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Genome-wide association study identifies five susceptibility loci for follicular lymphoma outside the HLA region.

About this Publication
Title
Genome-wide association study identifies five susceptibility loci for follicular lymphoma outside the HLA region.
Pubmed ID
25279986 (View this publication on the PubMed website)
Publication
Am. J. Hum. Genet. 2014 Oct; Volume 95 (Issue 4): Pages 462-71
Authors
Skibola CF, Berndt SI, Vijai J, Conde L, Wang Z, Yeager M, de Bakker PI, Birmann BM, Vajdic CM, Foo JN, Bracci PM, Vermeulen RC, Slager SL, de Sanjose S, Wang SS, Linet MS, Salles G, Lan Q, Severi G, Hjalgrim H, ...show more Lightfoot T, Melbye M, Gu J, Ghesquières H, Link BK, Morton LM, Holly EA, Smith A, Tinker LF, Teras LR, Kricker A, Becker N, Purdue MP, Spinelli JJ, Zhang Y, Giles GG, Vineis P, Monnereau A, Bertrand KA, Albanes D, Zeleniuch-Jacquotte A, Gabbas A, Chung CC, Burdett L, Hutchinson A, Lawrence C, Montalvan R, Liang L, Huang J, Ma B, Liu J, Adami HO, Glimelius B, Ye Y, Nowakowski GS, Dogan A, Thompson CA, Habermann TM, Novak AJ, Liebow M, Witzig TE, Weiner GJ, Schenk M, Hartge P, De Roos AJ, Cozen W, Zhi D, Akers NK, Riby J, Smith MT, Lacher M, Villano DJ, Maria A, Roman E, Kane E, Jackson RD, North KE, Diver WR, Turner J, Armstrong BK, Benavente Y, Boffetta P, Brennan P, Foretova L, Maynadie M, Staines A, McKay J, Brooks-Wilson AR, Zheng T, Holford TR, Chamosa S, Kaaks R, Kelly RS, Ohlsson B, Travis RC, Weiderpass E, Clavel J, Giovannucci E, Kraft P, Virtamo J, Mazza P, Cocco P, Ennas MG, Chiu BC, Fraumeni JF, Nieters A, Offit K, Wu X, Cerhan JR, Smedby KE, Chanock SJ, Rothman N
Affiliations
  • Department of Epidemiology, School of Public Health and Comprehensive Cancer Center, Birmingham, AL 35233, USA; Division of Environmental Health Sciences, University of California Berkeley School of Public Health, Berkeley, CA 94720, USA. Electronic address: cskibola@uab.edu.
  • Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
  • Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • Department of Epidemiology, School of Public Health and Comprehensive Cancer Center, Birmingham, AL 35233, USA; Division of Environmental Health Sciences, University of California Berkeley School of Public Health, Berkeley, CA 94720, USA.
  • Cancer Genomics Research Laboratory, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Gaithersburg, MD 20877, USA.
  • Department of Medical Genetics and of Epidemiology, University Medical Center Utrecht, Utrecht 3584 CG, the Netherlands; Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht 3584 CX, the Netherlands.
  • Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
  • Prince of Wales Clinical School, University of New South Wales, Sydney, NSW 2052, Australia.
  • Human Genetics, Genome Institute of Singapore, Singapore 138672, Singapore.
  • Department of Epidemiology & Biostatistics, University of California, San Francisco, San Francisco, CA 94118, USA.
...show more
  • Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht 3584 CX, the Netherlands; Institute for Risk Assessment Sciences, Utrecht University, Utrecht 3508 TD, the Netherlands.
  • Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA.
  • Unit of Infections and Cancer (UNIC), Cancer Epidemiology Research Programme, Institut Catala d'Oncologia, IDIBELL, Barcelona 8907, Spain; Centro de Investigación Biomédica en Red de Epidemiología y Salud Pública (CIBERESP), Barcelona 8036, Spain.
  • Department of Cancer Etiology, City of Hope Beckman Research Institute, Duarte, CA 91030, USA.
  • Department of Hematology, Hospices Civils de Lyon, Pierre benite Cedex 69495, France; Department of Hematology, Université Lyon-1, Pierre benite Cedex 69495, France; Laboratoire de Biologie Moléculaire de la Cellule UMR 5239, Centre National de la Recherche Scientifique, Pierre benite Cedex 69495, France.
  • Human Genetics Foundation, Turin 10126, Italy; Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, VIC 3053, Australia; Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Carlton, VIC 3010, Australia.
  • Department of Epidemiology Research, Division of Health Surveillance and Research, Statens Serum Institut, Copenhagen 2300, Denmark.
  • Department of Health Sciences, University of York, York YO10 5DD, UK.
  • Department of Epidemiology Research, Division of Health Surveillance and Research, Statens Serum Institut, Copenhagen 2300, Denmark; Department of Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • Department of Epidemiology, M.D. Anderson Cancer Center, Houston, TX 77030, USA.
  • Laboratoire de Biologie Moléculaire de la Cellule UMR 5239, Centre National de la Recherche Scientifique, Pierre benite Cedex 69495, France; Department of Hematology, Centre Léon Bérard, Lyon 69008, France.
  • Department of Internal Medicine, Carver College of Medicine, The University of Iowa, Iowa City, IA 52242, USA.
  • Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98117, USA.
  • Epidemiology Research Program, American Cancer Society, Atlanta, GA 30303, USA.
  • Sydney School of Public Health, The University of Sydney, Sydney, NSW 2006, Australia.
  • Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Baden-Württemberg 69120, Germany.
  • Cancer Control Research, BC Cancer Agency, Vancouver, BC V5Z 1L3, Canada; School of Population and Public Health, University of British Columbia, Vancouver, BC V6T 1Z3, Canada.
  • Department of Environmental Health Sciences, Yale School of Public Health, New Haven, CT 06520, USA.
  • Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, VIC 3053, Australia; Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Carlton, VIC 3010, Australia.
  • Human Genetics Foundation, Turin 10126, Italy; MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London W2 1PG, UK.
  • Environmental Epidemiology of Cancer Group, Inserm, Centre for Research in Epidemiology and Population Health (CESP), U1018, Villejuif Cedex 94807, France; UMRS 1018, Université Paris Sud, Villejuif Cedex 94807, France; Registre des hémopathies malignes de la Gironde, Institut Bergonié, Bordeaux Cedex 33076, France.
  • Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Department of Epidemiology, Harvard School of Public Health, Boston, MA 02115, USA.
  • Department of Population Health, New York University School of Medicine, New York, NY 10016, USA; Cancer Institute, New York University School of Medicine, New York, NY 10016, USA.
  • Department of Public Health, Clinical and Molecular Medicine, University of Cagliari, Monserrato, Cagliari 09042, Italy.
  • Health Studies Sector, Westat, Rockville, MD 20850, USA.
  • Department of Epidemiology, Harvard School of Public Health, Boston, MA 02115, USA; Department of Biostatistics, Harvard School of Public Health, Boston, MA 02115, USA.
  • Department of Epidemiology, Harvard School of Public Health, Boston, MA 02115, USA.
  • Department of Epidemiology, Harvard School of Public Health, Boston, MA 02115, USA; College of Information Science and Technology, Dalian Maritime University, Dalian, Liaoning Province 116026, China.
  • Department of Epidemiology, Harvard School of Public Health, Boston, MA 02115, USA; Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm 17177, Sweden.
  • Department of Oncology and Pathology, Karolinska Institutet, Karolinska University Hospital Solna, Stockholm 17176, Sweden; Department of Radiology, Oncology and Radiation Science, Uppsala University, Uppsala 75105, Sweden.
  • Departments of Laboratory Medicine and Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • Department of Medicine, Mayo Clinic, Rochester, MN 55905, USA.
  • Department of Family Medicine and Public Health Sciences, Wayne State University, Detroit, MI 48201, USA.
  • Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA 98117, USA; Department of Environmental and Occupational Health, Drexel University School of Public Health, Philadelphia, PA 19104, USA.
  • Department of Preventive Medicine, USC Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA; Norris Comprehensive Cancer Center, USC Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
  • Department of Biostatistics, University of Alabama at Birmingham, Birmingham, AL 35233, USA.
  • Division of Environmental Health Sciences, University of California Berkeley School of Public Health, Berkeley, CA 94720, USA.
  • Division of Endocrinology, Diabetes and Metabolism, The Ohio State University, Columbus, OH 43210, USA.
  • Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Carolina Center for Genome Sciences, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.
  • Department of Anatomical Pathology, Australian School of Advanced Medicine, Macquarie University, Sydney, NSW 2109, Australia; Department of Histopathology, Douglass Hanly Moir Pathology, Macquarie Park, NSW 2113, Australia.
  • The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
  • Group of Genetic Epidemiology, Section of Genetics, International Agency for Research on Cancer, Lyon 69372, France.
  • Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute and MF MU, Brno 656 53, Czech Republic.
  • EA 4184, Registre des Hémopathies Malignes de Côte d'Or, University of Burgundy and Dijon University Hospital, Dijon 21070, France.
  • School of Nursing and Human Sciences, Dublin City University, Dublin 9, Ireland.
  • Genetic Cancer Susceptibility Group, Section of Genetics, International Agency for Research on Cancer, Lyon 69372, France.
  • Genome Sciences Centre, BC Cancer Agency, Vancouver, BC V5Z 1L3, Canada; Department of Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, BC V5A 1S6, Canada.
  • Department of Biostatistics, Yale School of Public Health, New Haven, CT 06520, USA.
  • Health Department, BioDonostia Research Institute, Basque Region 20014, Spain.
  • MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London W2 1PG, UK; Department of Epidemiology, Harvard School of Public Health, Boston, MA 02115, USA.
  • Department of Clinical Sciences, Division of Internal Medicine, Skåne University Hospital, Lund University, Malmö 205 02, Sweden.
  • Cancer Epidemiology Unit, University of Oxford, Oxford OX3 7LF, UK.
  • Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm 17177, Sweden; Department of Community Medicine, Faculty of Health Sciences, University of Tromsø, Breivika 9037, Norway; Cancer Registry of Norway, Oslo 0304, Norway; Department of Genetic Epidemiology, Folkhalsan Research Center, Helsinki 00250, Finland.
  • Environmental Epidemiology of Cancer Group, Inserm, Centre for Research in Epidemiology and Population Health (CESP), U1018, Villejuif Cedex 94807, France; UMRS 1018, Université Paris Sud, Villejuif Cedex 94807, France.
  • Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Department of Epidemiology, Harvard School of Public Health, Boston, MA 02115, USA; Department of Nutrition, Harvard School of Public Health, Boston, MA 02115, USA.
  • Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki 00271, Finland.
  • Department of Hematology, Ospedale Nord, Taranto 74100, Italy.
  • Department of Biomedical Science, University of Cagliari, Monserrato, Cagliari 09042, Italy.
  • Department of Health Studies, University of Chicago, Chicago, IL 60637, USA.
  • Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg, Baden-Württemberg 79108, Germany.
  • Department of Medicine Solna, Karolinska Institutet, Stockholm 17176, Sweden.
Abstract

Genome-wide association studies (GWASs) of follicular lymphoma (FL) have previously identified human leukocyte antigen (HLA) gene variants. To identify additional FL susceptibility loci, we conducted a large-scale two-stage GWAS in 4,523 case subjects and 13,344 control subjects of European ancestry. Five non-HLA loci were associated with FL risk: 11q23.3 (rs4938573, p = 5.79 × 10(-20)) near CXCR5; 11q24.3 (rs4937362, p = 6.76 × 10(-11)) near ETS1; 3q28 (rs6444305, p = 1.10 × 10(-10)) in LPP; 18q21.33 (rs17749561, p = 8.28 × 10(-10)) near BCL2; and 8q24.21 (rs13254990, p = 1.06 × 10(-8)) near PVT1. In an analysis of the HLA region, we identified four linked HLA-DRβ1 multiallelic amino acids at positions 11, 13, 28, and 30 that were associated with FL risk (pomnibus = 4.20 × 10(-67) to 2.67 × 10(-70)). Additional independent signals included rs17203612 in HLA class II (odds ratio [OR(per-allele)] = 1.44; p = 4.59 × 10(-16)) and rs3130437 in HLA class I (OR(per-allele) = 1.23; p = 8.23 × 10(-9)). Our findings further expand the number of loci associated with FL and provide evidence that multiple common variants outside the HLA region make a significant contribution to FL risk.

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