Multiple HLA class I and II associations in classical Hodgkin lymphoma and EBV status defined subgroups.

The pathogenesis of classical Hodgkin lymphoma (cHL) involves environmental and genetic factors. To explore the role of the human leukocyte antigen (HLA) genes, we performed a case-control genotyping study in 338 Dutch cHL patients and more than 5,000 controls using a PCR-based sequence-specific oligonucleotide probe (SSOP) hybridization approach. HLA-A68 and HLA-DR11(5) were significantly increased in the cHL patient population as compared to the controls. Three class II associations were observed in the EBV- cHL population with an increase of HLA-DR15(2) and a decrease of HLA-DR4 and HLA-DR7. Allele frequencies of HLA-A1, HLA-B37 and HLA-DR10 were significantly increased in the EBV+ cHL population; these alleles are in strong linkage disequilibrium and form a common haplotype in Caucasians. The allele frequency of HLA-A2 was significantly decreased in the EBV+ cHL population. SSOP analysis revealed significant differences between EBV+ and EBV- cHL patients for 19 probes that discriminate between HLA-A*01 and HLA-A*02. In conclusion, the HLA-A1 and HLA-A2 antigens and not specific single nucleotide variants shared by multiple alleles are responsible for the association with EBV+ cHL. Furthermore several new protective and predisposing HLA class I and II associations for the EBV+, the EBV- and the entire cHL population were identified.