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A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease
Open accessAbstract
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 studies, 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.
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“Efforts to apply the approach–linkage analysis in multiplex pedigrees–that had been so successful for the high-penetrance variants responsible for Mendelian disease were, with notable exceptions34–36, largely unsuccessful for common, later-onset traits with more complex multifactorial aetiologies, such as asthma, diabetes and depression.”
From A brief history of human disease genetics (2020) · cites this paper as [35]
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“Among these, mutation in the NOD2 gene was the first to be confirmed to be strongly associated with susceptibility to CD.157,158”
From Interaction between microbiota and immunity in health and disease (2020) · cites this paper as [157]
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Metadata
- Authors
- Ogura, Y., Bonen, D. K., Inohara, N., Nicolae, D. L., Chen, F. F., Ramos, R., Britton, H., Moran, T., Karaliuskas, R., Duerr, R. H., Achkar, J.-P., Brant, S. R., Bayless, T. M., Kirschner, B. S., Hanauer, S. B., Nuñez, G., & Cho, J. H.
- Affiliations
- University of Michigan (US)
- University of Chicago Medical Center (US)
- University of Pittsburgh (US)
- Cleveland Clinic (US)
- Johns Hopkins University (US)
- University of Chicago (US)
- ORCID
- Venue
- Nature
- Published
- 2001-05
- Volume
- 411
- Issue
- 6837
- Pages
- 603-606
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W1670573097
- Cited by
- 5,030
- References
- 22
- Citations by year
- 2026: 41 · 2025: 64 · 2024: 81 · 2023: 174 · 2022: 99 · 2021: 108 · 2020: 117 · 2019: 120 · 2018: 147 · 2017: 146 · 2016: 143 · 2015: 156 · 2014: 211 · 2013: 219 · 2012: 218
- FWCI
- 155.51
- Type
- journal article
- Language
- en
- Open access
- green
- hdl.handle.net
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- Deep Blue (University of Michigan) (submittedVersion)
- Rutgers University Community Repository (Rutgers University) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- University of Tokushima
- National Institutes of Health
- Topics
- Health Sciences › Medicine › Gastroenterology › Inflammatory Bowel Disease
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- NOD2, Crohn's disease, frameshift mutation, chromosome 16, genetic susceptibility, NF-κB activation, lipopolysaccharide response, innate immunity, bacterial recognition, inflammatory bowel disease
- MeSH terms
- Adult, Alleles, Amino Acid Sequence, Base Sequence, Carrier Proteins, Cell Line, Child, Crohn Disease, Cytosine, DNA, Female, Gene Frequency, Heterozygote, Homozygote, Humans, Lipopolysaccharides, Male, Molecular Sequence Data, Proteins, Case-Control Studies, Polymerase Chain Reaction, Mutagenesis, Insertional, NF-kappa B, Frameshift Mutation, Protein Structure, Tertiary, Genetic Predisposition to Disease, Intracellular Signaling Peptides and Proteins, Nod2 Signaling Adaptor Protein
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