The role of TNF genetic variants and the interaction with cigarette smoking for gastric cancer risk: a nested case-control study

Background: The aim of this study was to investigate the role of TNF genetic variants and the combined effect between TNF gene and cigarette smoking in the development of gastric cancer in the Korean population. Methods: We selected 84 incident gastric cancer cases and 336 matched controls nested within the Korean Multi-Center Cancer Cohort. Six SNPs on the TNF gene, TNF-alpha-238 G/A, -308 G/A, 857 C/T, -863 C/A, -1031 T/C, and TNF-beta 252 A/G were genotyped. The ORs (95% CIs) were calculated using unconditional logistic regression model to detect each SNP and haplotype-pair effects for gastric cancer. The combined effects between the TNF gene and smoking on gastric cancer risk were also evaluated. Multi dimensionality reduction (MDR) analyses were performed to explore the potential TNF gene-gene interactions. Results: TNF-alpha-857 C/T containing the T allele was significantly associated with an increased risk of gastric cancer and a linear trend effect was observed in the additive model (OR = 1.6, 95% CI 1.0-2.5 for CT genotype; OR = 2.6, 95% CI 1.0-6.4 for TT genotype). All haplotype-pairs that contained TCT or CCC of TNF-alpha-1031 T/C, TNF-alpha-863 C/A, and TNF-alpha-857 C/T were associated with a significantly higher risk for gastric cancer only among smokers. In the MDR analysis, regardless of smoking status, TNF-alpha-857 C/T was included in the first list of SNPs with a significant main effect. Conclusion: TNF-alpha-857 C/T polymorphism may play an independent role in gastric carcinogenesis and the risk for gastric cancer by TNF genetic effect is pronounced by cigarette smoking.