Significance of interleukin-1 beta and interleukin-1 receptor antagonist genetic polymorphism in inflammatory bowel diseases

Objective: Genetic susceptibility to inflammatory bowel disease is well recognized. There is also increasing evidence for the activation of the mucosal immune system and the production of inflammatory cytokines, i.e., interleukin (IL)-1ra and IL-1 beta in the inflammatory bowel disease. The aim of this study was to analyze the IL-1 beta and IL-1ra gene polymorphism and Linkage disequilibrium coefficient between the different alleles of these genes in patients with Crohn's disease (CD) or ulcerative colitis (UC), according to the severity of the disease. Methods: Two hundred twenty-eight inflammatory bowel disease patients (87 UC and 141 CD) were included in this study and compared with 113 unrelated controls. The IL-1 beta and IL-1ra gene polymorphism was studied after specific amplification of variable regions by PCR. A penta-allelic polymorphism, corresponding to a VNTR region located in intron 2 of the IL-1ra gene, was analyzed, whereas bi-allelic RFLPs displayed by two restriction enzymes (TaqI and AvaI) at position -511 of the IL-1 beta gene were analyzed. Results: There was no significant difference of genotype distribution between controls and CD or UC patients. However, surgically treated UC patients were characterized by a higher frequency of genotype IL-1ra 1-2 (39 vs 16%, pc < 0.01) compared with nonoperated UC patients. Moreover, nonoperated UC patients displayed a lower frequency of IL-1ra allele 2 than surgically treated UC patients (14 vs 34%, pc < 0.002) or controls (14 vs 30%, pc < 0.005). Furthermore, simultaneous analysis of the IL-1 beta and IL-lra genes that are located in the same region of chromosome 2 revealed that CD patients carrying the IL-1 beta allele 2 were more often noncarriers of IL-lra allele 2 ip < 0.005). Moreover, UC and CD patients were characterized by a lower frequency of the association of IL-lra allele 2 and IL-1 beta allele 2 compared with controls (8.3 vs 20.3% and 10.6 vs 20.3%, p < 0.03). Conclusions: IL-1ra and IL-1 beta gene polymorphism analysis from a clinical standpoint might help in defining UC prognosis. However, functional studies al both the circulating and mucosal level with stratification on allele associations, especially IL-1ra allele 2-IL-1 beta allele 2 subgroups must be realized before therapeutic implications.