title: Modeling HLA associations with EBV-positive and -negative Hodgkin lymphoma suggests distinct mechanisms in disease pathogenesis.
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 modeling 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.
authors: Boyd Orr Centre for Population and Ecosystem Health, Institute of Biodiversity, Animal Health and Comparative Medicine, University of Glasgow, Glasgow, United Kingdom.
authors: Paul C D
authors: PC
authors: Johnson
authors: MRC - University of Glasgow Centre for Virus Research, Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom.
authors: Karen A
authors: KA
authors: McAulay
authors: MRC - University of Glasgow Centre for Virus Research, Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom.
authors: Dorothy
authors: D
authors: Montgomery
authors: MRC - University of Glasgow Centre for Virus Research, Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom.
authors: Annette
authors: A
authors: Lake
authors: MRC - University of Glasgow Centre for Virus Research, Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom.
authors: Lesley
authors: L
authors: Shield
authors: MRC - University of Glasgow Centre for Virus Research, Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom.
authors: Alice
authors: A
authors: Gallagher
authors: Histocompatibility and Immunogenetics Laboratory, Gartnavel General Hospital, Glasgow, United Kingdom.
authors: Ann-Margaret
authors: AM
authors: Little
authors: Anthony Nolan, Royal Free Hospital, Hampstead, London, United Kingdom.
authors: Anila
authors: A
authors: Shah
authors: Anthony Nolan, Royal Free Hospital, Hampstead, London, United Kingdom.|Cancer Institute, University College London, Royal Free Campus, London, United Kingdom.
authors: Steven G E
authors: SG
authors: Marsh
authors: Immunogenetics Group, University of Manchester, St Mary's Hospital, Manchester, United Kingdom.
authors: G Malcolm
authors: GM
authors: Taylor
authors: MRC - University of Glasgow Centre for Virus Research, Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, United Kingdom.
authors: Ruth F
authors: RF
authors: Jarrett
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D004198:Disease Susceptibility; D020031:Epstein-Barr Virus Infections / Q000235:genetics*; D005260:Female; D055106:Genome-Wide Association Study; D005838:Genotype; D015234:HLA-A Antigens / Q000235:genetics; D015235:HLA-B Antigens / Q000235:genetics; D059811:HLA-DRB1 Chains / Q000235:genetics; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D000949:Histocompatibility Antigens Class II / Q000235:genetics*; D006689:Hodgkin Disease / Q000235:genetics* / Q000473:pathology / Q000821:virology; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D055815:Young Adult
chemical_list: D015234:HLA-A Antigens; D015235:HLA-B Antigens; D059811:HLA-DRB1 Chains; D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II
keywords: EBV; HLA; Hodgkin lymphoma
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