The Study On The Association Of NF-kappa B Signaling Pathway Related Genes SNPs And Environmental Inflammatory Factors With The Gastric Cancer

【Objective】To investigate the environmental inflammatory risk factors of gastric cancer; To find the relationship between polymorphism of NF-kappa B signaling pathway related genes and the susceptibility of different gastric cancer; To explore the interaction effects of NF-kappa B signaling pathway related gene-gene and gene-environmental factors.【Methods】1. Multiple case-control study was conducted with 335 patients and 961 control subjects. Patients were recruited from the Xianyou county hospital with histologically confirmed. Hospital control subjects were collected from Xianyou county hospital at the same period with patients and were matched to the cases on gender and age(±3year).The control subjects were excluding cancer, digestive tract diseases. Healthy control subjects were collected in same villages with cases. Eligible subjects were personally interviewed using a questionnaire and collected general information, diet habit, habits and customs and so on. Univariate and multivariate conditional logistic regression, classification tree model, crossover analysis method were used to identify the risk factors of gastric cancer and their interactioneffects.2. Molecular epidemiology method was used in this research. 5ml blood samples were collected from each case and control. The genomic DNA was extracted from all blood samples. The genotypes of polymorphisms were determined by Sequenom platform. Logistic regression was used to analyse the relationship between gene polymorphism and gastric cancer. Generalized multifactor dimensionality reduction,crossover analysis were used to identify the interation between gene-gene and gene-environmental risk factors.【Results】1. Two case-control studies consistent results of environmental inflammatory factors in univariate logistic regression:(1) Chemical inflammatory factors: drinking green tea, smoking, start smoking>20, smoking years> 30 years, daily smoking cigarettes≤ 20, using pesticides,using pesticides age≤ 18, often intake pickles, taste(salt), eating spicy food.(2) Physical inflammatory factors: eating soft food, often gluttony.(3) Biological inflammatory factors: the association of Helicobacter pylori infection and gastric cancer had not been found, P>0.05. The infection rate of HpⅠtype in gastric cancer group was higher than the control group, P>0.05, the infection rate were 46.9% and 32.6% respectively.2. Multivariate conditional logistic regression results and interaction analysis results:(1) Multivariate conditional logistic regression results: often intake pickles, using pesticides age> 18, using pesticides age≤ 18, eating hot food, eating spicy food, taste(salt), chronic atrophic gastritis were the risk factor of gastric cancer, the OR(95%CI)were3.31(1.23,8.91),3.36(1.40,8.10),4.39(1.85,10.39),4.13(1.85,9.20), 3.11(1.37,7.10),2.10(1.27,3.48) and 7.85(1.79,34.43) respectively.(2) the age of using pesticides was regarded as an important factor in the classification tree model; combined effect was showed between the using pesticides age≤ 18 and often intake pickles,eating spicy food, the OR(95%CI) were9.79(4.68,20.52),5.60(2.92,10.72) respectively; and positive additive interaction was showed between using pesticides and often intake pickles; combined effect was also showed between taste(salt) and often intake pickles, eating spicy food, the OR(95%CI) were 4.02(2.13,7.60), 2.18(1.32,3.59) respectively.3. Population attributable risk analysis, the order of the adjusted factors in population attributable risk was: using pesticides age≤ 18 > eating hot food > often intake pickles > eating spicy food > taste(salt) > chronic atrophic gastritis. the PARc% were 38.95%, 26.92%, 25.38%, 22.70%, 21.59%, 17.97%, and the s PAR%was 84.82%.4. The association was showed between NFKBIA(rs696), COX-2(rs689466,rs5275) gene polymorphisms and gastric cardia cancer, specially in individuals who was carried with rs696 AA, rs689466 AA,rs5275CC, OR(95%CI) were 2.23(1.10,4.55),2.04(1.29,4.55), 12.22(1.59,94.2). Combined effect was showed between rs696 AA and/or rs5275 CC, rs689466 AA and/or rs5275 CC, OR(95%CI) were 2.04(1.11,3.74),2.05(1.06,3.96); High risk with gastric cardia cancer was showed in COX-2 gene Ars689466Crs5275 haplotype, OR:1.58, 95%CI:1.13,2.01; The association was showed between NFKBIA(rs2233406), RELA(rs7119750) gene polymorphism and non cardia cancer, specially in individuals who was carried with rs2233406CT+TT,rs7119750 TT, OR(95%CI) were 1.65(1.01,2.71), 2.16(1.12,4.17). Combined effect was showed between rs2233406CT+TT and/or rs7119750 TT, OR(95%CI) was2.21(1.37,3.59). Different effects were showed in non cardia cancer with haplotype analysis, low risk was showed in NFKBIA gene Ars696Crs2233406 haplotype,OR:0.71, 95%CI:(0.53,0.95), high risk was showed in NFKBIA gene Ars696Trs2233406 haplotype, OR:6.05, 95%CI:(1.74, 21.10).5. Gene-gene, gene-environmental factors interaction analysis: the interaction were showed in rs689466 AA genotype, using pesticides age≤ 18 and often intake pickles. The higher risk of gastric cardia cancer was showed in individual who carried rs689466 AA genotype and using pesticides age≤18,OR(95%CI) was 1.95(1.24,15.56),and positive multiplicative interaction was showed between the two factors,OR(95%CI) was 2.69(1.53,13.68); The higher risk of gastric cardia cancer was showed in individual who carried rs689466 AA genotype and often intake pickles,OR(95%CI) was 4.45(2.59,33.89); the interaction were showed in rs3755867 GA or GG genotype, using pesticides age≤ 18 and taste(salt); The higher risk of non cardia cancer was showed in individual who carried rs3755867 GA or GG genotype and taste(salt), OR(95%CI) was 8.19(1.86,58.24), and positive multiplicative interaction was showed between the two factors, OR(95%CI) was 1.52(1.05,3.72).【Conclusion】1. Environmental inflammatory risk factors and stomach disease were the main influencing factors on gastric cancer, the s PAR% of often intake pickles, using pesticide age≤ 18, eating hot food, eating spicy food, taste(salty) and chronic atrophic gastritis was 84.82%.2. The interaction effect was found in environmental inflammatory factors and it made an influencement on the occurrence of gastric cancer, comprehensive measures need to be taken on gastric cancer control.3. The occurrence of gastric cardia cancer and non cardia cancer were differently influenced by NF-kappa B signaling pathway related genes polymorphism, different Susceptibility polymorphism locis, different susceptibility haplotype and different gene-environment interaction, It was suggested that according to the different risk groups provide targeted guidance and prevention and control measures, it can be more effective for the prevention of gastric cancer.