ITPA polymorphisms do not predict additional risk beyond TPMT and NUDT15 for thiopurine-induced cytopenia in inflammatory bowel disease

Abstract

Introduction and aim: Thiopurine-related leukopenia is associated with polymorphisms in the thiopurine methyltransferase (TPMT) and nucleoside diphosphate-linked moiety X type motif 15 (NUDT15) genes. However, those polymorphisms explain only a fraction of thiopurine-related leukopenia. Our aim was to study the role of an inosine triphosphate pyrophosphatase (ITPA) polymorphism in patients with inflammatory bowel disease (IBD) and thiopurine-related leukopenia that was unexplained by the TPMT and NUDT15 polymorphisms.

Material and methods: We enrolled consecutive IBD patients on thiopurines (azathioprine or 6-mercaptopurine) from January 2019-March 2020, at a tertiary care center in North India. The presence of the ITPA (C.94C > A) polymorphism was evaluated in all patients, along with its association with thiopurine-related leukopenia.

Results: Of the 33 patients (from a total of 119 patients) that developed leukopenia, 8 had the TPMT (n = 1) or NUDT15 (n = 7) polymorphism. Of the remaining 111 patients, their mean age was 36.36 ± 13.54 years and 57 (51.3%) were males. Twenty-five (21.01%) had unexplained leukopenia. The ITPA polymorphism was detected in 4 (16%) patients in the unexplained leukopenia group and 24 (27.9%) patients in the non-leukopenia group (p = 0.228). The odds ratio for predicting leukopenia with the ITPA polymorphism was 0.4921 (95% CI 0.1520-1.5830, p = 0.234).

Conclusion: The ITPA (C.94C > A) polymorphism was frequently detected in the study population but was not predictive for leukopenia in patients with IBD on thiopurine therapy.

Keywords: 6-mercaptopurina; 6-mercaptopurine; Azathioprine; Azatioprina; Colitis ulcerosa; Crohn’s disease; Enfermedad de Crohn; Enfermedad inflamatoria intestinal; Inflammatory bowel disease; Ulcerative colitis.