Risk of EBV-Positive Hodgkin Lymphoma Varies Over 30-Fold by HLA Class I Genotype and History of Infectious Mononucleosis.

Markers in the human leukocyte antigen (HLA) class I locus and infectious mononucleosis (IM) have both been associated with Epstein-Barr (EBV)-positive Hodgkin lymphoma (HL). IM is caused by late infection with EBV. To further explore associations between HLA class I genes and EBV-positive HL and to investigate potential interactions between genetic (HLA) and environmental risk factors in the development of HL, we performed a case-only study of 934 HL cases.

HLA-A and B typing were performed by PCR sequence specific oligonucleotide assay. Logistic regression was used to estimate odds ratios (ORs) of EBV-positive HL relative to EBV-negative HL for HLA-A and B genotypes and other known risk factors.

Increasing age, male sex, HLA-A*01 and a previous history of IM were all associated with a statistically significant increased odds of EBV-positive HL while HLA-A*02 and HLA-B*07 were associated with a protective effect. Significant interactions were detected between HLA-A*01 and HLA-B*07 and between prior IM and HLA-A*02, such that HLA-B*07 abolished the increased odds associated with HLA-A*01 and HLA-A*02 abrogated the increased odds associated with prior IM. In our final model of EBV-positive HL, HLA-B*07 was associated with a dominant protective effect (OR=0.57, 95% confidence interval (CI): 0.34–0.94); HLA-A*02 was associated with a protective effect which was additive (for individuals with no prior IM, OR_{per allele} =0.69, 95% CI: 0.50–0.97); and HLA-A*01 was associated with an increased odds in patients who were HLA-B*07-negative (OR_{per allele}=2.15, 95% CI: 1.54–3.01). Prior IM was independently associated with EBV-positive HL (OR=3.35, 95% CI: 1.67–6.73). This resulted in a >32-fold higher odds of EBV-positive HL in HLA-A*01 homozygotes with IM compared to HLA-A*02 homozygotes without IM.

We have identified strong associations between both genetic and environmental risk factors and EBV-positive HL. Our findings suggest that HLA class I-restricted, cell-mediated responses to EBV and a prior history of IM play critical roles in the pathogenesis of EBV-positive HL.

No relevant conflicts of interest to declare.