprine, a common inflammatory bowel disease (IBD) treatment, carries a myelosuppression risk, particularly leukopenia. Thiopurine methyltransferase (TPMT) genotyping can predict azathioprine-induced leukopenia (AIL), but data on TPMT polymorphisms in Saudi IBD patients are scarce. We aimed to determine the frequency of TPMT genotype variations in adult Saudi IBD patients and its association with AIL. Methods: We conducted a retrospective analysis including 90 adult IBD patients treated with azathioprine. TPMT genotyping focused on *2, *3A, 3B, and 3C alleles. Patient demographics, clinical data, and azathioprine-related adverse events were extracted. Univariate and multivariate logistic regression identified leukopenia predictors. Results: The TPMT wild-type genotype (*1/*1) was predominant (98%), with only two patients (2.2%) having the heterozygous *1/*3C genotype. Leukopenia occurred in 13% of the cohort, with the higher, though not statistically significant (P = 0.054), incidence in heterozygous patients (50%) versus wild-type (12.5%). Lower hemoglobin (OR = 0.70, P = 0.039) and platelet counts (OR = 0.982, P = 0.005) were significant predictors of leukopenia in wild-type patients. No significant associations were found with age, gender, IBD type, or concomitant therapies. Conclusions: TPMT variants were rare in this Saudi IBD cohort, consistent with other Asian populations, which limited the ability to assess their clinical impact. The observed leukopenia in variant carriers is descriptive only and should be interpreted with caution. In contrast, lower hemoglobin and platelet counts emerged as important predictors of AIL among wild-type patients. These findings highlight the importance of comprehensive hematological monitoring and support the need for future research incorporating additional pharmacogenetic markers such as NUDT15.