| PURPOSE:1.1.To analyze the effect of the individual effects of the genetic variation of the MEG3-P53-MDM2-PTEN molecular pathway on the development of primary liver cancer.2.To analyze the effect of gene and environmental interactions of MEG3-P53-MDM2-PTEN molecular pathway on hepatocarcinogenesis.Methods:A frequency-matched case-control study was used.On the basis of reviewing the literature,combined with the functional annotation results of the bioinformatics database,a molecular pathway of MEG3 on liver cancer and potential functional genetic variations on the pathway were screened.Genotyping of target genetic variation was performed using TaqMan real-time PCR.Chi-square test was used to compare the distribution of basic characteristics and environmental factors between case group and control group.Logistic regression model was used to analyze the respective association between environmental factors,single genetic variation,genetic variation additive effect and risk of liver cancer.To explore the potential multi-factor gene-environment interaction,classification regression tree model was used;based on the principle of fork analysis,the multiplicative interaction term of the logistic regression model was conducted to calculate the multiplication interaction and the "delta" method of logistic regression model was for the additive interaction of the two factors.The interaction relative excess risk,the interaction attribution ratio and the interaction index were used to evaluate the additive interaction.Results1.A total of 1118 cases and 1248 controls were included in the study.The results of multivariate logistic regression model analysis showed that the risk of liver cancer in patients with chronic HBV infection was 17.09 times higher than that of uninfected patients(adjusted OR=17.09,95%CI=13.60~21.47).The adjusted OR among smokers and drinkers on the risk of liver cancer were 2.18 and 2.39,respectively(95% CI=1.72~2.77 and 1.85~3.09,respectively).2.The genetic variation of MEG3 rs4081134 and PTEN rs701848 was associated with the risk of liver cancer.The risk of liver cancer among the individuals carrying rs4081134 AA genotype was 1.55 times higher than that of the individuals carrying the GG genotype(95% CI=1.08~2.24).The risk of liver cancer among the individuals carrying rs4081134 AA genotype was increased by 57%(95% CI=1.12~2.25),compared with the individuals carrying(GA+GG)genotype.The risk of liver cancer amongthe individuals carrying rs701848 CC genotype was 1.34 times higher than that of the individuals carrying(TT+TC)genotype.3.The results of genetic risk scores has showed that the genetic risk scores of MEG3 rs4081134 and PTEN rs701848 on the risk of liver cancer increased gradually,for which the trend test was found statistically significant(trend P=0.039).The individuals with 2-4 genetic risk scores had a 37% increased risk of developing liver cancer,compared with the individuals with 0-1 genetic risk scores(95% CI=1.11~1.69).4.(1)CART model analysis of gene-environment interaction: A total of 8explanatory variables were screened: chronic HBV infection,smoking,drinking,family history of liver cancer,PTEN rs701848,MEG3rs4081134,P53 rs1042522,MDM2 rs2279744.Chronic HBV infection was the most important affecting factor for the risk of liver cancer.The risk of liver cancer in chronic HBV infection and smoking non-drinking and carrying rs701848 CC genotype is HBV infection without alcohol and carrying rs4082234(GG+GA)genotype 70.09 times(95% CI =16.09~305.38).(2)CART model analysis gene-gene interaction: MEG3 rs4081134 is the most important genetic affecting factor of liver cancer;the risk of liver cancer of individuals carrying rs4081134 AA and rs1042522 CC genotype at the same time is 2.81(95% CI =1.40~5.65)times higher than that of individuals carrying rs4081134(GG+GA),rs1042522 CCRs701848(TT+TC),rs7158663 GG genotype at the same time.(3)Two-factor interaction analysis: There was no interaction between PTEN rs701848,MEG3 rs4081134,P53 rs1042522,MDM2 rs2279744 and environmental factors.There was a positive additive interaction between chronic HBV infection and smoking.RERI and 95% CI were20.92 and 10.64 to 31.21,respectively.There was a positive additive interaction between chronic HBV infection and alcohol consumption,RERI and 95% CI = 16.27 and 6.34 to 26.21.Conclusion1.Chronic HBV infection,smoking and drinking are important environmental factors for liver cancer;2.MEG3 rs4081134 and PTEN rs701848 are genetic variations affecting the susceptibility of liver cancer.3.The gene-environment interaction of chronic HBV infection,smoking,and PTEN rs701848 have an important impact on the risk of liver cancer. |
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