| Gastric cancer is a malignant tumor with high morbidity and mortality,which affects the health of people all over the world.As one of the highest incidence areas of gastric cancer in the world,China has a huge health and economic burden due to gastric cancer every year.Most gastric cancers are hard to be detected at an early stage,which brings great physical and mental pain to patients and affects the treatment and prognosis of gastric cancer patients to a large extent.Therefore,it is necessary to study the susceptibility of gastric cancer.Single nucleotide polymorphisms(SNP)are an important type of mutation.The SNPs of various genes are related to the susceptibility to gastric cancer and can be acted as biomarkers.The inflammation affects the occurrence and development of gastric cancer,and interleukins(IL)are an important class of cytokines associated with inflammation.Previous studies have shown that the SNPs of ILs genes also have an effect on susceptibility to gastric cancer.Although many SNPs of ILs genes have been reported to be associated with gastric cancer susceptibility,there are still controversies.ObjectiveThe single nucleotide polymorphisms(SNPs)of ILs genes,which were related to gastric cancer susceptibility,were identified by meta-analysis.The samples of Chinese Han population in Henan Province were utilized to verify the relationship between ILs genes’ SNPs and the susceptibility to gastric cancer.Preliminary functional verification of SNPs was performed through bioinformatics.Methods(1)The relationship between ILs genes’ SNPs and gastric cancer susceptibility was quantitatively evaluated based on meta-analysis.NoteExpress software was used to retrieve and collate the research on the relationship between the SNP of ILs genes and susceptibility to gastric cancer in Chinese Han population.Review Manager 5.3 software was applied to perform meta-analysis on the studies those met the inclusion criteria.By obtaining the odds ratio(OR)and the 95%confidence interval(95%CI)of the relationship under four different genetic models(co-dominant,dominant,recessive and super-dominant),the SNPs related to gastric cancer susceptibility in all four models were identified by experiments.(2)Genotyping experiments were used to validate the results of the meta-analysis:genotyping experiments were carried out on SNPs which have a relationship with gastric cancer susceptibility in the four genetic models,obtained by meta-analysis in the Han population of Henan province,to test whether they were consistent with the results of meta-analysis and whether there was gene-environment interaction in the study.The study was designed according to the case-control study.Frequency matching method was adopted in the case group and the control group,and matching was conducted according to the age(±2 years old)and gender of the two groups.The sample size was calculated using PASS 15.0 software,and 1320 cases of gastric cancer and control population were included.For SNPs which related to gastric cancer susceptibility determined by meta-analysis,genotyping experiments were conducted in two groups of samples by the iMLDRTM(Improved multiplex ligation detection reaction)multiplex SNP detection method.(3)Two online bioinformatics analysis sites,3dSNP and VarCards,were used to explore possible changes in biological function caused by mutations about the SNPs which associated with gastric cancer susceptibility resulting from statistical analysis of genotyping experiment.(4)Statistical analysis method:SPSS 21.0 software was applied for statistical analysis in this study.Depending on the type of sample data,the t-test or χ2 test was selected to analyze the differences between the case and the control group.Chi-square test for goodness of fit was performed to detect whether SNPs met the Hardy-Weinberg equilibrium in the control group.The association between SNPs and gastric cancer susceptibility was analyzed based on logistic regression.PARP(Population attributable risk percentage)was used to evaluate the public health significance of SNPs.Multifactor dimensionality reduction(MDR)method was used to examine gene-environment interactions between SNPs and basic characteristic factors such as gender and age(MDR 3.0 software).Results(1)The SNPs associated with gastric cancer susceptibility under different genetic models obtained from the meta-analysis were:IL-1B rs1143627(recessive model),IL-1B rs16944(co-dominant,dominant,recessive model),IL-6 rs1800796(co-dominant model),IL-8 rs4073(co-dominant,dominant,recessive model),IL-10 rs1800896(co-dominant,dominant,recessive,super-dominant model),IL-17F rs763780(co-dominant,dominant,recessive,super-dominant model).Follow-up genotyping experiments and statistical analysis were performed at the rs1800896 and rs763780,which all associated with gastric cancer susceptibility under the four genetic models.(2)The results of genotyping experiments showed that IL-17F rs763780 was closely associated with gastric cancer susceptibility.Adjusted logistic regression analysis showed that the rs763780 CT genotype in the co-dominant model,the(CT+CC)genotype in the dominant model,and the CT genotype in the super-dominant model also increased the risk of gastric cancer(OR=1.41,95%CI:1.08-1.86;OR=1.41,95%CI:1.08-1.84;OR=1.40,95%CI:1.07-1.84).The results of stratified analysis of rs763780 showed that those who carried the rs763780 CT genotype had a higher risk than those who carried the TT genotype in the people aged≥60 years(OR=1.59,95%CI:1.06-2.38),males(OR=1.44,95%CI:1.05-1.98),non-smokers(OR=1.43,95%CI:1.01-2.02),drinkers(OR=1.96,95%CI:1.19-3.25),and people without family history of gastric cancer(OR=1.41,95%CI:1.07-1.85).The genotype(CT+CC)of rs763790 also had a higher risk than those who carried the TT genotype in the people aged≥60 years(OR=1.54,95%CI:1.04-2.30),males(OR=1.42,95%CI:1.04-1.94),non-smokers(OR=1.45,95%CI:1.03-2.04),drinkers(OR=2.04,95%CI:1.24-3.35),and people without family history of gastric cancer(OR=1.40,95%CI:1.07-1.84).It suggested that people who carry the corresponding genotype were more likely to suffer from gastric cancer.And rs1800896 had nothing to do with the susceptibility of gastric cancer.(3)For(CT/TT)or(CT+CC/TT)model,the results of false-positive report probability of rs763780 were all less than the default value of 0.5 in the whole population,people aged≥60 years,males,non-smokers,drinkers and people with no family history of gastric cancer,suggesting that the correlation between the variation and gastric cancer susceptibility was meaningful.(4)The results of the analysis on gene environment interaction based on the MDR model showed that the risk of gastric cancer in the population with a history of smoking and drinking and C allele of rs763780 was 2.37 times than the population without these three(OR=2.37,95%CI:1.86-3.01).(5)The predicted results of the online analysis websites 3dSNP and VarCards about the possible effects of biological functions brought by the rs763780 mutation showed that:the rs763780 mutation had an impact on the relationships of its associated genes and itself at the chromosome level,which might affect the biological functions they regulate.However,the mutation only had a weak influence on the function of the protein encoded by the gene.Conclusions(1)The IL-17F rs763780(T>C)was associated with increased susceptibility to gastric cancer,while the IL-10 rs1800896(T>C)mutation had not been found to be associated with gastric cancer susceptibility.(2)The results of gene-environment interaction analysis showed that people with a history of smoking and drinking and carrying the rs763780 C allele had a higher risk of gastric cancer.Therefore,there was a gene-environment interaction.(3)The rs763780 might affect the relationship between its related genes and itself in the chromatin loop.The specific biological mechanism of increased susceptibility to gastric cancer in rs763780 carriers needed to be further studied. |
PDF Full Text Request