Modeling HLA associations with EBV-positive and -negative Hodgkin lymphoma suggests distinct mechanisms in disease pathogenesis

Johnson, P. C.D. et al. (2015) Modeling HLA associations with EBV-positive and -negative Hodgkin lymphoma suggests distinct mechanisms in disease pathogenesis. International Journal of Cancer, 137(5), pp. 1066-1075. (doi:10.1002/ijc.29467) (PMID:25648508)

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Abstract

HLA genotyping and genome wide association studies provide strong evidence for associations between Human Leukocyte Antigen (HLA) alleles and classical Hodgkin lymphoma (cHL). Analysis of these associations is complicated by the extensive linkage disequilibrium within the major histocompatibility region and recent data suggesting that associations with EBV-positive and EBV-negative cHL are largely distinct. To distinguish independent and therefore potentially causal associations from associations confounded by linkage disequilibrium, we applied a variable selection regression modelling procedure to directly typed HLA class I and II genes and selected SNPs from EBV-stratified patient subgroups. In final models, HLA-A*01:01 and B*37:01 were associated with an increased risk of EBV-positive cHL whereas DRB1*15:01 and DPB1*01:01 were associated with decreased risk. Effects were independent of a prior history of infectious mononucleosis. For EBV-negative cHL the class II SNP rs6903608 remained the strongest predictor of disease risk after adjusting for the effects of common HLA alleles. Associations with ‘all cHL' and differences by case EBV status reflected the subgroup analysis. In conclusion, this study extends previous findings by identifying novel HLA associations with EBV-stratified subgroups of cHL, highlighting those alleles likely to be biologically relevant and strengthening evidence implicating genetic variation associated with the SNP rs6903608.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Jarrett, Professor Ruth and Little, Dr Ann-Margaret and Montgomery, Mrs Dorothy and Gallagher, Dr Alice and McAulay, Dr Karen and Johnson, Dr Paul and Lake, Ms Annette
Authors: Johnson, P. C.D., McAulay, K. A., Montgomery, D., Lake, A., Shield, L., Gallagher, A., Little, A.-M., Shah, A., Marsh, S. G.E., Taylor, G. M., and Jarrett, R. F.
College/School:College of Medical Veterinary and Life Sciences > Institute of Biodiversity Animal Health and Comparative Medicine
College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:International Journal of Cancer
Publisher:John Wiley and Sons
ISSN:0020-7136
ISSN (Online):1097-0215
Copyright Holders:Copyright © 2015 The Authors
First Published:First published in International Journal of Cancer
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
409572Investigation of the pathogenesis of Hodgkin lymphomaRuth JarrettLeukaemia & Lymphoma Research (LRF)08031MVLS III - CENTRE FOR VIRUS RESEARCH