It has been speculated thatIL-1genes play a crucial role in the genetic predisposition to duodenal ulcer uponH. pyloriinfection by modulating the host immune response. In the present study, 310 individuals from Eastern India were subjected to a case-control study to determine theIL1BandIL1RNrisk genotypes toH. pylorimediated duodenal ulcer. An analysis of genotype frequency revealed a significantly higher frequency ofIL1B -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 inH. pylori-infected individuals with duodenal ulcer compared to infected individuals with normal mucosa. Moreover, the T/C haplotype ofIL1B -511 andIL1B -31 loci was present in a significantly higher frequency inH. 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 amongH. 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. AnIL1Bpromoter activity assay showed that the promoter with -31T had a 10-fold increase in activity compared to the one with -31C. TheIL1Bpromoter bearing the different combinations of both polymorphic loci showed an interaction between the -511 and -31 loci. Our results show thatH. pyloriinfected 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 theIL1Bpromoter. Hum Mutat 27(5), 411-419, 2006. © 2006 Wiley-Liss, Inc.