Haplotype-Based Sequencing to Delineate the Associated HLA Class I Region for EBV Positive Hodgkin Lymphoma.

Various studies have indicated that the human leukocyte antigen (HLA) region is associated with Hodgkin Lymphoma (HL). We recently demonstrated a specific association of the HLA class I region with Epstein-Barr virus (EBV) positive HL cases. The positively associated haplotype was characterized by alleles 126 and 284 of the consecutive microsatellite markers D6S265 and D6S510 while the negatively associated haplotype was characterized by alleles 130 and 302. Further fine mapping of this region is necessary to find the causative SNP(s). To select the most promising candidate SNPs for screening the total study population, known SNPs were sequenced in an individual homozygous for the positively associated haplotype and an individual homozygous for the negatively associated haplotype. Five SNPs (rs2530388, rs2523972, rs4713276, rs2256543, and rs6457110) that were selected on the basis of displaying different alleles in these two individuals were analysed in the total study population. The five SNPs showed significant association with the EBV-positive patient group, three of them revealed a stronger association than the previously identified associations (−log p difference = 1). These five SNPs were also analysed in a Scottish population, and four of them showed association in that population as well. The associated region was narrowed down from 310 kb in the original study to a region comprising less than 60 kb in the present study. Of the genes mapping to this candidate region, HLA-A represents the most interesting target because of its consistent expression in EBV positive HL cases and its ability to present EBV derived peptides to cytotoxic T cells.