Letters to Nature

Nature 411, 603-606 (31 May 2001) | doi:10.1038/35079114; Received 18 January 2001; Accepted 30 March 2001

A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease

Yasunori Ogura1,2, Denise K. Bonen3,2, Naohiro Inohara1, Dan L. Nicolae4, Felicia F. Chen1, Richard Ramos3, Heidi Britton3, Thomas Moran3, Reda Karaliuskas3, Richard H. Duerr5, Jean-Paul Achkar6, Steven R. Brant7, Theodore M. Bayless7, Barbara S. Kirschner8, Stephen B. Hanauer3, Gabriel Nuñez1,10 & Judy H. Cho3,10

  1. Department of Pathology and Comprehensive Cancer Center, The University of Michigan Medical School, Ann Arbor, Michigan 48109, USA
  2. The Martin Boyer Laboratories, Gastroenterology Section, Department of Medicine, The University of Chicago Hospitals, Chicago, Illinois 60637, USA
  3. Department of Statistics, and
  4. Department of Pediatrics, University of Chicago, Chicago, Illinois 60637, USA
  5. Department of Medicine and Center for Genomic Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania 15260, USA
  6. Department of Gastroenterology, The Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA
  7. The Harvey M. and Lyn P. Meyerhoff Inflammatory Bowel Disease Center, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA
  8. These authors contributed equally to this work
  9. These authors share senior authorship

Correspondence to: Gabriel Nuñez1,10 Correspondence and request for materials should be addressed to G.N. (e-mail: Email: bclx@umich.edu).

Crohn's disease is a chronic inflammatory disorder of the gastrointestinal tract, which is thought to result from the effect of environmental factors in a genetically predisposed host. A gene location in the pericentromeric region of chromosome 16, IBD1, that contributes to susceptibility to Crohn's disease has been established through multiple linkage studies1, 2, 3, 4, 5, 6, but the specific gene(s) has not been identified. NOD2, a gene that encodes a protein with homology to plant disease resistance gene products is located in the peak region of linkage on chromosome 16 (ref. 7). Here we show, by using the transmission disequilibium test and case-control analysis, that a frameshift mutation caused by a cytosine insertion, 3020insC, which is expected to encode a truncated NOD2 protein, is associated with Crohn's disease. Wild-type NOD2 activates nuclear factor NF-kappaB, making it responsive to bacterial lipopolysaccharides; however, this induction was deficient in mutant NOD2. These results implicate NOD2 in susceptibility to Crohn's disease, and suggest a link between an innate immune response to bacterial components and development of disease.