Marginal zone lymphoma (MZL) is the third most common subtype of B-cell non-Hodgkin lymphoma. Here we perform a two-stage GWAS of 1,281 MZL cases and 7,127 controls of European ancestry and identify two independent loci near BTNL2 (rs9461741, P=3.95 × 10(-15)) and HLA-B (rs2922994, P=2.43 × 10(-9)) in the HLA region significantly associated with MZL risk. This is the first evidence that genetic variation in the major histocompatibility complex influences MZL susceptibility.

] Cancer Control Research BC Cancer Agency Vancouver British Columbia Canada V5Z1L3 [2] School of Population and Public Health University of British Columbia Vancouver British Columbia Canada V6T1Z3

] Cancer Epidemiology Centre Cancer Council Victoria Melbourne Victoria 3053 Australia [2] Centre for Epidemiology and Biostatistics Melbourne School of Population and Global Health University of Melbourne Carlton Victoria 3010 Australia

] Cancer Epidemiology Centre Cancer Council Victoria Melbourne Victoria 3053 Australia [2] Centre for Epidemiology and Biostatistics Melbourne School of Population and Global Health University of Melbourne Carlton Victoria 3010 Australia [3] Human Genetics Foundation Turin 10126 Italy

] Channing Division of Network Medicine Department of Medicine Brigham and Women's Hospital and Harvard Medical School Boston Massachusetts 02115 USA [2] Department of Epidemiology Harvard School of Public Health Boston Massachusetts 02115 USA

] Channing Division of Network Medicine Department of Medicine Brigham and Women's Hospital and Harvard Medical School Boston Massachusetts 02115 USA [2] Department of Epidemiology Harvard School of Public Health Boston Massachusetts 02115 USA [3] Department of Nutrition Harvard School of Public Health Boston Massachusetts 02115 USA

] Department of Epidemiology Harvard School of Public Health Boston Massachusetts 02115 USA [2] College of Information Science and Technology Dalian Maritime University Dalian 116026 China

] Department of Epidemiology Harvard School of Public Health Boston Massachusetts 02115 USA [2] Department of Biostatistics Harvard School of Public Health Boston Massachusetts 02115 USA

] Department of Epidemiology Harvard School of Public Health Boston Massachusetts 02115 USA [2] Department of Medical Epidemiology and Biostatistics Karolinska Institutet Stockholm 17177 Sweden

] Department of Epidemiology Julius Center for Health Sciences and Primary Care University Medical Center Utrecht Utrecht 3584 CX The Netherlands [2] Institute for Risk Assessment Sciences Utrecht University Utrecht 3508 TD The Netherlands

] Department of Epidemiology Research Division of Health Surveillance and Research Statens Serum Institut Copenhagen 2300 Denmark [2] Department of Medicine Stanford University School of Medicine Stanford California 94305 USA

] Department of Epidemiology School of Public Health and Comprehensive Cancer Center Birmingham Alabama 35233 USA [2] Division of Environmental Health Sciences University of California Berkeley School of Public Health Berkeley California 94720 USA

] Department of Epidemiology University of North Carolina at Chapel Hill Chapel Hill North Carolina 27599 USA [2] Carolina Center for Genome Sciences University of North Carolina at Chapel Hill Chapel Hill North Carolina 27599 USA

] Department of Medical Genetics Center for Molecular Medicine University Medical Center Utrecht Utrecht 3584 CG The Netherlands [2] Department of Epidemiology Julius Center for Health Sciences and Primary Care University Medical Center Utrecht Utrecht 3584 CX The Netherlands

] Department of Oncology and Pathology Karolinska Institutet Karolinska University Hospital Solna Stockholm 17176 Sweden [2] Department of Radiology Oncology and Radiation Science Uppsala University Uppsala 75105 Sweden

] Department of Population Health New York University School of Medicine New York New York 10016 USA [2] Cancer Institute New York University School of Medicine New York New York 10016 USA

] Department of Preventive Medicine USC Keck School of Medicine University of Southern California Los Angeles California 90033 USA [2] Norris Comprehensive Cancer Center USC Keck School of Medicine University of Southern California Los Angeles California 90033 USA

] Division of Public Health Sciences Fred Hutchinson Cancer Research Center Seattle Washington 98117 USA [2] Department of Environmental and Occupational Health Drexel University School of Public Health Philadelphia Pennsylvania 19104 USA

] Environmental Epidemiology of Cancer Group Inserm Centre for research in Epidemiology and Population Health U1018 Villejuif F 94807 France [2] UMRS 1018 Univ Paris Sud Villejuif F 94807 France

] Environmental Epidemiology of Cancer Group Inserm Centre for research in Epidemiology and Population Health U1018 Villejuif F 94807 France [2] UMRS 1018 Univ Paris Sud Villejuif F 94807 France [3] Registre des hémopathies malignes de la Gironde Institut Bergonié Bordeaux 33076 France

] Genome Sciences Centre BC Cancer Agency Vancouver British Columbia Canada V5Z1L3 [2] Department of Biomedical Physiology and Kinesiology Simon Fraser University Burnaby British Columbia Canada V5A1S6

] MRC PHE Centre for Environment and Health School of Public Health Imperial College London London W2 1PG UK [2] Human Genetics Foundation Turin 10126 Italy

] Pathology Australian School of Advanced Medicine Macquarie University Sydney New South Wales 2109 Australia [2] Department of Histopathology Douglass Hanly Moir Pathology Macquarie Park New South Wales 2113 Australia

] Unit of Infections and Cancer Barcelona 8036 Spain

Cancer Genomics Research Laboratory Division of Cancer Epidemiology and Genetics National Cancer Institute Gaithersburg Maryland 20877 USA

Center For Chronic Immunodeficiency University Medical Center Freiburg Freiburg 79108 Germany

Channing Division of Network Medicine Department of Medicine Brigham and Women's Hospital and Harvard Medical School Boston Massachusetts 02115 USA

Department of Biomedical Science University of Cagliari Monserrato Cagliari 09042 Italy

Department of Biostatistics Yale School of Public Health New Haven Connecticut 06520 USA

Department of Cancer Epidemiology and Genetics Masaryk Memorial Cancer Institute and MF MU Brno 65653 Czech Republic

Department of Cancer Etiology City of Hope Beckman Research Institute Duarte California 91030 USA

Department of Chronic Disease Prevention National Institute for Health and Welfare Helsinki FI 00271 Finland

Department of Environmental Health Sciences Yale School of Public Health New Haven Connecticut 06520 USA

Department of Epidemiology and Biostatistics University of California San Francisco San Francisco California 94118 USA

Department of Epidemiology Harvard School of Public Health Boston Massachusetts 02115 USA

Department of Epidemiology M D Anderson Cancer Center Houston Texas 77030 USA

Department of Epidemiology Research Division of Health Surveillance and Research Statens Serum Institut Copenhagen 2300 Denmark

Department of Family Medicine and Public Health Sciences Wayne State University Detroit Michigan 48201 USA

Department of Health Sciences Research Mayo Clinic Rochester Minnesota 55905 USA

Department of Health Sciences University of York York YO10 5DD UK

Department of Health Studies University of Chicago Chicago Illinois 60637 USA

Department of Internal Medicine Carver College of Medicine The University of Iowa Iowa City Iowa 52242 USA

Department of Medicine Mayo Clinic Rochester Minnesota 55905 USA

Department of Medicine Memorial Sloan Kettering Cancer Center New York New York 10065 USA

Department of Medicine Solna Karolinska Institutet Stockholm 17176 Sweden

Department of Pathological Anatomy University of Bari Bari 70124 Italy

Departments of Laboratory Medicine and Pathology Memorial Sloan Kettering Cancer Center New York New York 10065 USA

Division of Cancer Epidemiology and Genetics National Cancer Institute Bethesda Maryland 20892 USA

Division of Cancer Epidemiology German Cancer Research Center Heidelberg 69120 Germany

Division of Endocrinology Diabetes and Metabolism The Ohio State University Columbus Ohio 43210 USA

Division of Environmental Health Sciences University of California Berkeley School of Public Health Berkeley California 94720 USA

Division of Public Health Sciences Fred Hutchinson Cancer Research Center Seattle Washington 98117 USA

EA 4184 Registre des Hémopathies Malignes de Côte d'Or University of Burgundy and Dijon University Hospital Dijon 21070 France

Environmental and Occupational Epidemiology Unit Cancer Prevention and Research Institute Florence 50139 Italy

Epidemiology Research Program American Cancer Society Atlanta Georgia 30303 USA

Genetic Cancer Susceptibility Group Section of Genetics International Agency for Research on Cancer Lyon 69372 France

Group of Genetic Epidemiology Section of Genetics International Agency for Research on Cancer Lyon 69372 France

Health Studies Sector Westat Rockville Maryland 20850 USA

Interdisciplinary Department of Medicine University of Bari Bari 70124 Italy

MRC PHE Centre for Environment and Health School of Public Health Imperial College London London W2 1PG UK

Prince of Wales Clinical School University of New South Wales Sydney New South Wales 2052 Australia

School of Nursing and Human Sciences Dublin City University Dublin 9 Ireland

Sydney School of Public Health The University of Sydney Sydney New South Wales 2006 Australia

The Tisch Cancer Institute Icahn School of Medicine at Mount Sinai New York New York 10029 USA

Zobrazit více v PubMed

Doglioni C., Wotherspoon A. C., Moschini A., de Boni M. & Isaacson P. G. High incidence of primary gastric lymphoma in northeastern Italy. Lancet 339, 834–835 (1992). PubMed

Parsonnet J. et al. Helicobacter pylori infection and gastric lymphoma. New Engl. J. Med. 330, 1267–1271 (1994). PubMed

Wang Z. et al. Improved imputation of common and uncommon SNPs with a new reference set. Nat. Genet. 44, 6–7 (2012). PubMed PMC

Ku D. H. et al. A new growth-regulated complementary DNA with the sequence of a putative trans-activating factor. Cell Growth Differ. 2, 179–186 (1991). PubMed

Jia X. et al. Imputing amino acid polymorphisms in human leukocyte antigens. PLoS ONE 8, e64683 (2013). PubMed PMC

Mayerle J. et al. Identification of genetic loci associated with Helicobacter pylori serologic status. JAMA 309, 1912–1920 (2013). PubMed

Purdue M. P. et al. A pooled investigation of Toll-like receptor gene variants and risk of non-Hodgkin lymphoma. Carcinogenesis 30, 275–281 (2009). PubMed PMC

Arnett H. A. et al. BTNL2, a butyrophilin/B7-like molecule, is a negative costimulatory molecule modulated in intestinal inflammation. J. Immunol. 178, 1523–1533 (2007). PubMed

Nguyen T., Liu X. K., Zhang Y. & Dong C. BTNL2, a butyrophilin-like molecule that functions to inhibit T cell activation. J. Immunol. 176, 7354–7360 (2006). PubMed PMC

Swanson R. M. et al. Butyrophilin-like 2 modulates B7 costimulation to induce Foxp3 expression and regulatory T cell development in mature T cells. J. Immunol. 190, 2027–2035 (2013). PubMed

Kallberg H. et al. Gene-gene and gene-environment interactions involving HLA-DRB1, PTPN22, and smoking in two subsets of rheumatoid arthritis. Am. J. Hum. Genet. 80, 867–875 (2007). PubMed PMC

Ferreira R. C. et al. High-density SNP mapping of the HLA region identifies multiple independent susceptibility loci associated with selective IgA deficiency. PLoS Genet. 8, e1002476 (2012). PubMed PMC

Ferreira M. A. et al. Sequence variants in three loci influence monocyte counts and erythrocyte volume. Am. J. Hum. Genet. 85, 745–749 (2009). PubMed PMC

Hystad M. E. et al. Characterization of early stages of human B cell development by gene expression profiling. J. Immunol. 179, 3662–3671 (2007). PubMed

Dias C. & Isenberg D. A. Susceptibility of patients with rheumatic diseases to B-cell non-Hodgkin lymphoma. Nat. Rev. Rheumatol. 7, 360–368 (2011). PubMed

Lessard C. J. et al. Variants at multiple loci implicated in both innate and adaptive immune responses are associated with Sjogren’s syndrome. Nat. Genet. 45, 1284–1292 (2013). PubMed PMC

Raychaudhuri S. et al. Five amino acids in three HLA proteins explain most of the association between MHC and seropositive rheumatoid arthritis. Nat. Genet. 44, 291–296 (2012). PubMed PMC

Berndt S. I. et al. Genome-wide association study identifies multiple risk loci for chronic lymphocytic leukemia. Nat. Genet. 45, 868–876 (2013). PubMed PMC

Cerhan J. R. et al. Genome-wide association study identifies multiple susceptibility loci for diffuse large B cell lymphoma. Nat. Genet. 46, 1233–1238 (2014). PubMed PMC

Smedby K. E. et al. GWAS of follicular lymphoma reveals allelic heterogeneity at 6p21.32 and suggests shared genetic susceptibility with diffuse large B-cell lymphoma. PLoS Genet. 7, e1001378 (2011). PubMed PMC

Conde L. et al. Genome-wide association study of follicular lymphoma identifies a risk locus at 6p21.32. Nat. Genet. 42, 661–664 (2010). PubMed PMC

Vijai J. et al. Susceptibility loci associated with specific and shared subtypes of lymphoid malignancies. PLoS Genet. 9, e1003220 (2013). PubMed PMC

Skibola C. F. et al. Genome-wide association study identifies five susceptibility loci for follicular lymphoma outside the HLA region. Am. J. Hum. Genet. 95, 462–471 (2014). PubMed PMC

Morton L. M. et al. Proposed classification of lymphoid neoplasms for epidemiologic research from the Pathology Working Group of the International Lymphoma Epidemiology Consortium (InterLymph). Blood 110, 695–708 (2007). PubMed PMC

Turner J. J. et al. InterLymph hierarchical classification of lymphoid neoplasms for epidemiologic research based on the WHO classification (2008): update and future directions. Blood 116, e90–e98 (2010). PubMed PMC

Swerdlow S., Campo E. & Harris N. World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues IARC Press (2008).

Pritchard J. K., Stephens M. & Donnelly P. Inference of population structure using multilocus genotype data. Genetics 155, 945–959 (2000). PubMed PMC

Price A. L. et al. Principal components analysis corrects for stratification in genome-wide association studies. Nat. Genet. 38, 904–909 (2006). PubMed

Howie B. N., Donnelly P. & Marchini J. A flexible and accurate genotype imputation method for the next generation of genome-wide association studies. PLoS Genet. 5, e1000529 (2009). PubMed PMC

Abecasis G. R. et al. A map of human genome variation from population-scale sequencing. Nature 467, 1061–1073 (2010). PubMed PMC

Ferreira T. & Marchini J. Modeling interactions with known risk loci-a Bayesian model averaging approach. Ann. Hum. Genet. 75, 1–9 (2011). PubMed

Wang S. S. et al. Human leukocyte antigen class I and II alleles in non-Hodgkin lymphoma etiology. Blood 115, 4820–4823 (2010). PubMed PMC

Purcell S. et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am. J. Hum. Genet. 81, 559–575 (2007). PubMed PMC

Dixon A. L. et al. A genome-wide association study of global gene expression. Nat. Genet. 39, 1202–1207 (2007). PubMed

Cheung V. G. et al. Polymorphic cis- and trans-regulation of human gene expression. PLoS Biol. 8, 9 (2010). PubMed PMC

Chen W. M. & Abecasis G. R. Family-based association tests for genomewide association scans. Am. J. Hum. Genet. 81, 913–926 (2007). PubMed PMC

Abecasis G. R. & Wigginton J. E. Handling marker-marker linkage disequilibrium: pedigree analysis with clustered markers. Am. J. Hum. Genet. 77, 754–767 (2005). PubMed PMC

Barenboim M. & Manke T. ChroMoS: an integrated web tool for SNP classification, prioritization and functional interpretation. Bioinformatics 29, 2197–2198 (2013). PubMed PMC

Ernst J. et al. Mapping and analysis of chromatin state dynamics in nine human cell types. Nature 473, 43–49 (2011). PubMed PMC

Distinct germline genetic susceptibility profiles identified for common non-Hodgkin lymphoma subtypes

B-Cell NHL Subtype Risk Associated with Autoimmune Conditions and PRS

Genome-wide homozygosity and risk of four non-Hodgkin lymphoma subtypes

Genetic overlap between autoimmune diseases and non-Hodgkin lymphoma subtypes

Genetically Determined Height and Risk of Non-hodgkin Lymphoma

HLA Class I and II Diversity Contributes to the Etiologic Heterogeneity of Non-Hodgkin Lymphoma Subtypes

Genetically predicted longer telomere length is associated with increased risk of B-cell lymphoma subtypes