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P362. Pharmacogenetics study of TPMT and ITPA genes in patients with inflammatory bowel disease treated with azathioprine detects relation between ITPase deficiency and clinical response

M. Barreiro-de Acosta1, W. Zabala-Fernández2, A. Echarri3, D. Carpio4, A. Lorenzo1, J. Castro3, S. Pereira5, D. Martínez-Ares5, I. Martin-Granizo5, M. Cordón2, A. Carracedo2, F. Barros2

1University Hospital, Santiago de Compostela, Spain; 2Fundación Pública Galega de Medicina Xenómica, Santiago de Compostela, Spain; 3Arquitecto Marcide, Ferrol, Spain; 4CHOP, Pontevedra, Spain; 5CHUVI, Vigo, Spain

Aim: Pharmacogenetic studies in inflammatory bowel diseases (IBD) are mainly focused on genes involved in the metabolism of Azathioprine (AZA). Use of AZA is limited by lack of response (40%) and toxicity, which occurs in 20% of patients. Variants in the Thiopurine S-methyltransferase (TPMT) and Inosine triphosphate pyrophosphatase (ITPA) genes have been associated with AZA toxicity, but also can contribute to lack of response. The aim of our study was to determine the contribution of TPMT and ITPA variants in the development of AZA-related toxicity and response.

Material and Methods: This retrospective, multicenter study included patients with IBD who had been taking AZA for at least 6 months or who had experienced adverse effects during treatment. Patients were classified as cases and control based on the side effects developed after AZA treatment. Genotyping was made for gene polymorphisms that reduce TPMT and ITPA activities, selecting the following variants: c.238G>C, c.460G>A and c.719A>G in the TPMT gene and c.94C>A and IVS2+21A>C polymorphisms in the ITPA gene. The association between adverse effects and TPMT and ITPA polymorphisms was tested using two-sided Fisher's exact test; odds ratios and 95% confidence intervals were calculated.

Results: Two hundred and thirty-two IBD patients were included, 156 Crohn's disease (67.24%) and 76 ulcerative colitis (32.76%); mean age was 32.66 years, with similar distribution between genders. All patients received doses of AZA ranging from 1.5–3 mg-kg-day with a median of 2.32 mg-kg-day. According to toxicity, 75 (32%) patients presented side effects to AZA; the most frequent were pancreatitis, digestive intolerance, myelosuppression, skin reaction, arthralgia and hepatotoxicity. Regarding the TPMT polymorphism 217 individuals carried wild-type alleles, no mutant alleles were found in homozygosis, and only 15 mutant alleles were found. Concerning the c.94C>A variant of the ITPA gene, 210 individuals were homozygous for the wild-type allele, 22 were heterozygous, and no homozygous for the mutant allele were found. With respect to response, there was a statistically significant association between the variant c.94C>A in the ITPA gene and lack of response (p = 0.005). We found significant association between TPMT variants and myelosuppression (OR 7.5; 95%CI 1.4456–38.91, p = 0.0304), and between arthralgia and the variant c.94C>A in the ITPA gene (OR = 8.235, CI95% 1.752–38.87, p = 0.0041). No significant differences were found after comparing the frequencies of the TPMT and ITPA variants in patients with others side effects.

Conclusions: There is positive correlation between c.94C>A variant on ITPA with lack of clinical response. Mutant alleles on TPMT and the variant c.94C>A on ITPA gene predicted the onset of side effects induced by AZA in our population (myelosuppression and arthralgia respectively).