Association Study Of Variants In INTS10 With The Outcome Of Hepatitis B Virus Infection

Objectives1.To investigate effects of environmental factors on the outcome of hepatitis B virus?HBV?infection.2.To investigate effects of genetic variants of INTS10 on the outcome of HBV infection.3.To investigate effects of interaction between genetic variants of INTS10and environmental factors on the outcome of HBV infection.MethodsWe used case-control study to collect objects in HBV-related Hepatocellular Carcinoma?HCC?,Chronic HBV infection?CH?and Hepatitis B Virus Spontaneous Recovery?SR?and formed two comparison groups as CH vs.SR group and HCC vs.CH group.The genetic variants of INTS10 that may be associated with the outcome of HBV infection were selected by using the tagSNP and previous GWAS results,and the genetic variants and environmental factors?smoking,drinking,family history of cancer?were systematically analyzed for effects on the outcome of HBV infection.TaqMan-PCR technique was used to detect genotypes.?² test was applied to exame differences in distribution of environmental factors and genotypes among the groups.Logistic regression model was used to analyze effects of environmental factors on the outcome of HBV infection.Logistic regression model and Random Forest?RF?model were used to analyze effects of genetic variants on the outcome of HBV infection.Genetic risk score?GRS?was used to analyze the cumulative effects of genetic variants on the outcome of HBV infection.Logistic regression model and nonlinear mixed effects model?NLMEM?were used to analyze effects of interaction between genetic variants and environmental factors on the outcome of HBV infection.Results1.This case-control study included 737 participants in HBV-related HCC,750 participants in CH and 750 participants in SR,and divided into two comparison groups:CH vs.SR group and HCC vs.CH group.Analysis of effects of environmental factors found that smoking,drinking and family history of cancer were independent risk factor of HBV-related HCC?OR=6.04,95%CI=4.73-7.72;OR=3.93,95%CI=3.12-4.95;OR=3.73,95%CI=2.75-5.05?.2.Analysis of effects of genetic variants found that in CH vs.SR group,rs4268139 genetic variant was associated with chronic HBV infection in dominant mode?P=0.049?.Individuals with rs4268139 CC genotype had an OR of 1.25?95%CI=1.01-1.57?compared with the CG and GG genotype.Meanwhile,variants of genotype of rs4268139 was associated with chronic HBV infection in additive model?OR=1.23,95%CI=1.01-1.51,P=0.044?.In HCC vs.CH group,TC genotype of rs7000921 was associated with HBV-related HCC?P=0.030?.Compared with the TT genotype carriers of rs7000921,the risk of HBV-related HCC was reduced in TC genotype carriers?OR=0.77,95%CI=0.61-0.98?.3.The RF model analysis showed that the Gini coefficient of rs7000921and rs7822495 were significantly higher than other genetic variants among two comparison groups.It prompted that these two genetic variants may be associated with the outcome of HBV infection.4.Based on the results of single variant analysis and RF analysis,the three genetic variants of rs4268139,rs7000921 and rs7822495 were included in the subsequent analysis.GRS was used to analyze the cumulative effects of three genetic variants on the outcome of HBV infection.The results showed that the risk of HBV-related HCC in individuals with high-risk grades?4-6 points?was1.37 times higher than that in individuals with low-risk grades?0-3 points??95%CI=1.09-1.74,P=0.008?.5.Results of interaction analysis showed that there were no interaction between the three genetic variants and the environmental factors affecting the outcome of HBV infection.Analysis results of the interaction between genetic risk score grades and environmental factors showed that there was an additive interaction between genetic risk score grades and smoking affecting HBV-related HCC(P_add=0.041).There were multiplicative interactions and additive interactions between genetic risk score grades and drinking affecting HBV-related HCC(P_mult=0.014,P_add=0.002).Conclusions1.Smoking,drinking and family history of cancer were the independent risk factor for HBV-related HCC.2.The allele G?compared with allele C?of rs4268139 of the INTS10 could increase the risk of chronic HBV infection.The TC genotype of rs7000921 of INTS10?compared with TT genotype?could reduce the risk of HBV-related HCC.3.The cumulative effect of genetic variants?rs4268139,rs7000921,rs7822495?of INTS10 could increase the occurrence of HBV-related HCC.4.There was an interaction between the cumulative effect of genetic variants?rs4268139,rs7000921,rs7822495?of INTS10 and smoking?or drinking?increasing the occurrence of HBV-related HCC.