Association Study Between Polymorphism Of HLA-DP/HLA-DQ Variants And Hepatitis B Virus Infection And Progression Susceptibility

Hepatitis B virus (HBV) infection is one of the world’s most common and serious infectious diseases. There are approximately 240 million people in the world have chronic HBV infection. China, currently recognized as a low and high HBV endemicity co-existing region, still has more than 50,000 people die annually from the end stage of the disease。Because infection and progression of HBV-related diseases vary, genetic factors are considered to be important. Recently, several genome-wide association studies have revealed the HLA region on chromosome 6p21 as susceptibility loci for hepatitis B virus (HBV) infection, which was subsequently replicated in the independent samples. The HLA complex which contains 180 genes code several immune-related proteins i n a span of 4 Mb.Our study planned to explore more associated SNPs in this area and to determined which region and SNPs contribute to the detected association.By genotyping high density of SNPs within this broad region followed by both individual-based and haplotype-based association analysis, we identified 76 SNPs and 5 Linkage Disequilibrium (LD) blocks in HLA-DP/DQ clusters in HLA region that are significantly associated with the HBV infection, with the smallest P value of 3.88 x 10-18 for rs9277535 in HLA-DPB1 gene. With the conditional analysis, we further revealed that effect of HLA-DP and HLA-DQ are independent from each other and the LD block 5 in the 3’-UTR region of HLA-DPB1 showed a predominant effect in the association of HLA-DP with HBV infection. In addition, the SNPs in the 3’-UTR region of HLA-DPB1 still showed a significant association by analyzing the three case subgroups (HBV carrier, CHB, LC) vs. spontaneous HBV clearance subgroup(from control group). Further association analysis of SNPs in this region with different subgroups in the case group revealed no association of these SNPs with the progression of HBV-related diseases.In summary, we showed, for the first time, that the HLA-DP and HAL-DQ clusters contributed independently to HBV infection and the 3’-UTR region of HLA-DPB1 represents a potential important functional region involving in HBV infection, which deserves to be further investigated at the molecular level on how these variants are involved in the infection.