| Background and Objective:Hepatitis B virus(HBV)is the main pathogen of human viral hepatitis and the main cause of acute and chronic hepatitis,liver failure,cirrhosis and hepatocellular carcinoma(HCC).The 2017 Global Burden of Disease study showed that up to 2.14 million people died from liver-related diseases.Therefore,liver disease seriously threatens human life and health,especially in HBV endemic areas.According to reports,39%of liver cancers and 29%of liver cirrhosis are caused by HBV,and this proportion is even higher in East Asia.In the natural course of HBV infection,the course of disease development and clinical outcome are very individualized,depending on the transmission mode,timing of infection,gender,immune status,host genetic factors and underlying diseases of the infected individual.Many studies have supported that HBV infection is closely related to host genetic variation,and abnormal DNA methylation and nucleotide synthesis and repair,as important factors of genetic variation,are significantly affected by one-carbon metabolism.However,there are no reports about the genetic polymorphisms of related enzymes in the one-carbon metabolic pathway and chronic HBV infection,so we have conducted research on this.Methods:In order to study the genetic markers of early susceptibility to chronic hepatitis B infection,this project collected blood samples from 230 cases of chronic hepatitis B virus infection and 234 healthy controls.24 functional single nucleotide polymorphism(SNP)sites were screened from 10 candidate genes of one-carbon metabolic pathway(BHMT、SHMT1、SHMT2、CBS、GNMT、MTHFR、MTR、SAHH、MAT2A、MGMT).MassARRAY SNP genotyping technology was used to detect the polymorphisms of the above 24 SNPs.The χ2 test was used to compare the differences in the frequency distribution of alleles and genotypes between different groups,and the odds ratio(OR)and 95%confidence interval(CI)were evaluated.To address the multiple testing issue,the most stringent Bonferroni correction procedure was used to adjust raw p-values.The Mann-Whitney U test was used to analyze the correlation between genotype,HBV-DNA load and HBsAg level.All statistical analyses were performed using the SPSS program(version 22.0,SPSS).For all tests,P value of<0.05 was considered a significant statistical difference.Results:1.Association analysis found that the polymorphism site of SHMT2(rs10717122 and rs2229717)and a polymorphism site of BHMT(rs585800)are related to the risk of chronic HBV infection.Compared with T/T,the DEL/DEL and DEL/T genotypes of rs10717122 may increase the risk of chronic HBV infection(DEL/DEL:OR=2.00,95%CI=1.19-3.37,P=0.008;DEL/T:OR=1.83,95%CI=1.15-2.92,P=0.01).Compared with the T allele of rs10717122,the DEL allele may increase the risk of chronic HBV infection(OR=1:40,95%CI=1.08-1.82,P=0.01).Compared with G/G,the T/T genotype of s2229717 significantly reduced the risk of chronic HBV infection(OR=0.34,95%CI=0.12-0.98,P=0.03).Compared with the G allele of rs2229717,the T allele reduced the risk of chronic HBV infection(OR=0.66,95%CI:=0.48-0.92,P=0.01).Compared with A/A,the T/A genotype of rs585800 may increase the risk of chronic HBV infection(OR=2.19,95%CI=1.29-3.74,P=0.003).2.The gene polymorphism of SHMT2 significantly affects the expression load of HBV-DNA.Compared with the high HBV-DNA load group,the T allele frequency of rs2229717 in the low HBV-DNA load group was significantly lower(14%vs.25%,P=0.037).The results of age stratification analysis showed that the TT genotype frequency distribution of rs2229717 was significantly reduced in people younger than 50 years old with low HBV-DNA load and chronic HBV infection(OR=0.10,95%CI=0.01-1.22,P=0.031).3.The genetic polymorphism of SHMT2 significantly affects the level of HBsAg.Compared with the G/G genotype,the T/T genotype of rs2229717 showed a significant increase in the level of HBsAg in the T/T genotype(P<0.05).4.The results of gene-gene interaction analysis showed that people who carry both rs10717122 DEL/DEL or DEL/T and rs585800 T/T or T/A genotypes have a 2.74-fold increase in the risk of chronic HBV infection(OR=2.74,95%CI=1.45-5.17,P=0.002).Conclusions:1.The T>DEL mutation at rs10717122 of SHMT2 gene is related to the susceptibility to chronic HBV infection.Carrying DEL increases the risk of chronic HBV infection.2.The G>T mutation at rs2229717 of SHMT2 gene is related to the susceptibility to chronic HBV infection.Carrying T reduces the risk of chronic HBV infection.3.The A>T mutation at rs585800 of the BHMT gene is related to the susceptibility to chronic HBV infection,and the T/A genotype increases the risk of chronic HBV infection.4.The G>T mutation of SHMT2 gene rs2229717 is significantly correlated with the level of HBsAg,and the level of HBsAg in the T/T genotype is significantly increased.5.The interaction between SHMT2 rs10717122 and BHMT rs585800 is related to the sensitivity of chronic HBV infection.People who carry DEL/DEL or DEL/T and T/T or T/A genotype at the same time have an increased risk of chronic HBV infection. |
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