Gastroenterology
Volume 136, Issue 2 , Pages 523-529.e3, February 2009

Investigation of Crohn's Disease Risk Loci in Ulcerative Colitis Further Defines Their Molecular Relationship

  • Carl A. Anderson

      Affiliations

    • Genetic and Genomic Epidemiology Unit, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford
    • ,
  • Dunecan C.O. Massey

      Affiliations

    • Inflammatory Bowel Disease Research Group, Addenbrooke's Hospital, University of Cambridge, Cambridge
    • ,
  • Jeffrey C. Barrett

      Affiliations

    • The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge
    • ,
  • Natalie J. Prescott

      Affiliations

    • Department of Medical and Molecular Genetics, King's College London School of Medicine, London
    • ,
  • Mark Tremelling

      Affiliations

    • Inflammatory Bowel Disease Research Group, Addenbrooke's Hospital, University of Cambridge, Cambridge
    • ,
  • Sheila A. Fisher

      Affiliations

    • Department of Medical and Molecular Genetics, King's College London School of Medicine, London
    • ,
  • Rhian Gwilliam

      Affiliations

    • The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge
    • ,
  • Jemima Jacob

      Affiliations

    • Department of Medical and Molecular Genetics, King's College London School of Medicine, London
    • ,
  • Elaine R. Nimmo

      Affiliations

    • Gastrointestinal Unit, Division of Medical Sciences, School of Molecular and Clinical Medicine, University of Edinburgh, Western General Hospital, Edinburgh
    • ,
  • Hazel Drummond

      Affiliations

    • Gastrointestinal Unit, Division of Medical Sciences, School of Molecular and Clinical Medicine, University of Edinburgh, Western General Hospital, Edinburgh
    • ,
  • Charlie W. Lees

      Affiliations

    • Gastrointestinal Unit, Division of Medical Sciences, School of Molecular and Clinical Medicine, University of Edinburgh, Western General Hospital, Edinburgh
    • ,
  • Clive M. Onnie

      Affiliations

    • Department of Medical and Molecular Genetics, King's College London School of Medicine, London
    • ,
  • Catherine Hanson

      Affiliations

    • Department of Gastroenterology and Hepatology, University of Newcastle upon Tyne, Royal Victoria Infirmary, Newcastle upon Tyne
    • ,
  • Katarzyna Blaszczyk

      Affiliations

    • Department of Medical and Molecular Genetics, King's College London School of Medicine, London
    • ,
  • Radhi Ravindrarajah

      Affiliations

    • The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge
    • ,
  • Sarah Hunt

      Affiliations

    • The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge
    • ,
  • Dhiraj Varma

      Affiliations

    • The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge
    • ,
  • Naomi Hammond

      Affiliations

    • The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge
    • ,
  • Gregory Lewis

      Affiliations

    • Inflammatory Bowel Disease Research Group, Addenbrooke's Hospital, University of Cambridge, Cambridge
    • ,
  • Heather Attlesey

      Affiliations

    • Inflammatory Bowel Disease Research Group, Addenbrooke's Hospital, University of Cambridge, Cambridge
    • ,
  • Nick Watkins

      Affiliations

    • Department of Haematology, University of Cambridge, National Blood Service Centre, Long Road, Cambridge
    • ,
  • Willem Ouwehand

      Affiliations

    • Department of Haematology, University of Cambridge, National Blood Service Centre, Long Road, Cambridge
    • ,
  • David Strachan

      Affiliations

    • Division of Community Health Services, St. George's University of London, Cranmer Terrace, London
    • ,
  • Wendy McArdle

      Affiliations

    • ALSPAC, Dept Social Medicine, University of Bristol, Oakfield House, Oakfield Grove, Bristol
    • ,
  • Cathryn M. Lewis

      Affiliations

    • Department of Medical and Molecular Genetics, King's College London School of Medicine, London
    • ,
  • The Wellcome Trust Case Control Consortium
    • ,
  • Alan Lobo

      Affiliations

    • Division of Molecular and Genetic Medicine, University of Sheffield Medical School, Royal Hallamshire Hospital, Sheffield
    • ,
  • Jeremy Sanderson

      Affiliations

    • Department of Gastroenterology, Guy's and St. Thomas' NHS Foundation Trust, London
    • ,
  • Derek P. Jewell

      Affiliations

    • Gastroenterology Unit, Radcliffe Infirmary, University of Oxford, Oxford, United Kingdom
    • ,
  • Panos Deloukas

      Affiliations

    • The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge
    • ,
  • John C. Mansfield

      Affiliations

    • Department of Gastroenterology and Hepatology, University of Newcastle upon Tyne, Royal Victoria Infirmary, Newcastle upon Tyne
    • ,
  • Christopher G. Mathew

      Affiliations

    • Department of Medical and Molecular Genetics, King's College London School of Medicine, London
    • ,
  • Jack Satsangi

      Affiliations

    • Gastrointestinal Unit, Division of Medical Sciences, School of Molecular and Clinical Medicine, University of Edinburgh, Western General Hospital, Edinburgh
    • ,
  • Miles Parkes

      Affiliations

    • Inflammatory Bowel Disease Research Group, Addenbrooke's Hospital, University of Cambridge, Cambridge
    • Corresponding Author InformationAddress requests for reprints to: Miles Parkes, Inflammatory Bowel Disease Research Group, Addenbrooke's Hospital, University of Cambridge, Cambridge CB2 0QQ, United Kingdom

Received 2 September 2008; accepted 16 October 2008. published online 28 October 2008.

Background & Aims

Identifying shared and disease-specific susceptibility loci for Crohn's disease (CD) and ulcerative colitis (UC) would help define the biologic relationship between the inflammatory bowel diseases. More than 30 CD susceptibility loci have been identified. These represent important candidate susceptibility loci for UC. Loci discovered by the index genome scans in CD have previously been tested for association with UC, but those identified in the recent meta-analysis await such investigation. Furthermore, the recently identified UC locus at ECM1 requires formal testing for association with CD.

Methods

We analyzed 45 single nucleotide polymorphisms, tagging 29 of the loci recently associated with CD in 2527 UC cases and 4070 population controls. We also genotyped the UC-associated ECM1 variant rs11205387 in 1560 CD patients and 3028 controls.

Results

Nine regions showed association with UC at a threshold corrected for the 29 loci tested (P < .0017). The strongest association (P = 4.13 × 10−8; odds ratio = 1.27) was identified with a 170-kilobase region on chromosome 1q32 that contains 3 genes. We also found association with JAK2 and replicated a recently reported association with STAT3, further implicating the role of this signaling pathway in inflammatory bowel disease. Additional novel UC susceptibility genes were LYRM4 and CDKAL1. Twenty of the loci were not associated with UC, and several appear to be specific to CD. ECM1 variation was not associated with CD.

Conclusions

Collectively, these data help define the genetic relationship between CD and UC and characterize common, as well as disease-specific mechanisms of pathogenesis.

Abbreviations used in this paper: GWAS, genome-wide association scanning, SNP, single nucleotide polymorphism

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 C.A.A. and D.C.O.M. contributed equally to this work.

 The authors disclose the following: Supported by the NIHR Cambridge Biomedical Research Centre, by the Wellcome Trust (to C.A.A.), and by the Medical Research Council (to D.C.O.M.).

PII: S0016-5085(08)01867-2

doi:10.1053/j.gastro.2008.10.032

Refers to article:

  • Exposed: The Genetic Underpinnings of Ulcerative Colitis Relative to Crohn's Disease , 05 January 2009

    Steven R. Brant
    Gastroenterology February 2009 (Vol. 136, Issue 2, Pages 396-399)

Gastroenterology
Volume 136, Issue 2 , Pages 523-529.e3, February 2009

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