Pharmacogenomics of infliximab therapy, impact of TNFRSF1A and TNFRSF1B gene polymorphisms

Introduction. Anti-TNF alpha monoclonal antibodies present an effective way of treating Crohn's disease ( CD). Despite their high benefits, there is about 30% rate of a primary non-response. The main target of infliximab is the soluble form of TNF alpha, which blocks its pro-inflammatory activity and the induction of apoptosis via the TNF alpha membrane form. The activity of TNF alpha and balance between its pro-inflammatory and pro-apoptotic effect is mediated by the interaction with its receptors (TNFR). Mechanisms of signaling via TNF alpha-TNFR interaction has been recently intensively studied from a perspective of selecting appropriate candidates for the infliximab treatment. Aim. The aim of this study was to evaluate whether polymorphisms in TNFRSF1A and TNFRSF1B genes influence the efficacy of the infliximab therapy. Methods. A total of 116 Caucasian CD patients treated with infliximab were genotyped. After initial 10 weeks of the infliximab therapy, effectiveness was determined and patients were divided into responders (n=98) and non-responders (n=18). Genotypes TNFRSF1A (T4672G, G3794C) and TNFRSF1B (T11695C, T587G) were determined by PCR-RFLP. Results. Frequencies of variant alleles of TNFRSF1A were comparable between responders and non-responders. Variant allele TNFRSF1B 11695C was more common in non-responders (41.7% vs. 30.1%). Similarly, the frequency of TNFRSF1B 587G allele in non-responders was 33.3% vs. 18.9% in responders. Homozygotes for variant alleles of TNFRSF1B 11695C were found more often (P=0.013; OR 5.89, CI 95% 1.6-22.1) in non-responders (n=5, 27.8%) than in responders (n=6, 6.1%). Our results imply that TNFRSF1B 11695C variant allele is associated with a low therapeutic effect of infliximab.