Multiple Hodgkin lymphoma-associated loci within the HLA region at chromosome 6p21.3.

Since an association between the human leukocyte antigen (HLA) region and Hodgkin lymphoma (HL) was first reported in 1967, many studies have reported associations between HL risk and both single nucleotide polymorphism (SNP) and classic HLA allele variation in the major histocompatibility complex. However, population stratification and the extent and complexity of linkage disequilibrium within the major histocompatibility complex have hindered efforts to fine-map causal signals. Using SNP data to impute alleles at classic HLA loci, we have conducted an integrated analysis of HL risk within the HLA region in 582 early-onset HL cases and 4736 controls. We confirm that the strongest signal of association comes from an SNP located in the class II region, rs6903608 (odds ratio [OR] = 1.79, P = 6.63 × 10(-19)), which is unlikely to be driven by association to HLA-DRB, DQA, or DQB alleles. In addition, we identify independent signals at rs2281389 (OR = 1.73, P = 6.31 × 10(-13)), a SNP that maps closely to HLA-DPB1, and the class II HLA allele DQA1*02:01 (OR = 0.56, P = 1.51 × 10(-7)). These data suggest that multiple independent loci within the HLA class II region contribute to the risk of developing early-onset HL.