Association of the ILR1 and FAS gene variants with primary nonresponse to anti–tumor necrosis factor therapy in patients with Crohn disease

Abstract

INTROduCTION Crohn disease (CD) is a chronic inflammatory disease characterized by an uncontrolled immune response of the intestinal mucosal cells to antigens derived from the gut lumen. Specifically, the introduction of anti–tumor necrosis factor (TNF) drugs has changed the approach to the treatment of inflammatory bowel disease, and set new therapeutic goals, such as that of controlling clinical symptoms while simultaneously achieving complete endoscopic and mucosal remission. The mechanisms of action of anti‑TNF drugs—and consequently the mechanisms of resistance to anti‑TNF therapy—are unknown. ObjECTIvEs Our study was an attempt to discover whether the potential mechanism of nonresponse may be conditioned by polymorphisms in the genes involved in independent inflammatory or apoptotic pathways. PATIENTs ANd mEThOds The study included 196 diagnosed and clinically characterized Polish patients with CD treated with anti‑TNF therapy. Variants rs7539036, rs2041747, rs5746053, rs5746054, rs1061624, rs1143634, rs7896789, and rs55790676 of the FCGR3A, IL1R, TNFRSF1B, IL1B, FAS, and ADAM17 genes were genotyped using Sanger sequencing, and analyzed in the context of response to biologic treatment. REsuLTs We observed that 33 patients (16.8%) did not respond to the therapy, which was associated with carrying the rs2041747 G allele variant of the ILR1 gene (odds ratio [OR], 3.72; P = 0.009). Moreover, the presence of the FAS rs7896789 homozygous CC genotype correlated with increased susceptibility to the lack of response to the anti‑TNF therapy (OR, 15.22; P = 0.003), whereas TT was identified as a potentially protective genotype. CONCLusIONs In patients with CD treated with anti‑TNF drugs, complex pathways with multigene con‑ ditioning participate in the mechanism underlying treatment resistance. The genes involved in apoptosis, FAS and ILR1, seem to play an essential role in the lack of response to the treatment, and would be interesting objects of further population and functional research.