A growing number of loci within the human leukocyte antigen (HLA) region have been implicated in non-Hodgkin lymphoma (NHL) etiology. Here, we test a complementary hypothesis of "heterozygote advantage" regarding the role of HLA and NHL, whereby HLA diversity is beneficial and homozygous HLA loci are associated with increased disease risk. HLA alleles at class I and II loci were imputed from genome-wide association studies (GWAS) using SNP2HLA for 3,617 diffuse large B-cell lymphomas (DLBCL), 2,686 follicular lymphomas (FL), 2,878 chronic lymphocytic leukemia/small lymphocytic lymphomas (CLL/SLL), 741 marginal zone lymphomas (MZL), and 8,753 controls of European descent. Both DLBCL and MZL risk were elevated with homozygosity at class I HLA-B and -C loci (OR DLBCL = 1.31, 95% CI = 1.06-1.60; OR MZL = 1.45, 95% CI = 1.12-1.89) and class II HLA-DRB1 locus (OR DLBCL = 2.10, 95% CI = 1.24-3.55; OR MZL = 2.10, 95% CI = 0.99-4.45). Increased FL risk was observed with the overall increase in number of homozygous HLA class II loci (P trend < 0.0001, FDR = 0.0005). These results support a role for HLA zygosity in NHL etiology and suggests that distinct immune pathways may underly the etiology of the different NHL subtypes.Significance: HLA gene diversity reduces risk for non-Hodgkin lymphoma. Cancer Res; 78(14); 4086-96. ©2018 AACR.

Bill Lyons Informatics Centre UCL Cancer Institute University College London London United Kingdom

Braun School of Public Health and Community Medicine Hadassah Hebrew University Medical Center Jerusalem Israel

Cancer and Inflammation Program Leidos Biomedical Research Inc Frederick National Laboratory for Cancer Research Frederick Maryland and Ragon Institute of MGH MIT and Harvard Cambridge Massachusetts

Cancer Control Research British Columbia Cancer Agency Vancouver British Columbia Canada

Cancer Epidemiology and Intelligence Division Cancer Council Victoria Melbourne Australia

Cancer Epidemiology Unit University of Oxford Oxford United Kingdom

Center of Oncological Prevention Piemonte and Unit of Medical Statistics and Epidemiology Department Translational Medicine University of Piemonte Orientale Novara Italy

Centre for Big Data Research in Health The University of New South Wales Sydney New South Wales Australia

Centre for Chronic Immunodeficiency University Medical Center Freiburg Freiburg Baden Württemberg Germany

Centre for Epidemiology and Biostatistics Melbourne School of Population and Global Health University of Melbourne Melbourne Victoria Australia

Channing Division of Network Medicine Department of Medicine Brigham and Women's Hospital and Harvard Medical School Boston Massachusetts

CIBER Epidemiología y Salud Pública Madrid Spain

Department of Biomedical Physiology and Kinesiology Simon Fraser University Burnaby British Columbia Canada

Department of Biomedical Science University of Cagliari Monserrato Cagliari Italy

Department of Biostatistics Harvard T H Chan School of Public Health Boston Massachusetts

Department of Cancer Epidemiology and Genetics Masaryk Memorial Cancer Institute MF MU Brno Czech Republic

Department of Environmental Health Sciences Yale School of Public Health New Haven

Department of Environmental Medicine New York University School of Medicine New York City New York

Department of Epidemiology and Biostatistics School of Public Health Imperial College London London United Kingdom; Cancer Research Center of Lyon INSERM UMR1052 Center Léon Bérard Lyon France

Department of Epidemiology and Biostatistics University of California San Francisco San Francisco California

Department of Epidemiology Harvard T H Chan School of Public Health Boston Massachusetts

Department of Epidemiology Research Division of Health Surveillance and Research Statens Serum Institut Copenhagen Denmark

Department of Epidemiology School of Public Health Brown University Providence Rhode Island

Department of Family Medicine and Public Health Sciences Wayne State University Detroit Michigan

Department of Health Sciences Research Mayo Clinic Rochester Minnesota

Department of Health Sciences University of York York United Kingdom

Department of Hematology and Medical Oncology Emory University School of Medicine Atlanta Georgia

Department of Hematology Hospices Civils De Lyon Centre Hospitalier Lyon Sud and Université Claude Bernard Lyon France

Department of Hematology Rishospitalet Copenhagen Denmark

Department of Histopathology Douglass Hanly Moir Pathology Sydney Australia

Department of Immunology CHU Henri Mondor Créteil France

Department of Immunology Genetics and Pathology Uppsala University Uppsala Sweden

Department of Internal Medicine Carver College of Medicine The University of Iowa Iowa City Iowa

Department of Internal Medicine Huntsman Cancer Institute University of Utah School of Medicine Salt Lake City Utah

Department of Laboratory Medicine and Pathology Mayo Clinic Rochester Minnesota

Department of Medical Epidemiology and Biostatistics Karolinska Institutet Stockholm Sweden

Department of Medicine Memorial Sloan Kettering Cancer Center New York City New York

Department of Medicine Solna unit of clinical epidemiology Karolinska Institutet Stockholm Sweden

Department of Medicine Stanford University School of Medicine Stanford Calfornia

Department of Obstetrics and Gynecology New York University School of Medicine New York City New York

Department of Pathology City of Hope Duarte California

Department of Pathology School of Medicine and the UAB Comprehensive Cancer Center The University of Alabama at Birmingham Birmingham Alabama

Department of Population Sciences Beckman Research Institute and the City of Hope Duarte California

Department of Public Health Clinical and Molecular Medicine University of Cagliari Cagliari Italy

Department of Surgery Yale School of Medicine New Haven Connecticut

Division of Cancer Epidemiology and Genetics NCI Bethesda Maryland

Division of Clinical Epidemiology German Cancer Research Centre Heidelberg Baden Württemberg Germany

Division of Environmental Health Sciences School of Public Health University of California Berkeley Berkeley California

Division of Hematology S Francesco Hospital Nuoro Italy

Epidemiology of Childhood and Adolescent Cancers Group Inserm Center of Research in Epidemiology and Statistics Sorbonne Paris Cité Paris France

Epidemiology Research Program American Cancer Society Atlanta Georgia

Faculty of Medicine and Health Sciences Macquarie University Sydney Australia

Fred Hutchinson Cancer Research Center and School of Public Health and Community Medicine University of Washington Seattle Washington

Genetic Epidemiology Laboratory Department of Pathology University of Melbourne Melbourne Victoria Australia

Genome Sciences Centre BC Cancer Agency Vancouver British Columbia Canada

Hematology Center Karolinska University Hospital Stockholm Sweden

INSERM U 955 CHU Henri Mondor Créteil France

Institute for Risk Assessment Sciences Utrecht University Utrecht the Netherlands

International Agency for Research on Cancer Lyon France

Julius Center for Health Sciences and Primary Care University Medical Center Utrecht Utrecht the Netherlands

Laboratoire de Biologie Moléculaire de la Cellule UMR 5239 Centre National de la Recherche Scientifique Pierre benite Cedex France

Norris Comprehensive Cancer Center Keck School of Medicine of USC Departments of Preventive Medicine and Pathology University of Southern California Los Angeles Calfornia

Perlmutter Cancer Center NYU Langone Medical Center New York City New York

Registre des hémopathies malignes de la Gironde Institut Bergonié University of Bordeaux Inserm Team EPICENE UMR 1219 France

Registry of Hematological Malignancies of Cote d'Or INSERM UMR1231 University of Burgundy and Dijon University Hospital Dijon France

School of Nursing and Human Sciences Dublin City University Dublin Ireland

School of Population and Public Health University of British Columbia Vancouver British Columbia Canada

School of Public Health Imperial College London London United Kingdom

Sydney School of Public Health The University of Sydney Sydney Australia

The Tisch Cancer Institute Icahn School of Medicine at Mount Sinai New York City New York

Unit of Infections and Cancer Cancer Epidemiology Research Programme Institut Català d' Oncologia IDIBELL 08908 L'Hospitalet de Llobregat Barcelona Spain

Université Paris Descartes Paris France

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