Human Leukocyte Antigen Association with Hepatitis B Virus-Mediated Liver Cancer

Human leukocyte antigen (HLA) is a group of proteins that the human immune system uses to detect pathogens. HLA is highly polymorphic, especially in the peptide-binding groove, which allows the binding of a diverse range of peptides including peptides produced by pathogens. Hepatitis B virus (HBV), is a pathogen that can cause liver disease. Chronic HBV infection, if left untreated, can lead to hepatocellular carcinoma, the most common form of liver cancer. In this paper, the association of Class I and II HLA with HBV-mediated liver cancer in patients of East Asian and European ancestry was studied. Results showed that, in the initial combined ancestry analysis, some alleles from all HLA types are associated with HBV-mediated liver cancer. However, once stratified by population ancestry, most of the alleles are no longer significant but still associate with HBV-mediated liver cancer in the same directions. In contrast, HLA-DP is the only HLA with haplotypes that are significantly different before and after stratification by ancestry. Notably, DPA10103-DPB10401, a previously known protective haplotype in the Asian population, is associated negatively with HBV-mediated liver cancer in both East Asian and European populations. Additionally, DPA10202-DPB10501, a known risk haplotype in the Asian population, is associated positively with HBV-mediated liver cancer patients of European ancestry. To understand how HLA-DP is associated with HBV-mediated liver cancer, the binding affinity of HLA-DP to all peptides generated from HBV coding sequences of genotypes A-H was predicted. It was speculated that an individual with HLA types that can bind strongly to HBV peptides will be more likely to clear viral infection whereas an individual with HLA types that fail to bind strongly to HBV peptides will be less likely to clear viral infection, thus developing chronic infection. Results showed that DPA10103-DPB10401 binds strongly to HBV peptides (<50nM) whereas DPA10202-DPB10501 does not bind strongly to any HBV peptides (>50nM), consistent with the speculation that the binding affinity of HBV peptides to HLA will influence the association of HLA with HBV-mediated liver cancer.