HLA-DR, HLA-DQ, and TAP genes in familial Hodgkin disease

Abstract

The HLA region has long been implicated in sporadic and familial Hodgkin disease (HD), with recent case-control studies suggesting that HLA class II loci predispose to sporadic nodular sclerosis HD (NSHD). To determine whether this predisposition extends to familial HD, HLA class II loci (DRB1, DQA1, DQB1, DRB3, DRB4, and DRB5) and transporter associated with antigen processing (TAP) loci (TAP1, TAP2) were investigated in 100 members of 16 families with at least 2 confirmed cases of HD. With the use of the transmission disequilibrium test, evidence for linkage disequilibrium with familial HD and, in particular, familial NSHD was obtained for the DRB1*1501-DQA1*0102-DQB1*0602 haplotype, the TAP1 allele encoding Ile at residue 333, and the DRB5-0101 allele. These 3 markers were in linkage disequilibrium and may not represent independent susceptibility regions. Use of a family-based approach excludes population stratification as an explanation for these findings. The HLA class I region on chromosome 6 (particularly the B5, B8, B18, and A1 alleles) has been weakly but consistently associated with both sporadic and familial HD. [9][10][11] In familial HD, 60% to 70% of cases of which may be linked to this region, 12 there is significant HLA class I haplotype sharing among affected individuals. 11,13 More recent evidence suggests a role of HLA class II antigens. The DPB1*0301 allele was implicated in HD, 14,15 but an analysis of multiple HLA class II loci (eg, DRB1, DQA1, DQB1, and DPB1) discounted an independent role of DPB1. 16 Klitz et al 16 conducted a case-unrelated control study and reported that NSHD (but not other histologic subtypes) is positively associated with the DRB1*1501, DQB1*0602, and DRB1*1104 alleles and negatively associated with the DRB1*1601, DRB1*0404, and DQB1*0303 alleles. They concluded that susceptibility to NSHD was probably due to several HLA class II loci, including DRB1, DQB1, and perhaps other, yet-to-be-identified loci.We investigated whether alleles at HLA class II loci (DQA1, DQB1, DRB1, DRB3, DRB4, DRB5) and transporter associated with antigen processing (TAP) loci (TAP1 and TAP2) play a role in familial HD. We tested for linkage disequilibrium with familial HD and, in particular, with familial NSHD. Study design SubjectsSixteen white families with at least 2 members with histologically confirmed HD (9 sibling pairs; 4 parent-child pairs; 1 sibling-sibling-parent trio; 1 sibling-sibling-cousin trio; and 1 cousin-cousin-uncle trio) were ascertained through self-referral or physician referral to the National Cancer Institute between 1978 and 1993. Thirteen of these families had been studied previously in relation to HLA class I haplotypes 13 or EBV. 5 Four patients were excluded because they did not provide a blood sample for genetic analysis. The present analysis included 28 affected members (23 NSHD, 5 non-NSHD) with at least one parent available for genotyping; 3 affected family members (all non-NSHD) with both parental genotypes unknown; and 69 unaffected family members (27 parent...

Epidemiology of Hodgkin's Lymphoma

“…We found significant increase in the frequency of HLA DRB1*0403 and *1202 and DQ131*0604, *0201 and *0203 alleles which may confer suscepilibity (Al-Tonbary et al, 2004). Similar results were reported by Klitz et al (1994) who reported a significant association of HLA class II alleles with Hodgkin's lymphoma and Harty et al (2002) who reported that the DRB1*1501 allele is related to the development of familial Hodgkin's lymphoma particularly the familial nodular sclerosis type. The association of Hodgkin's lymphoma with different HLA-DRB1 and -DRQ1 alleles may be explained by three possibilities, first one implies that genes determining Hodgkin's lymphoma are located close to the major histocompatibility loci, and are thus transmitted along with whatever HLA haplotypes in the family (Hafez et al, 1985).…”

IL-6 levels and genotype are associated with risk of young adult Hodgkin lymphoma

“…Nodular sclerosis is the most common histology found in young adult Hodgkin lymphoma and is considered by some to be a separate disease on the basis of distinct epidemiology, 3 lower prevalence of EBV, 57 and association with polymorphisms of the antigen processing genes (TAP I1e) 16 and specific HLA types. 16,58 In our study, we found that both nodular sclerosis and the other subtypes showed the same general pattern of decreasing risk with increasing number of C alleles, although the trend was slightly stronger for the nodular sclerosis subset.…”

“…11,12 We also reported that identical (monozygotic) twins of case subjects have a 100-fold higher risk of developing this lymphoma than that expected on the basis of population incidence, whereas no increased risk was observed among fraternal (dizygotic) twins of case subjects. 13 We hypothesized that an inherited immune phenotype was responsible for the development of young adult Hodgkin lymphoma, based on several pieces of evidence: depression of cell-mediated immunity in patients, 14 secretion of numerous cytokines by Hodgkin-Reed-Sternberg cells, 14 the association with certain HLA types, 15,16 and the presence of lipoid nephrosis in one monozygotic young adult Hodgkin lymphoma-concordant twin pair. 13 Lipoid nephrosis is an autoimmune renal disease occasionally observed in patients with Hodgkin lymphoma 17 and thought to be caused by a T-cell defect.…”

Genetic susceptibility to lymphoma

“…Also, HLA class II DRB1*1501 and DQB1*0602 alleles, or linked loci, may increase risk of sporadic and familial HL. 89,91 Thus far, few studies have explored the association of HLA polymorphisms with NHL risk and results have been inconclusive. 92,93 Fine map genotyping in the HLA region may help to clarify the significance of variability in this region for HL and other lymphoma subtypes.…”