| Background:Hepatitis B virus(HBV)infection is one of the global serious and noteworthy public health problems.According to the World Health Organization(WHO),about 2 billion people worldwide have ever been infected with HBV,of whom about 1/8 is of chronic HBV infection.HBV infection probably results in chronic hepatitis B(CHB),liver cirrhosis and hepatocellular carcinoma(HCC).30%of individuals with liver cirrhosis and 45%of individuals with HCC worldwide were caused by HBV infection.China has the global largest number of HBV infection individuals.More than 90 million persons nationwide are chronically infected with HBV,accounting for 1/4 of the global number of chronic HBV infection,of which about 20 million individuals are of CHB.The clinical outcome of HBV infection shows obvious individual differences.Studies have shown that age at infection is the most important factor in determining viral persistence.Individuals who suffer HBV infection at a young age tend to develop a chronic HBV infection.In addition to host age,persistent HBV infection or HBV clearance is also influenced by gender,chronic alcohol abuse and co-infection with other hepatitis viruses.In addition,the segregation analyses and twin studies strongly supported the roles of host genetic factors in determining various outcomes of HBV infection.It is known that only a minority of chronic carriers of HBV will develop HCC and the chronic HBV carriers with a family history of HCC have a two-fold risk for HCC than those without the family history,strongly suggesting the importance of genetic susceptibility for HBV-related HCC.Before genome-wide association study(GWAS)was put forward,candidate gene association study had mainly been used to search for susceptibility genes for HBV persistence,identifying a number of related genetic susceptibility regions.However,the exact mechanisms of HBV persistence are yet to be elucidated.In 2009,Kamatani et al.conducted for the first time a genome-wide association study(GWAS)in Japanese and Thai populations and identified a strong association of CHB with two single nucleotide polymorphisms(SNPs)(rs3077 and rs9277535)in the HLA-DP genes.In 2011,the same group including Mbarek et al.also performed a second CHB GWAS in Japanese population.They succeeded in repeating the association between persistent HBV infection and the two SNPs(rs3077and rs9277535)in HLA-DP.Subsequently,many studies have been carried out to investigate the role of the two SNPs in HLA-DP in relation to various outcomes of HBV infection(chronic HBV infection,HBV spontaneous clearance,CHB activity,liver cirrhosis and HCC)among various populations.Unfortunately,the conclusions were inconsistent probably due to the small sample size,ethnic diversity,phenotypic heterogeneity,insufficient power of SNPs and other factors.Meta-analysis can increase the sample size by combining multiple homogeneous studies,increase the degree of concurrence,and solve the problem of inconsistent research results.We carried out a meta-analysis on all eligible studies all over the world to estimate relationship between the two polymorphisms(rs3077 and rs9277535 in HLA-DP)and various outcomes of HBV infection,which is of great significance for clarifying the pathogenesis of HBV-related liver diseases and prevention and treatment of such diseases.Objectives:To explore whether the two polymorphisms(rs3077 and rs9277535 in HLA-DP)are the genetic susceptibility loci for HBV-related liver diseases,so as to provide scientific evidence for clarifying the pathogenesis of HBV-related liver diseases and the prevention and treatment of such diseases.Methods:Databases including CNKI,WANFANG,CBM,PubMed,EMBASE and Cochrane Library and the specified Chinese and English search strategies were employed to search the aimed papers involved in the association between the two polymorphisms(rs3077 and rs9277535 in HLA-DP genes)and various outcomes of HBV infection.In addition,relevant studies were supplemented by reviewing reference lists of included studies,reviews and meta-analysis.The eligible publications were finally identified according to the inclusion and exclusion criteria.Newcastle-Ottawa Scale(NOS)was employed to assess the quality of the included studies.Two individuals collected information related to rs3077 and rs9277535 from the included literatures independently.In order to detect the association between rs3077,rs9277535 and HBV infection,HBV spontaneous clearance,CHB activity,liver cirrhosis and HCC development,the data from each SNP was divided into five groups according to the phenotypes of the case and control groups:1.chronic HBV infection vs healthy controls;2.HBV spontaneous clearance individuals vs chronic HBV infection;3.asymptomatic HBsAg carrier(AsC)vs symptomatic HBV infection;4.liver cirrhosis vs CHB and 5.HCC vs HBV carriers.For any of the above groups,a minimum of three independent data sources was required for meta-analysis.The meta-analysis was conducted using RevMan5.3 software.The strength of the association between various outcomes of HBV infection and the two SNPs was estimated using ORs,with the corresponding 95%CIs.Meta-analyses stratified by ethnicity(Asians and Non-Asians)were done if data permitted.Cochran Q statistic was used to assess heterogeneity between studies and with a P value less than 0.1 was considered to have significant heterogeneity.In addition,heterogeneity between studies was also assessed by the I2 statistic.If the data were heterogeneous,the random effect model would be used for the combined analysis and if the data were homogeneous,the fixed effect model would be used to synthesize the statistics.Sensitivity analysis was performed by deleting a single study involved in the meta-analysis each time and re-analysing the remainder.Publication bias was evaluated using the funnel plot.All P values are bilateral.Unless otherwise stated,P?0.05 was considered statistically significant.Results:The present study totally contained 33 originally eligible literatures which were all of high quality assessed by NOS.A total of 30 groups from 17 literatures discussed the correlation between rs3077 and chronic HBV infection.Meta-analysis suggested that rs3077 A allele significantly reduced the risk of chronic HBV infection both in Asian and non-Asian populations(OR=0.60,95%CI 0.56-0.63,P<0.00001 OR=0.74,95%CI 0.65-0.84;P<0.00001).A total of 33 groups from 17 literatures discussed the correlation between rs9277535 and chronic HBV infection.Meta-analysis suggested that rs9277535 A allele significantly reduced the risk of chronic HBV infection in Asians(OR=0.60,95%CI 0.56-0.64,P<0.00001).A total of 27 studies from 19 literatures discussed the correlation between rs3077 and spontaneous clearance of HBV.Meta-analysis showed that rs3077 A allele significantly increased chance of HBV clearance both in Asian and non-Asian populations(OR=1.50,95%CI 1.37-1.65,P<0.00001;OR=1.38,95%CI 1.10-1.72,P=0.005).A total of 28 studies from 20 literatures discussed the correlation between rs9277535 and spontaneous clearance of HBV.Meta-analysis showed that rs9277535 A allele significantly increased chance of HBV clearance in the Asian population(OR=1.57,95%CI 1.48-1.67,P<0.00001).A total of 4 studies from 4 literatures discussed the correlation between rs3077 and CHB activity.Meta-analysis suggested that rs3077 was not statistically associated with CHB activity(OR=1.09,95%CI 0.76-1.57,P=0.63).A total of 7 studies from 6 literatures discussed the correlation between rs9277535 and CHB activity.Meta-analysis suggested that rs9277535 was not statistically associated with CHB activity in Asians(OR=1.04,95%CI 0.93-1.16,P=0.47).We did not conduct meta-analysis of the correlation between rs3077,rs9277535 and liver cirrhosis because there were only 2 studies from 2 literatures respectively discussing the correlation between rs3077,rs9277535 and liver cirrhosis.A total of 8 studies from 8 literatures discussed the correlation between rs3077 and HCC occurrence.Meta-analysis suggested that rs3077 was not statistically associated with HCC occurrence in Asians(OR=1.01,95%CI 0.93-1.10,P=0.83).A total of 7 studies from 6 literatures discussed the correlation between rs9277535 and HCC occurrence.Meta-analysis suggested that rs9277535 was not statistically associated with HCC occurrenc in Asians(OR=1.04,95%CI 0.98-1.11,P=0.17).Sensitivity analyses showed that the pooled effects were not qualitatively altered when a single study involved in the meta-analysis was deleted each time except for the Arabian study associated with rs3077 and CHB activity.The funnel plots showed that no significant publication bias existed except association studies between HCC and rs3077 or rs9277535.Conclusions:The present study showed that the A allele of rs3077 and the A allele of rs9277535 in HLA-DP gene were the protective factors against HBV infection,and significantly increased chance of spontaneous clearance of HBV.However,there is no significant associations were observed for CHB activity or HCC occurrence with rs3077 or rs9277535. |
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