It is believed that the host genetic factors involved in genetic polymorphisms are responsible for the susceptibility to and clinical outcomes of infectious diseases. In recent years, genetic susceptibility to chronic HBV infection has been a research focus, and it has been identified that the polymorphisms of a number of immune-response-associated genes, including HLA
loci, affected the susceptibility to and clearance of persistent chronic HBV infection among different populations. HLA plays an essential role in the pathogenesis of virus-associated hepatitis. The HLA class II molecules are expressed as cell surface glycol-proteins that bind short peptide epitope to CD4+ T cells. HLA-DR, a subtype of HLA class II molecule, has a particular binding motif that dictates a specific range of peptides that can physically bind in a groove on the surface of the HLA molecule[14
Wide variations have been documented in the frequencies of HLA-DR gene polymorphisms which have been most widely investigated in healthy populations and been demonstrated to influence TNF-α expression. The association between HLA-DR polymorphisms and outcome of HBV infection has been investigated by several research groups. However, the previous studies have yielded conflicting results, and included no more than a few hundred CHB cases, which are too few to assess the genetic effects reliably. Meta-analysis has been recognized as an important tool to precisely assess the effect of the selected genetic polymorphisms on the risk of diseases and to identify potentially important sources of between-study heterogeneity. In our present meta-analysis, a total of 2609 patients with CHB and 2606 controls spontaneously recovering prior to HBV infection were included from 19 case-control studies which were evaluated using the NOS. It could provide the most comprehensive assessment to draw reliable conclusions.
Heterogeneity is a potential problem when interpreting the results of all meta-analyses, and finding the sources of heterogeneity is one of the most important goals of meta-analysis[46
]. In this present meta-analysis, we assessed the between-study heterogeneity by different methods, including the χ2
statistic test (Cochran’s Q
] (to test for heterogeneity) and the I2
statistic (to quantify the between-study heterogeneity)[29
]. For the meta-analyses comparing persistent HBV infection cases with spontaneously recovering controls, there was significant between-study heterogeneity in pooled meta-analyses of total eligible studies on HLA-DR*11
allele, which suggested obvious consistency of effects across those included studies. Subgroup analyses by ethnicity showed that the heterogeneity was still significant in subgroup analyses in Chinese Han populations for HLA-DR*11
polymorphism. Univariate analysis of meta-regression suggested that the publishing year and language were not important causes of between-study heterogeneity in both general analyses and subgroup analyses. We presumed that the quality of the primary studies would be the main cause of heterogeneity. Interesting, we found no significant between-study heterogeneity in pooled meta-analyses of total eligible studies and subgroup analyses by ethnicity for other alleles.
Some limitations still exist in this meta-analysis. First, meta-analysis essentially remains with observational study that was subject to the methodological deficiencies of the included studies. Since only published studies written in English and Chinese were included in the meta-analysis, publication bias may occur, even though it was not found by statistical tests. Second, the associations were investigated in all kinds of cases (asymptomatic carriers, patients with CHB, patients with liver cirrhosis), and there may be specific genetic effects among these cases, but we could not obtain enough information to further estimate these effects. It is necessary to conduct large trials using standardized unbiased methods on homogeneous CHB patients and well matched controls, with the assessors blinded to the data. Third, our results were based on unadjusted estimates. A more precise analysis should be conducted with individual data, which would allow the adjustment by other co-varieties including age, ethnicity, family history, environmental factors and lifestyle. Finally, gene-gene and gene-environment interactions were not addressed in this meta-analysis due to the lack of sufficient data. For instance, the major genotypes of HBV in Chinese are B and C, but most of the studies did not analyze them separately, which could not be solved because of the methodological limitations of the meta-analysis.
Despite these limitations, this meta-analysis suggests that HLA-DR*04 and DR*13 alleles may be the protective factors for HBV clearance, and HLA-DR*03 and DR*07 alleles may be the risk factors for HBV persistence. For the HLA-DR*01 polymorphism, a significantly association with HBV clearance was found in Chinese Han group, but not found in other ethnic groups. In summary, ethnicity may play an important role in HBV infection outcome, leading to conflicting results. More studies on individuals from various ethnic groups and large and carefully designed case-control studies will be necessary to determine the role of HLA-DR polymorphisms in the outcome of HBV infection.