Association of the ILR1 and FAS genes variants with a primary non-response to Anti-TNF therapy in Crohn's disease patients

ABSTRACT

Introduction: Crohn's disease (CD) is a chronic inflammatory disease characterized by an uncontrolled immune response by the intestinal mucosa cells to antigens derived from the gut lumen. Specifically, the introduction of anti-TNF drugs changed the approach to inflammatory bowel disease (IBD) treatment and set new therapeutic goals as controlling clinical symptoms while simultaneously achieving complete endoscopic and mucosal remission. Mechanism of action of – and therefore mechanisms of resistance to anti-TNF therapy are unknown.

Objectives: Our research is an attempt to answer whether the potential mechanism of non-responders may be conditioned by polymorphisms in genes involved in independent inflammatory or apoptotic pathways.

Patients and methods: The study included 196 diagnosed and clinically characterized CD Polish patients following anti-TNF therapy. Variants rs7539036, rs2041747, rs5746053, rs5746054, rs1061624, rs1143634, rs7896789, and rs55790676 of the FCGR3A, IL1R, TNFRSF1B, IL1B, FAS, and ADAM17 genes, respectively, were genotyped using Sanger sequencing and were analysed with the response to biological treatment.

Results: We observed that 33 patients (16.8%) did not respond to the induction therapy, which was associated with the ILR1 rs2041747 G allele (OR 3.72, P = 0.009). Moreover, the FAS rs7896789 CC homozygote related with increased susceptibility to anti-TNF therapy nonresponse (OR 15.22, P = 0.003) and TT might act as the protective genotype.

Conclusions: In CD patients' response to anti-TNF therapy, complex pathways with multigene conditioning participate. Genes involved in apoptosis, FAS, and ILR1, seem to play here an essential role, and are an interesting object for further, population and functional, research.