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The interferon gamma receptor 1 (IFNGR1) –56C/T gene polymorphism is associated with increased risk of early gastric carcinoma

P Canedo^1,2, G Corso³, F Pereira¹, N Lunet⁴, G Suriano¹, C Figueiredo^1,2, C Pedrazzani³, H Moreira², H Barros⁴, F Carneiro^1,2, R Seruca^1,2, F Roviello³, J C Machado^1,2

¹ Institute of Molecular Pathology and Immunology of the University of Porto, Porto, Portugal
² Faculty of Medicine, Porto, Portugal
³ Department of Human Pathology and Oncology, Surgical Oncology Unit, University of Siena, Istituto Toscano Tumori, Siena, Italy
⁴ Department of Hygiene and Epidemiology, Faculty of Medicine, Porto, Portugal

Dr J C Machado, IPATIMUP, Rua Dr Roberto Frias, s/n, 4200-465 Porto, Portugal; josem{at}ipatimup.pt

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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