Protective and Predisposing HLA Alleles In Dutch Classical Hodgkin Lymphoma Patients

Abstract 749

Classical Hodgkin lymphoma (cHL) is characterized by an overwhelming reactive infiltrate and the involvement of Epstein Barr virus (EBV) as a causative agent in a proportion of patients. We previously did a population-based genetic screening study of the Human Leukocyte Antigen (HLA) region in Dutch cHL patients and found a strong association between HLA class I (HLA-A1) and susceptibility to EBV+ cHL. This association might be explained by the known lack of HLA-A1 restricted T cell responses to EBV latent antigens. We now performed a case-control study to determine allele frequencies of all major HLA class I and class II genes in this cHL population. HLA genotyping of 294 cHL patients was performed by a polymerase chain reaction-based sequence-specific oligonucleotide probe hybridization (PCR-SSOP) approach in Luminex assays. The resulting single nucleotide polymorphism (SNP) data were converted into two-digit HLA typing for the HLA class I and class II genes. Phenotype frequencies of serologically defined HLA-A, HLA-B and HLA-DR blood donors were retrieved from the database of the blood bank of the University Medical Center Groningen. Allele frequency differences between these controls and cHL patients (total group and EBV+ and EBV- subgroups separately) were analyzed by Chi-square tests. In addition, we analyzed the HLA genotyping data for every PCR-SSOP probe to assess potential differences between the EBV+ and EBV- cHL group using PLINK software. Frequencies of HLA-DR4 and HLA-DR7 were significantly decreased and HLA-B5 and HLA-B37 were significantly increased in cHL as compared to the controls. In EBV+ cHL, HLA-A1, HLA-B37 and HLA-DR10 frequencies were significantly increased and HLA-A2 was decreased. An increase in HLA-B8, an allele that can present EBV peptides and that usually is in strong linkage disequilibrium with HLA-A1, was not present in these patients. In EBV- cHL, HLA-DR5 was significantly more common and HLA-DR4 was underrepresented. The SNP analysis revealed significant differences for 16 HLA-A probes between EBV+ and EBV- cHL. Eight probes that represented a high susceptibility for EBV+ cHL were specific for HLA-A1, whereas the other 8 probes correlated with a low risk for EBV+ cHL and were specific for HLA-A2. Most of the corresponding SNPs had a presumed antigenic peptide or T cell receptor binding function. In conclusion, the current study demonstrates that certain HLA alleles are protective or predisposing for cHL with specific associations for the EBV+ and EBV- cHL subgroups. The genotype analysis indicates that the complete HLA-A1 and HLA-A2 alleles are more important than individual T-cell receptor or antigen binding polymorphisms for the association with EBV+ cHL.