The DOI matches its Crossref record; 28 of the 28 references it cites were found in a registry or an index.
Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease
Abstract
Crohn's disease and ulcerative colitis, the two main types of chronic inflammatory bowel disease, are multifactorial conditions of unknown aetiology. A susceptibility locus for Crohn's disease has been mapped to chromosome 16. Here we have used a positional-cloning strategy, based on linkage analysis followed by linkage disequilibrium mapping, to identify three independent associations for Crohn's disease: a frameshift variant and two missense variants of NOD2, encoding a member of the Apaf-1/Ced-4 superfamily of apoptosis regulators that is expressed in monocytes. These NOD2 variants alter the structure of either the leucine-rich repeat domain of the protein or the adjacent region. NOD2 activates nuclear factor NF-kB; this activating function is regulated by the carboxy-terminal leucine-rich repeat domain, which has an inhibitory role and also acts as an intracellular receptor for components of microbial pathogens. These observations suggest that the NOD2 gene product confers susceptibility to Crohn's disease by altering the recognition of these components and/or by over-activating NF-kB in monocytes, thus documenting a molecular model for the pathogenic mechanism of Crohn's disease that can now be further investigated.
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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 [34]
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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 [158]
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Metadata
- Authors
- Hugot, J.-P., Chamaillard, M., Zouali, H., Lesage, S., Cézard, J.-P., Belaiche, J., Almer, S., Tysk, C., O'Morain, C. A., Gassull, M., Binder, V., Finkel, Y., Cortot, A., Modigliani, R., Laurent-Puig, P., Gower-Rousseau, C., Macry, J., Colombel, J.-F., Sahbatou, M., & Thomas, G.
- Affiliations
- Fondation Jean Dausset-CEPH (FR)
- Inserm (FR)
- Hôpital Robert-Debré (FR)
- Linköping University (SE)
- Örebro University Hospital (SE)
- Tallaght University Hospital (IE)
- Hospital Universitari Germans Trias i Pujol (ES)
- Herlev Hospital (DK)
- Hôpital Albert Calmette (FR)
- Hôpital Saint-Louis (FR)
- Corresponding author
- Thomas, Gilles
- ORCID
- Venue
- Nature
- Published
- 2001-05
- Volume
- 411
- Issue
- 6837
- Pages
- 599-603
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W1642457845
- Cited by
- 5,591
- References
- 28
- Citations by year
- 2026: 58 · 2025: 72 · 2024: 81 · 2023: 185 · 2022: 118 · 2021: 122 · 2020: 136 · 2019: 141 · 2018: 163 · 2017: 154 · 2016: 163 · 2015: 186 · 2014: 228 · 2013: 248 · 2012: 260
- FWCI
- 171.27
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- 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
- Crohn's disease, NOD2, genetic susceptibility, ulcerative colitis, inflammatory bowel disease, NF-κB activation, monocytes, frameshift mutation, missense mutations, positional cloning, association mapping, pathogen recognition
- MeSH terms
- Alleles, Carrier Proteins, Chromosomes, Human, Pair 16, Cloning, Molecular, Colitis, Ulcerative, Crohn Disease, Gene Frequency, Genotype, Humans, Leucine, Genetic Linkage, Proteins, Genetic Variation, Signal Transduction, NF-kappa B, Genetic Predisposition to Disease, Repetitive Sequences, Amino Acid, Polymorphism, Single Nucleotide, Intracellular Signaling Peptides and Proteins, Nod2 Signaling Adaptor Protein
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