Interaction between ERAP Alleles and HLA Class I Types Support a Role of Antigen Presentation in Hodgkin Lymphoma Development.

Genetic variants in the HLA region are the strongest risk factors for developing Hodgkin lymphoma (HL), suggesting an important role for antigen presentation. This is supported by another HL-associated genomic region which contains the loci of two enzymes that process endogenous proteins to peptides to be presented by HLA class I, i.e., endoplasmic reticulum aminopeptidase 1 () and . We hypothesized that and HLA class I type interact in HL susceptibility, as shown previously for several autoimmune diseases. We detected ERAP1 and ERAP2 expression in tumor cells and cells in the microenvironment in primary HL tissue samples. Seven SNPs and haplotypes showed strong associations with RNA and protein levels of and in LCLs and HL cell lines. Analysis of HLA class I types, SNPs and haplotypes by direct genotyping or imputation from genome-wide association data in 390 HL patients revealed significant interactions between , rs27038 and the rs27038 associated haplotype, as well as between and rs26618. In conclusion, our results show that and HLA class I interact in genetic susceptibility to HL, providing further evidence that antigen presentation is an important process in HL susceptibility and pathogenesis.