Functional Promoter -308G>A Variant in Tumor Necrosis Factor α Gene Is Associated with Risk and Progression of Gastric Cancer in a Chinese Population

Abstract

BackgroundTumor necrosis factor-α (TNF-α) plays a crucial role in the development and progression of gastric cancer. A functional polymorphism, -308 G>A (rs1800629), which is located in the promoter of TNFA gene, has been suggested to alter the production of TNF-α and influence cancer risk. In the present study, we sought to investigate whether this polymorphism has effects on the risk and progression of gastric cancer in a Chinese population.MethodsWe genotyped the TNFA -308 G>A polymorphism using the TaqMan method in a two-stage case-control study comprising a total of 1686 gastric cancer patients and 1895 cancer-free subjects. The logistic regression was used to assess the genetic associations with occurrence and progression of gastric cancer.ResultsWe found a significant association between the variant genotypes and increased risk of gastric cancer [P = 0.034, odds ratio (OR) = 1.39, 95% confidence interval (CI) = 1.01–1.67, GA/AA vs. GG]. Similar results were observed in the follow-up replication study. When combined the data from the two studies, we found a more significant association (P = 0.001, OR = 1.34, 95%CI = 1.13–1.59), especially for older subjects (>65 years). Furthermore, the patients carrying the variant genotypes had a significantly greater prevalence of T4 stage of disease (P = 0.001, OR = 2.19, 95%CI = 1.39–3.47) and distant metastasis (P = 0.013, OR = 1.61, 95%CI = 1.10–2.35).ConclusionsOur results suggest that the functional promoter -308 G>A polymorphism in TNFA influence the susceptibility and progression of gastric cancer in the Chinese population.

Role of TNF-α -308G/A gene polymorphism in gastric cancer risk: A case control study and meta-analysis

“…However, other reports from Beijing (10) and Hubei province (7) showed a lower prevalence of heterozygous mutations (8-9%). Interestingly, the distribution of TNF-α (-308G>A) genotypes deviated from HWE in all earlier reports including the present study in a Chinese population (7)(8)(9)(10)(11)(12)(13)36). Deviation of a genotype distribution from HWE has been attributed to genotyping error, population stratification, or selection pressure.…”

“…The filled diamond represents the combined odds ratio and 95% confidence interval Table 6. Statistics to test publication bias and heterogeneity in the meta-analysis (Caucasians) controls from Hubei province (9,36), Henan province (13), Taiwan (11,12) and Nanjing (8). However, other reports from Beijing (10) and Hubei province (7) showed a lower prevalence of heterozygous mutations (8-9%).…”

“…Deviation of a genotype distribution from HWE has been attributed to genotyping error, population stratification, or selection pressure. The present study and earlier reports enrolled controls from an ethnic group and employed robust genotyping methods (7)(8)(9)(10)(11)(12)(13)36). Deviation from HWE is possibly due to prevalence of various infectious diseases in Chinese populations, which applies selection pressure on the human genome (41).…”

“…Various studies have been conducted in different populations of China to identify a possible association of TNF-α -308G>A with the development of GC (7)(8)(9)(10)(11)(12)(13)36). Most of the studies showed an association of variants with susceptibility to GC.…”

“…An association of TNF-α -308G>A (rs1800629) with susceptibility/resistance to GC development has been widely investigated and yielded conflicting results. Studies including GC patients and controls from China (7)(8)(9)(10)(11)(12)(13)(14), Brazil (15,16), Portugal (17,18), United States (19), Poland (20), South Korea (21-23), Honduras (24), Italy (25), Colombia (26), and Japan (27) have been associated with susceptibility to GC development. However, other studies including those from India (28), Brazilian (29,30), Romania (31), Spain (32,33), South Korea (34,35), China (36), Mexico (37), Germany (38) and Finland (39) failed to show a possible link between the TNF-α (-308G>A) polymorphism and GC.…”