Background: Thiopurine-methyltransferase (TPMT) polymorphisms have been investigated for decades, notably after the toxicity of azathioprine (AZA), a commonly used drug in the treatment of inflammatory bowel diseases (IBD), was recognized. Other genes have also been accused of AZA-related side effects, as well as concomitant therapy. The aim of our study was to investigate a relationship between the most common TPMT polymorphisms, AZA side-effects and concomitant therapy that is regularly applied in IBD, in a cohort of Croatian IBD patients.
Methods: The most prevalent TPMT-gene polymorphisms (TPMT*2, *3A, *3C) were investigated using validated Real-time PCR method, TaqMan® Drug Metabolism Genotyping Assays. The use of azathioprine, its side effect and the use of concomitant therapy (aminosalicylates, corticosteroids and anti-TNF) were assessed retrospectively, using patients' medical records. The statistical package “R” was used for the analysis. A statistical significance was set at p<0.5.
Results: 451 IBD patients were included in the study (48.7% female pts, 51.2% male pts; 66.51% MC pts, 33.48% UC pts). None of the patients was homozygous for any of the investigated TMPT polymorphism. 95.3% of patients had a wild-type gene, 0.4%, 3.3% and 0.9% of patients were heterozygous for TPMT*2, TPMT*3A and TPMT *3C, respectively. 58.3% patients received azathioprine therapy. 61.1%, 28.6% and 2.2% patients concomitantly received aminosalicylates, corticosteroids and anti-TNF therapy, respectively. 14.2% patients developed side-effects (13.68% myelotoxicity 7.6% hepatotoxicity and 8.3% pancreatic toxicity). In a regression model, with AZA-related side-effects as outcome variable and TPMT genotype, diagnosis, gender, concomitant aminosalicylates, corticosteroids and anti-TNF therapy as predictive variables, only TPMT genotype was statistically significantly related to AZA side-effects (p=0.0372). Out of three investigated polymorphisms, in the post-hoc analysis only TPMT*3A appeared statistically significantly related to AZA side-effects (p=0.0036).
Conclusions: AZA-related toxicity is related to polymorphic versions of TPMT gene in a Croatian IBD cohort; statistically significantly to TPMT*3A allelic variant. We found no influence of concomitant therapy – either aminosalicylate, corticosteroid or anti-TNF - on AZA-related toxicity.