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Nat Commun. 2017 Feb 6;8:14175. doi: 10.1038/ncomms14175.

Genome-wide association analysis implicates dysregulation of immunity genes in chronic lymphocytic leukaemia.

Author information

1
Division of Genetics and Epidemiology, The Institute of Cancer Research, London SW7 3RP, UK.
2
Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland 20892, USA.
3
Department of Internal Medicine, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah 84112, USA.
4
Department of Epidemiology, School of Public Health and Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama 35233, USA.
5
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
6
Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne NE2 4HH, UK.
7
Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg, Baden-Württemberg 79108, Germany.
8
Institut d'Investigacions Biomèdiques August Pi iSunyer (IDIBAPS), Hospital Clínic, Barcelona 08036, Spain.
9
Registre des hémopathies malignes de la Gironde, Institut Bergonié, Inserm U1219 EPICENE, 33076 Bordeaux, France.
10
Epidemiology of Childhood and Adolescent Cancers Group, Inserm, Center of Research in Epidemiology and Statistics Sorbonne Paris Cité, Paris, F-94807, France.
11
Université Paris Descartes, Paris 75270, France.
12
Epidemiology Research Program, American Cancer Society, Atlanta, Georgia 30303, USA.
13
Grupo de Medicina Xenomica, Universidade de Santiago de Compostela, Centro Nacional de Genotipado (CeGen-PRB2-ISCIII), CIBERER, 15782 Santiago de Compostela, Spain.
14
Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
15
Ernest and Helen Scott Haematological Research Institute, University of Leicester, Leicester LE2 7LX, UK.
16
Department of Preventive Medicine, USC Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA.
17
Norris Comprehensive Cancer Center, USC Keck School of Medicine, University of Southern California, Los Angeles, California 90033, USA.
18
Unit of Clinical Epidemiology, Department of Medicine Solna, Karolinska Institutet, Hematology Center, Karolinsak University Hospital, Stockholm 17176, Sweden.
19
The Royal Marsden NHS Foundation Trust, London SM2 5PT, UK.
20
Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia, Canada V5Z1L3.
21
Department of Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, British Columbia V5A1S6, Canada.
22
Haematological Sciences, Medical School, Newcastle University, Newcastle-upon-Tyne NE2 4HH, UK.
23
Centre for Big Data Research in Health, University of New South Wales, Sydney, New South Wales 2052, Australia.
24
Department of Haematology, Royal Victoria Infirmary, Newcastle upon Tyne NE1 4LP, UK.
25
Department of Public Health, Clinical and Molecular Medicine, University of Cagliari, Monserrato, Cagliari 09042, Italy.
26
Department of Environmental Health Sciences, Yale School of Public Health, New Haven, Connecticut 06520, USA.
27
Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Victoria 3004, Australia.
28
Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Victoria 3010, Australia.
29
Westat, Rockville, Maryland 20850, USA.
30
Division of Hematology, Mayo Clinic, Rochester, Minnesota 55905, USA.
31
Department of Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA.
32
Department of Epidemiology Research, Division of Health Surveillance and Research, Statens Serum Institut, 2300 Copenhagen, Denmark.
33
Department of Medicine, Stanford University School of Medicine, Stanford, California 94305, USA.
34
Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, 75105 Uppsala, Sweden.
35
Department of Internal Medicine, Carver College of Medicine, The University of Iowa, Iowa City, Iowa 52242, USA.
36
Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California 94118, USA.
37
Division of Endocrinology, Diabetes and Metabolism, Ohio State University, Columbus, Ohio 43210, USA.
38
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98117, USA.
39
Cancer Epidemiology Research Programme, Catalan Institute of Oncology-IDIBELL, L'Hospitalet de Llobregat, Barcelona 08908, Spain.
40
CIBER de Epidemiología y Salud Pública (CIBERESP), Barcelona 08036, Spain.
41
The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York 10029, USA.
42
International Agency for Research on Cancer, Lyon 69372, France.
43
Registre des Hémopathies Malignes de Côte d'Or, University of Burgundy and Dijon University Hospital, Dijon 21070, France.
44
Department of Computational Biology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
45
Department of Family Medicine and Public Health Sciences, Wayne State University, Detroit, Michigan 48201, USA.
46
School of Public Health, Imperial College London, London W2 1PG, UK.
47
MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London W2 1PG, UK.
48
Human Genetics Foundation, 10126 Turin, Italy.
49
Institute for Risk Assessment Sciences, Utrecht University, Utrecht 3508 TD, The Netherlands.
50
Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht 3584 CX, The Netherlands.
51
Genetic Epidemiology Laboratory, Department of Pathology, University of Melbourne, Melbourne, Victoria 3010, Australia.
52
Epidemiology of Childhood and Adolescent Cancers Group, Inserm, Center of Research in Epidemiology and Statistics Sorbonne Paris Cité (CRESS), Paris F-94807, France.
53
Université Paris Descartes, 75270 Paris, France.
54
Cancer Control Research, BC Cancer Agency, Vancouver, British Columbia, Canada V5Z1L3.
55
School of Population and Public Health, University of British Columbia, Vancouver, British Columbia, Canada V6T1Z3.
56
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts 02115, USA.
57
Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, Massachusetts 02115, USA.
58
Department of Biomedical Science, University of Cagliari, Monserrato, Cagliari 09042, Italy.
59
Department of Haematology, Queen Elizabeth Hospital, Gateshead NE9 6SX, UK.
60
Interdisciplinary Department of Medicine, University of Bari, Bari 70124, Italy.
61
Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool L69 3BX, UK.
62
Environmental and Occupational Epidemiology Unit, Cancer Prevention and Research Institute (ISPO), Florence 50139, Italy.
63
Department of Epidemiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
64
Carolina Center for Genome Sciences, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
65
Queens Centre for Haematology and Oncology, Castle Hill Hospital, Hull and East Yorkshire NHS Trust, Cottingham HU16 5JQ, UK.
66
Department of Haematology, Birmingham Heartlands Hospital, Birmingham B9 5SS, UK.
67
Division of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK.
68
Cardiff and Vale National Health Service Trust, Heath Park, Cardiff CF14 4XW, UK.
69
Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah 21589, KSA.
70
Division of Molecular Pathology, The Institute of Cancer Research, London SW7 3RP, UK.
71
Unitat de Hematología, Hospital Clínic, IDIBAPS, Universitat de Barcelona, Barcelona 08036, Spain.
72
Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota 55905, USA.

Abstract

Several chronic lymphocytic leukaemia (CLL) susceptibility loci have been reported; however, much of the heritable risk remains unidentified. Here we perform a meta-analysis of six genome-wide association studies, imputed using a merged reference panel of 1,000 Genomes and UK10K data, totalling 6,200 cases and 17,598 controls after replication. We identify nine risk loci at 1p36.11 (rs34676223, P=5.04 × 10-13), 1q42.13 (rs41271473, P=1.06 × 10-10), 4q24 (rs71597109, P=1.37 × 10-10), 4q35.1 (rs57214277, P=3.69 × 10-8), 6p21.31 (rs3800461, P=1.97 × 10-8), 11q23.2 (rs61904987, P=2.64 × 10-11), 18q21.1 (rs1036935, P=3.27 × 10-8), 19p13.3 (rs7254272, P=4.67 × 10-8) and 22q13.33 (rs140522, P=2.70 × 10-9). These new and established risk loci map to areas of active chromatin and show an over-representation of transcription factor binding for the key determinants of B-cell development and immune response.

Conflict of interest statement

The authors declare no competing financial interests.

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