| Backgrounds and ObjectivesGastric cancer is one of the most common cancers worldwide. The incidence of gastric cancer has been declined in recent years; however, it is still the fourth most commonly occurring cancer, and the second most common cause of death from cancer. In China, gastric cancer accounts for about one-third of all tumors, half of all gastrointestinal tumors, the mortality rate took the first place in the year of 2004. Gastric cancer remains a vital cancer burden in China. It is widely accepted that both the lifestyle and genetic factors contribute to the etiology of gastric cancer. Lifestyle factors such as smoking, alcohol consumption, tea drinking was considered to be intimately associated with gastric cancer risk. However, exposure to the same environmental factors, not everyone will develop gastric cancer. Genetic polymorphism plays a key role in individual's susceptibility to gastric cancer. More and more evidences suggest that deficiency in apoptosis pathway may influence the etiology of gastric cancer. The caspase families are main executors of the apoptotic process. Genetic polymorphism located with caspase genes may influence apoptosis activity.Therefore, we conducted a population-based case-control study in Jiashan County, Zhejiang Province. Combining the traditional epidemiology and the molecular epidemiology organically, we can evaluate the lifestyle factors and caspase instric pathway polymorphisms relate to gastric cancer risk comprehensive. The gene-environment and gene-gene interactions were further evaluated.Materials and MethodsAll 278 cases were histological confirmed as gastric cancer and were reported by cancer registry system during 2005-2008. The control subjects were determined to be cancer free and frequency matched (1:1) to cases on the basis of same gender, age (+5 years) and the same residential area. Each participant was interviewed by trained personnel to collect demographic data and relevant risk factors. In addition, a 2 ml venous blood sample was drawn from each subject with the permission and saved in vacuum tube containing sodium citrate anticoagulation. TagSNPs were selected by searching Han Chinese data from the HapMap project using the Haploview software. We performed Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP) assay to determine the genotypes of selected polymorphisms. Multiple statistical methods were used when estimating the major effect and the interactive effect of environmental factors and the genetic polymorphisms involved in caspase mitochondrial pathway, including logistic regression, crossover analysis, Multifactor Dimensionality Reduction (MDR) and Polymorphism Interaction Analysis (PIA).ResultsThe demographic characteristics, gastrointestinal disease and family cancer histories did not differ significantly from cases and controls. There was no association between variable concerning drinking and gastric cancer. The smokers in case group were higher than those in controls, but not reached the statistical significance. The smoke swallowers suffered increased risk of gastric cancer than the non-smoke swallowers among the smokers (OR=1.78,95%CI=1.01-3.15). Compared with the non-smokers, individuals started smoking before 23 years had significant increased risk of gastric cancer (OR=1.65,95%CI=1.01-2.70). Tea drinking could decrease the risk of gastric cancer, and the reduction were more evident in the green tea drinkers (OR=0.62, 95%CI=0.40-0.96), consuming tea more than 33 years (OR=0.60,95%CI=0.36-1.00), consuming tea above 5kg/year (OR=0.55,95%CI=0.33-0.93).In this study, totally 8 tagging single nucleotide polymorphisms were analyzed. The CASP3 polymorphisms were associated with increased risk of gastric cancer (rs4647693:ORGA=1.58,95%CI=1.09-2.30; rs4647610:ORAG=1.63,95%CI=1.13-2.34; ORGG=2.41,95%CI=1.32-4.43; rs12108497:ORTC=1.53,95%CI=1.07-2.30; ORCC=2.30, 95%CI=1.22-4.36). Individuals with haplotype AGGC showed a significantly association with gastric cancer (OR=1.54,95%CI=1.08-2.21) in comparison to those with haplotype GGAT. The CASP9 polymorphisms were not related to gastric cancer.The gene-environment and gene-gene interactions were assessed by multiple methods. The results from MDR and PIA software were consistent, revealing the gene-gene interaction between CASP3 rs4647693 and CASP9 rs4646018. The Logistic model confirmed the interaction was an antagonist effect (OR=0.29,95%CI=0.13-0.64). Smoking and tea consumption may modify the gastric cancer risk together with the caspase genes polymorphisms.ConclusionsOur findings verified the important influence of lifestyle factors on gastric cancer risk. CASP3 polymorphisms may increase the risk of gastric cancer, as well as its haplptype. CASP9 polymorphisms have nothing to do the gastric caner risk. There is an antagonist interaction between CASP3 rs4647693 and CASP9 rs4646018. Further studies with large sample size are warranted to validate our findings.
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