While it can be expected that variations in the HLA-DP coding regions will affect antigen presentation and hence viral clearance, selleck chemicals the 3 studied SNPs do not lie within the HLA-DP coding region. The SNP rs3077 lies in the 3�� untranslated region of HLA-DPA1, rs9277378 lies in the second intron of HLA-DPB1, and rs3128917 is located ~2.5kb downstream of HLA-DPB1 (Figure 1). As variations in these SNPs will not cause specific changes in the HLA-DP coding sequence, the effect of variations in these 3 SNPs on HLA-DP function and viral clearance is likely to be indirect. There are at least two possible mechanisms. Firstly, it is possible that variation in these SNPs may alter the expression of the HLA-DP genes, through the alternation of non-coding RNA sequence or microRNA binding site, as demonstrated in a recent study that variations in rs3077/rs3128917 and rs9277535 affect the expression of HLA-DPA1 and HLA-DPB1 respectively [28].

Secondly, as these SNPs are in a strong LD with the HLA-DP alleles, it is also likely that variations in these 3 SNPs reflect some yet to be identified variations in HLA-DP coding sequence [13], [16]. Thus variations in these 3 SNPs may be a marker for the variations in the HLA-DP coding sequence, which in turn affect antigen presentation of HBV-derived peptides and alter immune response and chronicity of infection. In fact, it has been demonstrated in a chimpanzee HBV infection model that the outcome of HBV infection is determined by the kinetics of viral spread and CD4 T-cell priming [29].

This suggests that the outcome of HBV infection can be influenced by the physical binding of HBV-derived peptides and their subsequent recognition by CD4 T-cell, which is dependent on HLA-DP polymorphism. The correlation between variations in HLA-DPA1 and HLA-DPB1 SNPs and the change in HLA-DP gene expression and molecule structure deserves a more thorough sequence analysis, and the functional roles of these polymorphisms remain to be studied. Haplotype-based association analysis is more sensitive than individual SNP association analysis and can capture additional phenotype-related variants with a greater statistical power. This study found that both haplotypes TAT and CAT were associated with an increase chance of HBV clearance, with ORs of 1.64 and 1.98, respectively, both of which were greater than that of the individual SNPs (Table 1).

However, there are two caveats. First, although the haplotype CAT showed the greatest OR of 1.98, its relatively greater 95% CI range and low overall haplotype frequency (0.097; data not shown) suggested AV-951 that its effect on HBV clearance requires further investigations. Second, compared to the OR for individual alleles in the SNPs (for example, for rs9277378, OR=1.61; Table 1), there was only a small increase in OR by the current haplotype analysis.