Multiple HLA class I and II associations in classical Hodgkin lymphoma and EBV status defined subgroups

Xin Huang,Kushi Kushekhar,Ilja Nolte,Wierd Kooistra,Lydia Visser,Ilby Bouwman,Niels Kouprie,Rianne Veenstra,Gustaaf Van Imhoff,Bianca Olver,Richard S Houlston,Sibrand Poppema,Arjan Diepstra,Bouke Hepkema,Anke Van Den Berg

doi:10.1182/blood-2011-04-342998

Abstract

AbstractThe pathogenesis of classical Hodgkin lymphoma (cHL) involves environmental and genetic factors. To explore the role of the human leukocyte antigen (HLA) genes, we performed a case-control genotyping study in 338 Dutch cHL patients and more than 5000 controls using a PCR-based sequence-specific oligonucleotide probe hybridization approach. HLA-A68 and HLA-DR11 (5) were significantly increased in the cHL patient population compared with the controls. Three class II associations were observed in the EBV− cHL population with an increase of HLA-DR15 (2) and a decrease of HLA-DR4 and HLA-DR7. Allele frequencies of HLA-A1, HLA-B37, and HLA-DR10 were significantly increased in the EBV+ cHL population; these alleles are in strong linkage disequilibrium and form a common haplotype in whites. The allele frequency of HLA-A2 was significantly decreased in the EBV+ cHL population. Sequence-specific oligonucleotide probe analysis revealed significant differences between EBV+ and EBV− cHL patients for 19 probes that discriminate between HLA-A*01 and HLA-A*02. In conclusion, the HLA-A1 and HLA-A2 antigens and not specific single nucleotide variants shared by multiple alleles are responsible for the association with EBV+ cHL. Furthermore, several new protective and predisposing HLA class I and II associations for the EBV+, the EBV−, and the entire cHL population were identified.

Highlights

R in the Classical Hodgkin lymphoma (cHL) patient population compared A with the controls
Allele frequencies of human leukocyte antigen (HLA)-A1, HLA-B37, and HLA-DR10 were significantly increased in the EBV؉ cHL population; these alleles are in strong linkage disequilibrium and form a common haplotype in whites
Inherited variations within the HLA genes as well as variations in host immune responses have long been recognized to be associated with susceptibility to disease, including cHL.25

Summary

Introduction

Three class II associaU Introduction tions were observed in the EBV؊ cHL population with an increase of HLA-DR15 [2] and a decrease of HLA-DR4 and HLA-DR7. Allele frequencies of HLA-A1, HLA-B37, and HLA-DR10 were significantly increased in the EBV؉ cHL population; these alleles are in strong linkage disequilibrium and form a common haplotype in whites. The allele frequency of HLA-A2 was significantly decreased in the EBV؉ cHL population. The HLA-A1 and HLA-A2 antigens and not specific single nucleotide variants shared by multiple alleles are responsible for the association with EBV؉ cHL. Several new protective and predisposing HLA class I and II associations for the EBV؉, the EBV؊, and the entire cHL population were identified. Genetic associations with specific HLA alleles have been reported in both sporadic and familial cHL.. D Reed-Sternberg cells is restricted to the 2 latent membrane proteins E (LMP1 and LMP2) and the EBV nuclear antigen 1 (EBNA1).

Methods

Results

Conclusion