Interaction between IL1B gene promoter polymorphisms in determining susceptibility to Helicobacter pylori associated duodenal ulcer

Abstract

It has been speculated that IL-1 genes play a crucial role in the genetic predisposition to duodenal ulcer upon H. pylori infection by modulating the host immune response. In the present study, 310 individuals from Eastern India were subjected to a case–control study to determine the IL1B and IL1RN risk genotypes to H. pylori mediated duodenal ulcer. An analysis of genotype frequency revealed a significantly higher frequency of IL1B −511TT (NT_022135.14:g.2302610C>T), OR=4.22 (95% CI=1.8−9.4) and −31CC (NT_022135.14:g.2302130C>T), OR=2.16 (95% CI 1.12−4.15) genotypes in H. pylori-infected individuals with duodenal ulcer compared to infected individuals with normal mucosa. Moreover, the T/C haplotype of IL1B −511 and IL1B −31 loci was present in a significantly higher frequency in H. pylori-infected duodenal ulcer patients than in infected controls (OR=2.47, CI=1.27−4.8). Quantitative analysis of the mucosal IL1B mRNA revealed that among H. pylori-infected individuals, carriers of the −31CC genotype had significantly lower IL1B transcript levels than carriers of the CT (P<0.001) and TT (P<0.001) genotypes, independently of disease status. An IL1B promoter activity assay showed that the promoter with −31T had a 10-fold increase in activity compared to the one with −31C. The IL1B promoter bearing the different combinations of both polymorphic loci showed an interaction between the −511 and −31 loci. Our results show that H. pylori-infected individuals with the −31CC genotype secrete less IL1B and are susceptible to duodenal ulcers. They also suggest that the allelic interaction between the −511 and −31 polymorphic sites determines the overall strength of the IL1B promoter.