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

Abstract

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. (Blood. 2011; 118(3):670-674) IntroductionHodgkin lymphoma (HL) is a common lymph node cancer of germinal center B-cell origin, which is characterized by malignant Hodgkin and Reed-Sternberg (HRS) cells mixed with a dominant background population of reactive lymphocytes and other inflammatory cells. 1 Although Epstein-Barr virus (EBV) infection may be causally related to a number of cases, there is little evidence to support the involvement of other environmental risk factors. 2 Evidence for inherited genetic influence on susceptibility is provided by the increased familial risk and high concordance between monozygotic twins. 3 Since an association between the human leukocyte antigen (HLA) region and HL risk was first reported in 1967, 4 studies have subsequently identified associations between both HLA class I and class II alleles and common HL (cHL) risk. [5][6][7][8][9][10] Studies to date have evaluated only specific HLA alleles and have not taken into account the existence of complex linkage disequilibrium patterns between the multiple risk loci mapping to the major histocompatibility complex (MHC) region, associations between HLA alleles at different resolution, and the need to control rigorously for population stratification. In view of the limitations of these previously published studies, we have conducted a more comprehensive analysis.It has recently been shown that single nucleotide polymorphism (SNP) data within the 6p21 region can be used to impute alleles at key classic class I (HLA-A, HLA-B, and HLA-C) and class II (HLA-DRB1, HLA-DQA1, and HLA-DQB1) loci with accuracy that exceeds 90% at the 4-digit level. 11,12 Using existing genotype data from a previous genome-wide association study of HL, which identified many SNPs within the HLA region that are strongly associated with disea...

Genetic Associations in Classical Hodgkin Lymphoma: A Systematic Review and Insights into Susceptibility Mechanisms

“…In addition, several other HLA class II SNPs are associated with cHL (15,45 Ã 07:01 allele (45). This is in line with HLA typing studies that showed that HLA-DRB1 Ã 07:01 is a protective allele for developing NS cHL (26,29,30). Two SNPs mapping to nonclassical HLA genes in the HLA region, that is, MHC class I polypeptiderelated sequence B (MICB) (6p21.33) and proline-rich transmembrane protein 1 (PRRT1) (6p21.32) are associated with cHL overall, NS cHL, or EBV À cHL (15,45,47).…”

“…In a hallmark study on HLA associations, two microsatellite markers located in the HLA class I region were found to be associated with EBV þ cHL in Caucasians (23 (30,31), whereas HLA-DPB1 Ã 03:01 and HLA-DPB1 Ã 34:01 were risk alleles for cHL overall, NS cHL, cHL in females and MC cHL in males, respectively (30)(31)(32)(33).…”

Familial predisposition and genetic risk factors for lymphoma

“…78 Five GWAS analyses have been published in HL, [69][70][71]73,74 and the strongest findings have been for SNPs mapping to HLA class II 69,71,73 in close proximity to HLA-DRA and HLA-DRB1, regions previously linked to HL by HLA-typing studies. 79,80 The 6p21.32 locus marked by rs6903608 (near HLA-DRA) was associated with cHL overall, and more specifically to EBV2 cHL, 69,71 early onset, 69,72 and young adult nodular sclerosing HL 73 (largely EBV2). Additional GWAS signals at 6p21 have been identified in HLA class I, 71 with statistically independent associations for rs2248462 (near MICB) for all cHL (irrespective of EBV status); and rs2734986 (39 untranslated region of HLA-G and near HLA-A) and rs6904029 (near HCG9) for EBV1 cHL.…”

“…Using SNPs to impute classic HLA alleles, two independent signals in the HLA class II region (rs6903608 and rs2281389) were linked to early onset HL, but no specific classical HLA alleles from this region were significant after conditioning on these two SNPs. 72 The class II SNP rs6903608 was estimated to account for ;6% of the familial risk in HL. 72 Outside of the MHC region, GWAS-discovered loci for HL include 2p16.…”

A Novel Risk Locus at 6p21.3 for Epstein–Barr Virus-Positive Hodgkin Lymphoma

“…EBV-positive cases are associated with recent EBV infection, as evidenced by an association with infectious mononucleosis, and also with weakened immunity, for example, HIV infection or iatrogenic immunosuppression after organ transplantation (4)(5)(6). The human leukocyte antigen (HLA) genes, located within the MHC region, have been implicated in the etiology of cHL (7)(8)(9)(10)(11). Some associations show heterogeneity by tumor EBV status (9,(11)(12)(13)(14) reinforcing the importance of acknowledging EBV status in examining the etiology of cHL.…”