Letter | Published:

Common variants at the MHC locus and at chromosome 16q24.1 predispose to Barrett's esophagus

Nature Genetics volume 44, pages 11311136 (2012) | Download Citation

Abstract

Barrett's esophagus is an increasingly common disease that is strongly associated with reflux of stomach acid and usually a hiatus hernia, and it strongly predisposes to esophageal adenocarcinoma (EAC), a tumor with a very poor prognosis. We report the first genome-wide association study on Barrett's esophagus, comprising 1,852 UK cases and 5,172 UK controls in the discovery stage and 5,986 cases and 12,825 controls in the replication stage. Variants at two loci were associated with disease risk: chromosome 6p21, rs9257809 (Pcombined = 4.09 × 10−9; odds ratio (OR) = 1.21, 95% confidence interval (CI) =1.13–1.28), within the major histocompatibility complex locus, and chromosome 16q24, rs9936833 (Pcombined = 2.74 × 10−10; OR = 1.14, 95% CI = 1.10–1.19), for which the closest protein-coding gene is FOXF1, which is implicated in esophageal development and structure. We found evidence that many common variants of small effect contribute to genetic susceptibility to Barrett's esophagus and that SNP alleles predisposing to obesity also increase risk for Barrett's esophagus.

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Acknowledgements

We acknowledge the individuals with Barrett's esophagus who participated in the study and the physicians who helped in recruitment. We thank the many research nurses who also helped recruit, including S. Prew. We thank S. Bertrand, J. Bryant, S.L. Clark, J.S. Conquer, T. Dibling, J.C. Eldred, S. Gamble, C. Hind, A. Wilk, C.R. Stribling and S. Taylor of the Wellcome Trust Sanger Institute's Sample and Genotyping Facilities for technical assistance. We also thank J. Barrett for design of the Immunochip array. Funding for this study was provided by the WTCCC2 project (085475/B/08/Z and 085475/Z/08/Z) and the Wellcome Trust (072894/Z/03/Z, 090532/Z/09/Z and 075491/Z/04/B). P. Donnelly was supported in part by a Wolfson-Royal Society Merit Award. D.C.W. is supported by a Future Fellowship from the Australian Research Council. S.M. is supported by an Australian National Health & Medical Research Council (NHMRC) Career Development Award. C.C.A.S. was supported by a Wellcome Trust Fellowship (097364/Z/11/Z). We acknowledge use of the British 1958 Birth Cohort DNA collection, funded by the UK Medical Research Council (grant G0000934) and the Wellcome Trust (grant 068545/Z/02), the UK National Blood Service controls, funded by the Wellcome Trust, and the People of the British Isles collection, funded by the Wellcome Trust. This work was also supported by the Esophageal Adenocarcinoma GenE Consortia incorporating the ChOPIN project (grant C548/A5675) and Inherited Predisposition of neoplasia analysis of genomic DNA (IPOD) from AspECT and BOSS clinical trials project (grant MGAG1G7R); Cancer Research UK (AspECT, grants C548/A4584 and D9612L00090, and Histological AssessmeNt Determining EpitheliaL Response (HANDEL), grant C548/A9085); AstraZeneca UK educational grant; University Hospitals of Leicester R and D grant; and AspECT (T91 5211 University of Oxford grant HDRMJQ0). The Barrett's and Esophageal Adenocarcinoma Genetic Susceptibility Study (BEAGESS) within the BEACON Consortium was supported by US National Institutes of Health grant R01CA13672501. We acknowledge the Dublin Centre for Clinical Research (funded by the Health Research Board and the Wellcome Trust) for support in sample collection and the Irish Blood Transfusion Service and TCD DNA Biobank for provision of control samples. R.M. is supported by the Science Foundation Ireland grant 09/IN.1/B2640.

Author information

Author notes

    • Leena Peltonen

    Deceased.

    • Zhan Su
    •  & Laura J Gay

    These authors contributed equally to this work.

    • Peter Donnelly
    •  & Janusz A Z Jankowski

    These authors jointly directed this work.

Affiliations

  1. Wellcome Trust Centre for Human Genetics, Oxford, UK.

    • Zhan Su
    • , Amy Strange
    • , Claire Palles
    • , Gavin Band
    • , Céline Bellenguez
    • , Kimberley Howarth
    • , Colin Freeman
    • , Matti Pirinen
    • , Anna Rautanen
    • , Jean-Baptiste Cazier
    • , Chris C A Spencer
    • , Ian Tomlinson
    •  & Peter Donnelly
  2. Centre for Digestive Diseases, Blizard Institute, Queen Mary University of London, London, UK.

    • Laura J Gay
    • , Manoj Nanji
    • , Anna M Nicholson
    • , Nichola L Gellatly
    • , Elia Stupka
    •  & Janusz A Z Jankowski
  3. Oxford National Institute for Health Research Comprehensive Biomedical Research Centre, Oxford, UK.

    • Claire Palles
    •  & Ian Tomlinson
  4. Queensland Institute of Medical Research, Brisbane, Queensland, Australia.

    • David C Whiteman
    • , Stuart MacGregor
    •  & Weronica Ek
  5. University College London (UCL) Cancer Institute, University College London, London, UK.

    • Francesco Lescai
    •  & Elia Stupka
  6. Wellcome Trust Sanger Institute, Cambridge, UK.

    • Cordelia Langford
    • , Sarah Edkins
    • , Panos Deloukas
    • , Sarah E Hunt
    • , Emma Gray
    • , Serge Dronov
    • , Simon C Potter
    •  & Avazeh Tashakkori-Ghanbaria
  7. Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, The Netherlands.

    • Anouk van der Winkel
    • , Maikel P Peppelenbosch
    •  & Ernst J Kuipers
  8. Department of Biostatistics, University of Washington, Seattle, Washington, USA.

    • David Levine
    •  & Rui Zhang
  9. Centre for Cancer Prevention, Wolfson Institute of Preventive Medicine, Barts and The London School of Medicine and Dentistry, London, UK.

    • Peter Sasieni
  10. Department of Gastroenterology, Sandwell General Hospital, Lyndon, UK.

    • Nigel Trudgill
    •  & Sheldon C Cooper
  11. Centre for Clinical Pharmacology, William Harvey Research Institute, Queen Mary University of London, London, UK.

    • Art T Tucker
  12. Department of Surgery, Erasmus University Medical Center, Rotterdam, The Netherlands.

    • Luc J W van der Laan
  13. Department of Gastroenterology and Hepatology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.

    • Joost P H Drenth
    •  & Wilbert H Peters
  14. Department of Surgery, Institute of Molecular Medicine, St. James' Hospital and Trinity College Dublin, Dublin, Ireland.

    • John V Reynolds
  15. Department of Clinical Medicine, Institute of Molecular Medicine, St. James' Hospital and Trinity College Dublin, Dublin, Ireland.

    • Dermot P Kelleher
    •  & Ross McManus
  16. Section of Pathology and Tumour Biology, Leeds Institute of Molecular Medicine, University of Leeds, St. James's University Hospital, Leeds, UK.

    • Heike Grabsch
  17. Department of Digestive Oncology, University Hospital Gasthuisberg, Leuven, Belgium.

    • Hans Prenen
    •  & Raf Bisschops
  18. Department of Gastroenterology and Hepatology, Academic Medical Center Amsterdam, Amsterdam, The Netherlands.

    • Kausila Krishnadath
  19. Department of Gastroenterology and Hepatology, University Medical Center Utrecht, Utrecht, The Netherlands.

    • Peter D Siersema
    •  & Jantine W P M van Baal
  20. Department of Medical Oncology, Churchill Hospital, University of Oxford, Oxford, UK.

    • Mark Middleton
    • , Richard Gillies
    •  & Janusz A Z Jankowski
  21. Institute of Medical Sciences, School of Medicine and Dentistry, University of Aberdeen, Aberdeen, UK.

    • Russell Petty
  22. Digestive Diseases Centre, Leicester Royal Infirmary, Leicester, UK.

    • Nicola Burch
    • , Deborah Glancy
    • , Barrie Rathbone
    •  & Janusz A Z Jankowski
  23. Gastroenterology and Hepatology Services, Queen Alexandra Hospital, Portsmouth, UK.

    • Pradeep Bhandari
  24. Department of Gastroenterology, Forth Valley Royal Hospital, Larbert, UK.

    • Stuart Paterson
  25. Department of Gastroenterology, Torbay Hospital, Torquay, UK.

    • Cathryn Edwards
  26. Gastrointestinal Unit, Western General Hospital, Edinburgh, UK.

    • Ian Penman
  27. Gastrointestinal Unit, Royal Infirmary of Edinburgh, Edinburgh, UK.

    • Ian Penman
  28. Gastrointestinal Unit, Victoria Hospital, Kirkcaldy, UK.

    • Kishor Vaidya
  29. Department of Gastroenterology, Royal Albert Edward Infirmary, National Health Service (NHS) Trust, Wigan, UK.

    • Yeng Ang
  30. Department of Gastroenterology, Royal Cornwall Hospital, Truro, UK.

    • Iain Murray
  31. Department of Gastroenterology, Southampton University Hospitals, NHS Trust, Southampton, UK.

    • Praful Patel
  32. Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

    • Weimin Ye
  33. Department of Gastroenterology, East Lancashire Hospitals, NHS Trust Royal Blackburn Hospital, Blackburn, UK.

    • Paul Mullins
  34. Department of Preventive Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, California, USA.

    • Anna H Wu
  35. Department of Oncology, The University of Sheffield Medical School, University of Sheffield, Sheffield, UK.

    • Nigel C Bird
  36. South Tees NHS Foundation Trust, Middlesbrough, UK.

    • Helen Dallal
  37. Division of Gastroenterology and Hepatology, University of North Carolina School of Medicine, University of North Carolina, Chapel Hill, North Carolina, USA.

    • Nicholas J Shaheen
  38. Centre for Public Health, Queen's University, Belfast, UK.

    • Liam J Murray
  39. Department of Gastroenterology, Macclesfield General Hospital, Macclesfield, UK.

    • Konrad Koss
  40. Department of Population Sciences, Beckman Research Institute and City of Hope Comprehensive Cancer Center, Duarte, California, USA.

    • Leslie Bernstein
  41. Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA.

    • Yvonne Romero
  42. Division of Epidemiology, University of Leeds, Leeds, UK.

    • Laura J Hardie
  43. Department of Oncology, Great Western Hospital, Swindon, UK.

    • Helen Winter
  44. Oakland Medical Center, Division of Research, Kaiser Permanente, Oakland, California, USA.

    • Douglas A Corley
  45. Department of Gastroenterology, South Tyneside District Hospital, South Shields, UK.

    • Simon Panter
  46. Department of Epidemiology and Public Health, Yale University School of Medicine, New Haven, Connecticut, USA.

    • Harvey A Risch
  47. Fred Hutchinson Cancer Research Center, Division of Human Biology, Seattle, Washington, USA.

    • Brian J Reid
  48. Gastroenterology and Hepatology Services, Lister Hospital, London, UK.

    • Ian Sargeant
  49. Department of Epidemiology, University of North Carolina School of Public Health, Chapel Hill, North Carolina, USA.

    • Marilie D Gammon
  50. Departments of Gastroenterology and Hepatology, Royal Liverpool University Hospital, Liverpool, UK.

    • Howard Smart
  51. County Durham and Darlington NHS Foundation Trust, Darlington, UK.

    • Anjan Dhar
  52. Lancashire Teaching Hospitals NHS Foundation Trust, Chorley, UK.

    • Hugh McMurtry
  53. Department of Surgery, Maidstone Hospital, Maidstone, UK.

    • Haythem Ali
  54. Department of Medicine, Princess Margaret Hospital-University Health Network, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.

    • Geoffrey Liu
  55. Department of Medical Biophysics, Princess Margaret Hospital-University Health Network, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.

    • Geoffrey Liu
  56. Division of Epidemiology, Princess Margaret Hospital-University Health Network, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.

    • Geoffrey Liu
  57. Department of Surgery, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.

    • Alan G Casson
  58. Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA.

    • Wong-Ho Chow
  59. Department of Gastroenterology, University Hospital of North Tees, Stockton-on-Tees, UK.

    • Matt Rutter
  60. Gastroenterology and Hepatology Services, North Devon District Hospital, Barnstaple, UK.

    • Ashref Tawil
  61. Department of Gastroenterology, East & North Herts NHS Trust, Queen Elizabeth Hospital, Welwyn Garden City, UK.

    • Danielle Morris
  62. Department of Gastroenterology, University Hospital of Coventry, Coventry, UK.

    • Chuka Nwokolo
  63. Gastroenterology and Hepatology Services, Blackpool Victoria Hospital, Blackpool, UK.

    • Peter Isaacs
  64. Department of Gastroenterology, Antrim and Whiteabbey United Hospitals, Antrim, UK.

    • Colin Rodgers
  65. Wolfson Digestive Diseases Centre, Queens Medical Centre, Nottingham, UK.

    • Krish Ragunath
  66. Gastroenterology Clinic, Cumberland Infirmary, Carlisle, UK.

    • Chris MacDonald
  67. Department of Gastroenterology, Wansbeck General Hospital, Ashington, UK.

    • Chris Haigh
  68. Department of General Surgery, Countess of Chester Hospital, Chester, UK.

    • David Monk
  69. Gastroenterology and Hepatology Services, Harrogate District Hospital, Harrogate, UK.

    • Gareth Davies
  70. Department of Thoracic and Upper Gastrointestinal Surgery, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK.

    • Saj Wajed
  71. Department of Gastroenterology, Ninewells Hospital, Dundee, UK.

    • David Johnston
  72. Department of Gastroenterology, Craigavon Area Hospital, Craigavon, UK.

    • Michael Gibbons
  73. Department of Gastroenterology, Wycombe Hospital, High Wycombe, UK.

    • Sue Cullen
  74. Centre for Liver and Digestive Diseases Edinburgh Royal Infirmary, Edinburgh, UK.

    • Nicholas Church
  75. Medical Research Council Clinical Trials Unit, London, UK.

    • Ruth Langley
  76. Northern Osophago Gastirc Unit, Royal Victoria Infirmary, Newcastle upon Tyne, UK.

    • Michael Griffin
  77. Academic Department of Surgery, School of Cancer Sciences, University of Birmingham College of Medical and Dental Sciences, Queen Elizabeth Hospital, Birmingham, UK.

    • Derek Alderson
  78. Gastrointestinal Unit, City Hospital Birmingham, Birmingham, UK.

    • Mark Anderson
  79. Oncology Clinical Trials Office, Department of Oncology, University of Oxford, Oxford, UK.

    • Claire Brooks
  80. Telethon Institute for Child Health Research, Centre for Child Health Research, University of Western Australia, Perth, Western Australia, Australia.

    • Jenefer M Blackwell
  81. Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK.

    • Jenefer M Blackwell
  82. Department of Psychoisis Studies, National Institute for Health Research Biomedical Research Centre for Mental Health at the Institute of Psychiatry, King's College London, London, UK.

    • Elvira Bramon
  83. The South London and Maudsley NHS Foundation Trust, London, UK.

    • Elvira Bramon
  84. University of Queensland Diamantina Institute, Princess Alexandra Hospital, University of Queensland, Brisbane, Queensland, Australia.

    • Matthew A Brown
  85. Department of Epidemiology and Public Health, University College London, London, UK.

    • Juan P Casas
  86. Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, UK.

    • Juan P Casas
  87. Neuropsychiatric Genetics Research Group, Institute of Molecular Medicine, Trinity College Dublin, Dublin, Ireland.

    • Aiden Corvin
  88. Molecular and Physiological Sciences, The Wellcome Trust, London, UK.

    • Audrey Duncanson
  89. Centre for Clinical Neurosciences, St. George's University of London, London, UK.

    • Hugh S Markus
  90. Department of Medical and Molecular Genetics, King's College London, King's Health Partners, Guy's Hospital, London, UK.

    • Christopher G Mathew
    •  & Richard C Trembath
  91. Biomedical Research Centre, Ninewells Hospital and Medical School, Dundee, UK.

    • Colin N A Palmer
  92. Social Genetic and Developmental Psychiatry Centre, Institute of Psychiatry, King's College London, London, UK.

    • Robert Plomin
  93. Department of Clinical Neurosciences, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK.

    • Stephen J Sawcer
  94. National Institute for Health Research Biomedical Research Centre for Ophthalmology, Moorfields Eye Hospital NHS Foundation Trust and University College London Institute of Ophthalmology, London, UK.

    • Ananth C Viswanathan
  95. Department of Molecular Neuroscience, Institute of Neurology, University College London, London, UK.

    • Nicholas Wood
  96. Department of Genetics, University Medical Center Groningen and University of Groningen, Groningen, The Netherlands.

    • Gosia Trynka
    •  & Cisca Wijmenga
  97. UCB Pharma, Slough, UK.

    • Paul Atherfold
  98. Department of Clinical Pharmacology, University of Oxford, Oxford, UK.

    • Paul Atherfold
  99. The Gastrointestinal Unit, Royal Marsden Hospital, London, UK.

    • David Cunningham
  100. Reasearch and Development, AstraZeneca, Lund, Sweden.

    • Tore Lind
  101. Gloucestershire Research & Development Support Unit, Gloucestershire Royal Hospital, Gloucester, UK.

    • Julie Hapeshi
  102. Department of Oncology, New Cross Hospital, Royal Wolverhampton Hospitals NHS Trust, Wolverhampton, UK.

    • David Ferry
  103. Clinical Trial Research Unit, Leeds Institute of Molecular Medicine, Leeds, UK.

    • Julia Brown
  104. Centre for Statistics in Medicine, Oxford Clinical Trials Research Unit, Oxford, UK.

    • Sharon Love
  105. Department of General Surgery, North Tyneside General Hospital, North Shields, UK.

    • Stephen Attwood
  106. Department of Medicine, Institute of Clinical Science, Royal Victoria Hospital, Belfast, UK.

    • Peter Watson
  107. Department of Cellular Pathology, Warwick Hospital, Warwick, UK.

    • Scott Sanders
  108. Department of Pathology, Leicester Royal Infirmary, Leicester, UK.

    • Rebecca F Harrison
  109. Department of Medicine, McMaster University Medical Centre, Division of Gastroenterology, Hamilton, Ontario, Canada.

    • Paul Moayyedi
  110. Department of Gastroenterology, Leicester General Hospital, Leicester, UK.

    • John de Caestecker
  111. Department of Upper Gastrointestinal Surgery, Gloucestershire Royal Hospital, Gloucester, UK.

    • Hugh Barr
  112. Center for Translational Genomics and Bioinformatics, San Raffaele Scientific Institute, Milan, Italy.

    • Elia Stupka
  113. Fred Hutchinson Cancer Research Center, Division of Public Health Sciences, Seattle, Washington, USA.

    • Thomas L Vaughan
  114. Department of Statistics, University of Oxford, Oxford, UK.

    • Peter Donnelly
  115. Gastrointestinal Cancer Group, University of Oxford, Oxford, UK.

    • Janusz A Z Jankowski

Consortia

  1. The Esophageal Adenocarcinoma Genetics Consortium

    A full list of members and affiliations is provided in the Supplementary Note.

  2. The Wellcome Trust Case Control Consortium 2

    A full list of members and affiliations is provided in the Supplementary Note.

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Contributions

J.A.Z.J., I.T., L.J.G. and M.N. oversaw cohort collection for the discovery and replication data sets. N.T., N.B., P.B., S. Paterson, C.E., I.P., K.V., Y.A., I.M., P.P., P. Mullins, H.D., K. Koss, D.C., M. Griffin, D.A., H.W., S. Panter, I.S., H.S., A. Dhar, H.M., H.A., M.R., A.T., D. Morris, C.N., R.L., P.I., C.R., K.R., C.M., C.H., D. Monk, G.D., S.W., D.J., M. Gibbons, S.C., N.C., D.G., S.A., P.W., J.d.C., H.B. and J.A.Z.J. recruited over 50 cases to the AspECT and/or ChOPIN studies. L.J.G., M.N., K.H., P.A., A.M.N. and N.L.G. processed AspECT and/or ChOPIN samples. The AspECT and ChOPIN management groups (P.S., A.T.T., P.B., D.J., M.A., C. Brooks, J.H., D.F., B.R., J.B., S.L., S.A., P.W., S.S., R.F.H., P. Moayyedi, J.d.C., H.B. and J.A.Z.J.) monitored the appropriate use of samples and data from these studies. A.v.d.W., N.T., M.P.P., L.J.W.v.d.L., E.J.K., J.P.H.D., W.H.P., J.V.R., D.P.K., R.M., H.G., H.P., R.B., K. Krishnadath, P.D.S., J.W.P.M.v.B., M.M., R. Petty, R.G. and S.C.C. provided samples as part of the EAGLE Consortium. T.L. was involved in EAGLE project design. The BEACON Consortium (D.C.W., D.L., W.Y., A.H.W., N.C.B., N.J.S., L.J.M., L.B., Y.R., L.J.H., R.Z., D.A.C., H.A.R., B.J.R., M.D.G., G.L., A.G.C., W.-H.C., S.M., W.E. and T.L.V.) provided data on the two lead SNPs for the second replication phase. G.T. and C.W. provided Dutch control samples for the first replication phase. The WTCCC2 DNA, genotyping, data quality control and informatics group (S.D., S.E.H., S.E., E.G., C.L., S.C.P., A.T.-G. and L.P.) executed gnome-wide association study sample handling, genotyping and quality control. The WTCCC2 data and analysis group (Z.S., A.S., C.C.A.S., G.B., C. Bellenguez, C.F., M.P. and P. Donnelly) led the statistical analyses. C.P., E.S., F.L., P.S. and J.-B.C. also undertook statistical analyses. A.S., C.P., I.T., J.A.Z.J., C.C.A.S. and P. Donnelly contributed to writing the manuscript. The WTCCC2 management committee (J.M.B., E.B., M.A.B., J.P.C., A.C., P. Deloukas, P. Donnelly (chairperson), A. Duncanson, J.A.Z.J., H.S.M., C.G.M., C.N.A.P., L.P., R. Plomin, A.R., S.J.S., R.C.T., A.C.V. and N.W.) monitored the execution of the genome-wide association study. All authors reviewed the final manuscript.

Competing interests

J.A.Z.J. is a consultant to AstraZeneca and is the Chief Investigator of the AspECT and ChOPIN trials.

Corresponding authors

Correspondence to Ian Tomlinson or Peter Donnelly or Janusz A Z Jankowski.

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    Supplementary Text and Figures

    Supplementary Figures 1–6, Supplementary Tables 1–11 and Supplementary Note

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DOI

https://doi.org/10.1038/ng.2408

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