Population Based Genotyping of Human Leukocyte Antigen (HLA) in Hodgkin Lymphoma: EBV Positive HL Is Associated with HLA Class I and EBV Negative HL Is Associated with HLA Class III.

Abstract

An inherited susceptibility to Hodgkin Lymphoma (HL) is indicated by the variation in incidence among race/ethnicity groups, aggregation of the disease in families and by association with human leukocyte antigens (HLA). In this study we conducted a detailed screening analysis of the complete HLA region in EBV-positive and EBV-negative patients with HL.In total, 200 patients and 348 family-based controls of the Caucasian population of the Northern Netherlands participated in this population-based study. Paraffin embedded tissue of all patients was obtained and used for revision according to the WHO classification. In addition, analysis of EBV status was performed. 54 patients were EBV-positive (33 NS, 14 MC, and 7 other classical cases) and 146 patients were EBV-negative (124 NS, 4 MC, 13 NLP, and 5 other classical cases). 33 microsatellite markers located in the HLA region 6p21 were used for genotype screening.Allele, genotype and two-locus haplotype association analyses were used to search for differences between EBV-positive and negative patients and family controls using a t-test to assess significance. In the EBV-positive patient group, HL was associated with an allele of 126 bp for D6S265 and an allele of 284 bp for D6S510 (p=0.00031). These markers are located in the HLA class I subregion. Individuals homozygous for 126 allele of D6S265 were observed in 34.4% of the EBV-positive patient group and 5.2% of controls (odds ratio (OR)= 6.6). The odds ratio for individuals heterozygous for 126 allele of D6S265 was lower (OR= 2.5).In addition, Haplotype Sharing Statistics (HSS) was used to search for differences in haplotype sharing between patients and family controls. The HSS assumes that haplotype segments of patients from a founder population are conserved in the region spanning a disease locus.The HSS analysis showed strongest haplotype sharing around marker D6S273 in patients compared to controls (p<0.0001). The sharing was less evident in the EBV-positive subgroup compared to the EBV-negative subgroup, possibly due to low power. D6S273 is located at the telomeric end of the HLA class III region nearby TNF-alpha, TNF-beta and heat shock protein genes. Our results indicate that part of the HLA class I and part of the HLA class III region are associated with susceptibility to classical HL, with the HLA class I association being specific for EBV positive HL. We will further analyze both regions aiming to find genes and polymorphisms associated with the development of HL.