Background and aim: It has been demonstrated that polymorphisms within inflammation-related genes are associated with the risk of gastric carcinoma (GC) in people infected with Helicobacter pylori. Recently, polymorphisms in the gene encoding the interferon gamma receptor 1 (IFNGR1) were found to be associated with increased susceptibility to H pylori infection. We aimed to determine the association between polymorphisms in the IFNGR1 gene and development of chronic gastritis and GC.
Methods: In a case–control study including 733 controls, 213 patients with chronic gastritis and 393 patients with GC, the IFNGR1 −611*G/*A, −56*C/*T, +1004*A/*C and +1400*T/*C polymorphisms were genotyped. A second independent case–control study including 100 controls and 65 patients with GC was used for confirmation of the original results. The effect of the −56*C/*T promoter polymorphism in the level of expression of the IFNGR1 gene was evaluated by an IFNGR1 −56*C/*T allele specific luciferase reporter assay.
Results: In patients with early onset GC (defined as being less than 40 years of age at the time of diagnosis) we found a significant over-representation of the IFNGR1 −56*T/*T homozygous genotype with an odds ratio (OR) of 4.1 (95% confidence interval (CI) 1.6 to 10.6). This result was confirmed in a second independent case–control study. In the luciferase reporter assay we observed a 10-fold increase (p<0.001) in luciferase expression associated with the IFNGR1−56*T allele.
Conclusions: Our results indicate that the IFNGR1 −56C/T polymorphism is a relevant host susceptibility factor for GC development. Our data also indicate that this genetic polymorphism is functionally relevant and may be related to the early development of GC.
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Funding: This work was supported by (1) Fundação para a Ciência e Tecnologia (REEQ/218/SAU/2005, POCTI/SAU-ESP/56126/2004 and POCTI/SAU-ESP/61685/2004); (2) Programa Operacional Ciência, Tecnologia e Inovação (POCTI), by Fundo Comunitário Europeu (FEDER); (3) Programa Operacional de Saúde/SAUDE XXI; (4) Associação Portuguesa da Industria Farmacêutica (APIFARMA); (5) the Sixth Research Framework Programme of the European Union, Project INCA (LSHC-CT-2005-018704); and (6) a grant from Istituto Toscano Tumori (ITT) Region of Tuscany, Italy.
Competing interests: None.
Ethics approval: Approval for this study was given by the Medical Faculty of Porto in October 2002.