HLA Associations in Classical Hodgkin Lymphoma:EBV Status Matters

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 using a PCR-based sequence-specific oligonucleotide probe (SSOP) hybridization approach. The allele frequencies were compared to HLA typings of more than 6,000 controls. The age of the cHL patients varied between 13 and 81 years with a median of 35 years. Nodular sclerosis subtype was the most common subtype (87%) and EBV was detected in 25% of the cHL patients. HLA-B5 was significantly increased and HLA-DR7 significantly decreased in the total cHL patient population as compared to controls. Two class II associations were observed to be specific for the EBV- cHL population with an increase of HLA-DR2 and HLA-DR5. 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. Analysis of haplotypes with a frequency of >1% revealed a significant increase of HLA-A2-B7-DR2 in EBV- cHL as compared to controls. SSOP association 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

Odds ratios and 99.9% confidence intervals of the genotype allele frequencies.

<p>The graph shows the (nearly) significant differences between the controls and either the total cHL patient group (grey), the EBV+ (black), or the EBV− (white) subgroup of patients. The size of the diamonds reflects the allele frequency.</p

Association of the rs6903608 SNP alleles with HLA alleles in 278 cHL patients.

*<p>Indicated are the number of alleles (the total number of alleles is 556).</p

Allele frequencies of HLA-A, HLA-B, and HLA-DR alleles with (nearly) significant difference between controls and EBV+ or EBV− cHL subgroups.

+<p>HLA-B5 is included because these alleles had significantly different frequencies in the total group of cHL cases compared with controls (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0039986#pone-0039986-t002" target="_blank">Table 2</a>). *Significant differences (p<0.001) are shown in bold, suggestive ones (p<0.003) in italic.</p