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

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posted on 04.04.2017, 11:09 by Philip J. Law, Sonja I. Berndt, Helen E. Speedy, Nicola J. Camp, Georgina P. Sava, Christine F. Skibola, Amy Holroyd, Vijai Joseph, Nicola J. Sunter, Alexandra Nieters, Silvia Bea, Alain Monnereau, David Martin-Garcia, Lynn R. Goldin, Guillem Clot, Lauren R. Teras, Inés Quintela, Brenda M. Birmann, Sandrine Jayne, Wendy Cozen, Aneela Majid, Karin E. Smedby, Qing Lan, Claire Dearden, Angela R. Brooks-Wilson, Andrew G. Hall, Mark P. Purdue, Tryfonia Mainou-Fowler, Claire M. Vajdic, Graham H. Jackson, Pierluigi Cocco, Helen Marr, Yawei Zhang, Tongzhang Zheng, Graham G. Giles, Charles Lawrence, Timothy G. Call, Mark Liebow, Mads Melbye, Bengt Glimelius, Larry Mansouri, Martha Glenn, Karen Curtin, W. Ryan Diver, Brian K. Link, Lucia Conde, Paige M. Bracci, Elizabeth A. Holly, Rebecca D. Jackson, Lesley F. Tinker, Yolanda Benavente, Paolo Boffetta, Paul Brennan, Marc Maynadie, James McKay, Demetrius Albanes, Stephanie Weinstein, Zhaoming Wang, Neil E. Caporaso, Lindsay M. Morton, Richard K. Severson, Elio Riboli, Paolo Vineis, Roel C. H. Vermeulen, Melissa C. Southey, Roger L. Milne, Jacqueline Clavel, Sabine Topka, John J. Spinelli, Peter Kraft, Maria Grazia Ennas, Geoffrey Summerfield, Giovanni M. Ferri, Robert J. Harris, Lucia Miligi, Andrew R. Pettitt, Kari E. North, David J Allsup, Joseph F. Fraumeni, James R. Bailey, Kenneth Offit, Guy Pratt, Henrik Hjalgrim, Chris Pepper, Stephen J. Chanock, Chris Fegan, Richard Rosenquist, Silvia de Sanjose, Angel Carracedo, Martin J. S. Dyer, Daniel Catovsky, Elias Campo, James R. Cerhan, James M. Allan, Nathanial Rothman, Richard Houlston, Susan Slager
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.

Funding

In the United Kingdom, Bloodwise provided funding for the study (LRF05001, LRF06002 and LRF13044) with additional support from Cancer Research UK (C1298/A8362 supported by the Bobby Moore Fund) and the Arbib Fund. G.P.S. is in receipt of a PhD studentship from The Institute of Cancer Research. The NCI/InterLymph NHL GWAS initiative was supported by the intramural programme of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, US National Institutes of Health. ATBC—This research was supported in part by the Intramural Research Program of the NIH and the National Cancer Institute. In addition, this research was supported by U.S. Public Health Service contracts N01-CN-45165, N01-RC-45035, N01-RC-37004 and HHSN261201000006C from the National Cancer Institute, Department of Health and Human Services. BC—Canadian Institutes for Health Research (CIHR); Canadian Cancer Society; Michael Smith Foundation for Health Research. CPS-II—The Cancer Prevention Study-II (CPS-II) Nutrition Cohort is supported by the American Cancer Society. Genotyping for all CPS-II samples was supported by the Intramural Research Program of the National Institutes of Health, NCI, Division of Cancer Epidemiology and Genetics. We also acknowledge the contribution to this study from central cancer registries supported through the Centers for Disease Control and Prevention National Program of Cancer Registries, and cancer registries supported by the National Cancer Institute Surveillance Epidemiology and End Results program. ELCCS—Leukemia and Lymphoma Research. ENGELA—Association pour la Recherche contre le Cancer (ARC), Institut National du Cancer (INCa), Fondation de France, Fondation contre la Leucémie, Agence nationale de sécurité sanitaire de l’alimentation, de l’environnement et du travail (ANSES). EPIC—Coordinated Action (Contract #006438, SP23-CT-2005-006438); HuGeF (Human Genetics Foundation), Torino, Italy; Cancer Research UK. EpiLymph—European Co

History

Citation

Nature Publishing Group, 2017, 8, 14175

Author affiliation

/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/School of Medicine/Department of Cancer Studies and Molecular Medicine

Version

VoR (Version of Record)

Published in

Nature Publishing Group

Publisher

Nature Publishing Group

eissn

2041-1723

Acceptance date

06/12/2016

Copyright date

2017

Available date

04/04/2017

Publisher version

http://www.nature.com/articles/ncomms14175

Notes

Supplementary Information accompanies this paper at http://www.nature.com/naturecommunications

Language

en