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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Linkage analysis in multiplex pedigrees was largely unsuccessful for common, later-onset traits with complex multifactorial aetiologies, with notable exceptions.
“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]
Mutation in the NOD2 gene is strongly associated with susceptibility to Crohn's disease.
“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]
Cites
Defective LPS Signaling in C3H/HeJ and C57BL/10ScCr Mice: Mutations in <i>Tlr4</i> Gene
Poltorak, A., He, X., Smirnova, I., Liu, M.-Y., Huffel, C. V., Du, X., Birdwell, D., Alejos, E., Silva, M., Galanos, C., et al. (1998) · Science · doi:10.1126/science.282.5396.2085 · Cited by 7,631 · see citing works
Spielman, R. S., McGinnis, R. E., & Ewens, W. J. (1993) · PubMed · Cited by 3,679 · see citing works
Auphan, N., DiDonato, J. A., Rosette, C., Helmberg, A., & Karin, M. (1995) · Science · doi:10.1126/science.270.5234.286 · Cited by 2,390 · see citing works
Classification of Inflammatory Bowel Disease
Lennard‐Jones, J. E. (1989) · Scandinavian Journal of Gastroenterology · doi:10.3109/00365528909091339 · Cited by 2,022 · see citing works
Nod2, a Nod1/Apaf-1 Family Member That Is Restricted to Monocytes and Activates NF-κB
Ogura, Y., Inohara, N., Benito, A., Chen, F. F., Yamaoka, S., & Núñez, G. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m008072200 · Cited by 1,357 · see citing works
Mapping of a susceptibility locus for Crohn's disease on chromosome 16
Hugot, J., Laurent‐Puig, P., Gower‐Rousseau, C., Olson, J. M., Lee, J. C., Beaugerie, L., Naom, I., Dupas, J., Gossum, A. V., Af, G. D. T. D., et al. (1996) · Nature · doi:10.1038/379821a0 · Cited by 950 · see citing works
Self-citationActivation of nuclear factor κB in inflammatory bowel disease
Schreiber, S., Nikolaus, S., & Hampe, J. (1998) · Gut · doi:10.1136/gut.42.4.477 · Cited by 752 · see citing works
Sulfasalazine: A potent and specific inhibitor of nuclear factor kappa B
Wahl, C., Liptay, S., Adler, G., & Schmid, R. M. (1998) · Journal of Clinical Investigation · doi:10.1172/jci992 · Cited by 742 · see citing works
Nod1, an Apaf-1-like Activator of Caspase-9 and Nuclear Factor-κB
Inohara, N., Koseki, T., del Peso, L., Hu, Y., Yee, C., Chen, S., Carrio, R., Merino, J., Liu, D., Ni, J., et al. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.21.14560 · Cited by 742 · see citing works
Satsangi, J., Parkes, M., Louis, E. J., Hashimoto, L., Kato, N., Welsh, K. I., Terwilliger, J. D., Lathrop, M. G., Bell, J. I., & Jewell, D. P. (1996) · Nature Genetics · doi:10.1038/ng1096-199 · Cited by 694 · see citing works
An Induced Proximity Model for NF-κB Activation in the Nod1/RICK and RIP Signaling Pathways
Inohara, N., Koseki, T., Lin, J., del Peso, L., Lucas, P. C., Chen, F. F., Ogura, Y., & Núñez, G. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m003415200 · Cited by 538 · see citing works
A Test for Linkage and Association in General Pedigrees: The Pedigree Disequilibrium Test
Martin, E. R., Monks, S. A., Warren, L. L., & Kaplan, N. L. (2000) · The American Journal of Human Genetics · doi:10.1086/302957 · Cited by 537 · see citing works
Human Nod1 Confers Responsiveness to Bacterial Lipopolysaccharides
Inohara, N., Ogura, Y., Chen, F. F., Muto, A., & Núñez, G. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m009728200 · Cited by 532 · see citing works
Rioux, J. D., Silverberg, M. S., Daly, M. J., Steinhart, A. H., McLeod, R. S., Griffiths, A. M., Green, T. J., Brettin, T. S., Stone, V., Bull, S. B., et al. (2000) · The American Journal of Human Genetics · doi:10.1086/302913 · Cited by 498 · see citing works
Human CARD4 Protein Is a Novel CED-4/Apaf-1 Cell Death Family Member That Activates NF-κB
Bertin, J., Nir, W.-J., Fischer, C., Tayber, O., Errada, P. R., Grant, J. R., Keilty, J., Gosselin, M., Robison, K. E., Wong, G. H., et al. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.19.12955 · Cited by 366 · see citing works
Linkage of Inflammatory Bowel Disease to Human Chromosome 6p
Hampe, J., Shaw, S. H., Saiz, R., et al. (1999) · The American Journal of Human Genetics · doi:10.1086/302677 · Cited by 227 · see citing works
Spontaneous, heritable colitis in a new substrain of C3H/HeJ mice
Sundberg, J. P., Elson, C. O., Bedigian, H. G., & Birkenmeier, E. H. (1994) · Gastroenterology · doi:10.1016/0016-5085(94)90813-3 · Cited by 201 · see citing works
Cavanaugh, J. A. (2001) · The American Journal of Human Genetics · doi:10.1086/320119 · Cited by 199 · see citing works
High-Density Genome Scan in Crohn Disease Shows Confirmed Linkage to Chromosome 14q11-12
Duerr, R. H., Barmada, M. M., Zhang, L., et al. (2000) · The American Journal of Human Genetics · doi:10.1086/302947 · Cited by 195 · see citing works
Clinical characteristics of Crohn's disease in 72 families
Colombel, J. F., Grandbastien, B., Gower‐Rousseau, C., et al. (1996) · Gastroenterology · doi:10.1053/gast.1996.v111.pm8780563 · Cited by 183 · see citing works
Self-citationKüster, W., Pascoe, L., Purrmann, J., et al. (1989) · American Journal of Medical Genetics · doi:10.1002/ajmg.1320320122 · Cited by 109 · see citing works
Investigation of inheritance of chronic inflammatory bowel diseases by complex segregation analysis.
Orholm, M. K., Iselius, L., Sørensen, T. I. A., et al. (1993) · BMJ · doi:10.1136/bmj.306.6869.20 · Cited by 103 · see citing works
Cho, J. H. (2000) · Human Molecular Genetics · doi:10.1093/hmg/9.9.1425 · Cited by 78 · see citing works
Etiology of the inflammatory bowel diseases
Hugot, J., Zouali, H., Lesage, S., & Thomas, G. D. (1999) · International Journal of Colorectal Disease · doi:10.1007/s003840050175 · Cited by 72 · see citing works
Self-citationIntestinal Inflammation and the Gut Microflora
McKay, D. M. (1999) · Canadian Journal of Gastroenterology · doi:10.1155/1999/680206 · Cited by 53 · see citing works
Spiro, H. M. (1996) · JAMA · doi:10.1001/jama.1996.03530260071036 · Cited by 44 · see citing works
Olavesen, M., Hampe, J., Mirza, M., Saiz, R., Lewis, C., Bridger, S., Teare, D., Easton, D., Herrmann, T., Scott, G., et al. (2000) · Immunogenetics · doi:10.1007/s002510050001 · Cited by 41 · see citing works
MUTATION SCREENING IN THE CD19 AND CD43 (SIALOPHORIN) GENES IN CROHN DISEASE PATIENTS
Hugot, J., Zouali, H., Colombel, J. F., et al. (1999) · Journal of Pediatric Gastroenterology and Nutrition · doi:10.1097/00005176-199905000-00079 · Cited by 4 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls
The Wellcome Trust Case Control Consortium, Management Committee, Burton, P. R., Clayton, D. G., Cardon, L. R., Craddock, N., Deloukas, P., Duncanson, A., Kwiatkowski, D. P., McCarthy, M. I., et al. (2007) · Nature · doi:10.1038/nature05911 · Cited by 9,442 · see citing works
Janeway, C. A., & Medzhitov, R. (2002) · Annual Review of Immunology · doi:10.1146/annurev.immunol.20.083001.084359 · Cited by 8,394 · see citing works
The International HapMap Project
†The International HapMap Consortium, Genotyping centres: Baylor College of Medicine and ParAllele BioScience, Gibbs, R. A., Belmont, J. W., Hardenbol, P., Willis, T. D., Yu, F., Chinese HapMap Consortium, Yang, H., Ch'ang, L.-Y., et al. (2003) · Nature · doi:10.1038/nature02168 · Cited by 6,057 · see citing works
A haplotype map of the human genome
The International HapMap Consortium (2005) · Nature · doi:10.1038/nature04226 · Cited by 5,858 · see citing works
The Structure of Haplotype Blocks in the Human Genome
Gabriel, S. B., Schaffner, S. F., Nguyen, H., Moore, J. M., Roy, J., Blumenstiel, B., Higgins, J., DeFelice, M., Lochner, A., Faggart, M., et al. (2002) · Science · doi:10.1126/science.1069424 · Cited by 5,863 · see citing works
Schroder, K., & Tschopp, J. (2010) · Cell · doi:10.1016/j.cell.2010.01.040 · Cited by 5,475 · see citing works
Unravelling the pathogenesis of inflammatory bowel disease
Xavier, R. J., & Podolsky, D. K. (2007) · Nature · doi:10.1038/nature06005 · Cited by 4,364 · see citing works
Recognition of Commensal Microflora by Toll-Like Receptors Is Required for Intestinal Homeostasis
Rakoff-Nahoum, S., Paglino, J., Eslami-Varzaneh, F., Edberg, S., & Medzhitov, R. (2004) · Cell · doi:10.1016/j.cell.2004.07.002 · Cited by 4,251 · see citing works
Interactions Between the Microbiota and the Immune System
Hooper, L. V., Littman, D. R., & Macpherson, A. J. (2012) · Science · doi:10.1126/science.1223490 · Cited by 4,173 · see citing works
Proteobacteria: Microbial signature of dysbiosis in gut microbiota
Shin, N.-R., Whon, T. W., & Bae, J.-W. (2015) · Trends in Biotechnology · doi:10.1016/j.tibtech.2015.06.011 · Cited by 3,954 · see citing works
Interaction between microbiota and immunity in health and disease
Zheng, D., Liwinski, T., & Elinav, E. (2020) · Cell Research · doi:10.1038/s41422-020-0332-7 · Cited by 3,947 · see citing works
Multi-omics of the gut microbial ecosystem in inflammatory bowel diseases
Lloyd-Price, J., Arze, C., Ananthakrishnan, A. N., Schirmer, M., Avila-Pacheco, J., Poon, T. W., Andrews, E., Ajami, N. J., Bonham, K. S., Brislawn, C. J., et al. (2019) · Nature · doi:10.1038/s41586-019-1237-9 · Cited by 3,143 · see citing works
Toll-like receptors in innate immunity
Takeda, K. (2004) · International Immunology · doi:10.1093/intimm/dxh186 · Cited by 3,328 · see citing works
A Genome-Wide Association Study Identifies <i>IL23R</i> as an Inflammatory Bowel Disease Gene
Duerr, R. H., Taylor, K. D., Brant, S. R., Rioux, J. D., Silverberg, M. S., Daly, M. J., Steinhart, A. H., Abraham, C., Regueiro, M., Griffiths, A., et al. (2006) · Science · doi:10.1126/science.1135245 · Cited by 3,039 · see citing works
Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels
Saxena, R., Voight, B. F., Lyssenko, V., Burtt, N. P., de Bakker, P. I. W., Chen, H., Roix, J. J., Kathiresan, S., Hirschhorn, J. N., Daly, M. J., et al. (2007) · Science · doi:10.1126/science.1142358 · Cited by 2,843 · see citing works
Points of control in inflammation
Nathan, C. (2002) · Nature · doi:10.1038/nature01320 · Cited by 2,738 · see citing works
Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease
the NIDDK IBD Genetics Consortium, Barrett, J. C., the Belgian-French IBD Consortium, the Wellcome Trust Case Control Consortium, Hansoul, S., Nicolae, D. L., Cho, J. H., Duerr, R. H., Rioux, J. D., Brant, S. R., et al. (2008) · Nature Genetics · doi:10.1038/ng.175 · Cited by 2,593 · see citing works
Self-citationReduced diversity of faecal microbiota in Crohn’s disease revealed by a metagenomic approach
Manichanh, C., Rigottier-Gois, L., Bonnaud, E., Gloux, K., Pelletier, E., Frangeul, L., Nalin, R., Jarrin, C., Chardon, P., Marteau, P., et al. (2006) · Gut · doi:10.1136/gut.2005.073817 · Cited by 2,277 · see citing works
Role of the gut microbiota in immunity and inflammatory disease
Kamada, N., Seo, S.-U., Chen, G. Y., & Núñez, G. (2013) · Nature reviews. Immunology · doi:10.1038/nri3430 · Cited by 2,256 · see citing works
Inflammatory bowel disease: cause and immunobiology
Baumgart, D. C., & Carding, S. R. (2007) · The Lancet · doi:10.1016/s0140-6736(07)60750-8 · Cited by 2,147 · see citing works
Azziz, R., Carmina, E., Dewailly, D., Diamanti-Kandarakis, E., Escobar-Morreale, H. F., Futterweit, W., Janssen, O. E., Legro, R. S., Norman, R. J., Taylor, A. E., et al. (2009) · Fertility and Sterility · doi:10.1016/j.fertnstert.2008.06.035 · Cited by 2,132 · see citing works
The microbiome and innate immunity
Thaiss, C. A., Zmora, N., Levy, M., & Elinav, E. (2016) · Nature · doi:10.1038/nature18847 · Cited by 2,012 · see citing works
A cytokine-mediated link between innate immunity, inflammation, and cancer
Lin, W.-W., & Karin, M. (2007) · Journal of Clinical Investigation · doi:10.1172/jci31537 · Cited by 1,940 · see citing works
Microbial Influences in Inflammatory Bowel Diseases
Sartor, R. B. (2008) · Gastroenterology · doi:10.1053/j.gastro.2007.11.059 · Cited by 1,927 · see citing works
Kaser, A., Zeissig, S., & Blumberg, R. S. (2010) · Annual Review of Immunology · doi:10.1146/annurev-immunol-030409-101225 · Cited by 1,806 · see citing works
Rioux, J. D., Xavier, R. J., Taylor, K. D., Silverberg, M. S., Goyette, P., Huett, A., Green, T., Kuballa, P., Barmada, M. M., Datta, L. W., et al. (2007) · Nature Genetics · doi:10.1038/ng2032 · Cited by 1,769 · see citing works
Intestinal barrier function: molecular regulation and disease pathogenesis
Groschwitz, K. R., & Hogan, S. P. (2009) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2009.05.038 · Cited by 1,775 · see citing works
Epidemiology and risk factors for IBD
Ananthakrishnan, A. N. (2015) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/nrgastro.2015.34 · Cited by 1,741 · see citing works
Gut microbiota: Role in pathogen colonization, immune responses, and inflammatory disease
Pickard, J. M., Zeng, M. Y., Caruso, R., & Núñez, G. (2017) · Immunological Reviews · doi:10.1111/imr.12567 · Cited by 1,699 · see citing works
Reciprocal interactions of the intestinal microbiota and immune system
Maynard, C. L., Elson, C. O., Hatton, R. D., & Weaver, C. T. (2012) · Nature · doi:10.1038/nature11551 · Cited by 1,598 · see citing works
Darfeuille-Michaud, A., Boudeau, J., Bulois, P., Neut, C., Glasser, A.-L., Barnich, N., Bringer, M.-A., Swidsinski, A., Beaugerie, L., & Colombel, J.-F. (2004) · Gastroenterology · doi:10.1053/j.gastro.2004.04.061 · Cited by 1,566 · see citing works
Self-citationNegative regulation of Toll-like receptor-mediated immune responses
Liew, F. Y., Xu, D., Brint, E. K., & O'Neill, L. A. J. (2005) · Nature Reviews Immunology · doi:10.1038/nri1630 · Cited by 1,509 · see citing works
Png, C. W., Lindén, S. K., Gilshenan, K. S., Zoetendal, E. G., McSweeney, C. S., Sly, L. I., McGuckin, M. A., & Florin, T. H. J. (2010) · American Journal of Gastroenterology · doi:10.1038/ajg.2010.281 · Cited by 1,364 · see citing works
Replicating genotype–phenotype associations
NCI-NHGRI Working Group on Replication in Association Studies, Chanock, S. J., Manolio, T., Boehnke, M., Boerwinkle, E., Hunter, D. J., Thomas, G., Hirschhorn, J. N., Abecasis, G., Altshuler, D., et al. (2007) · Nature · doi:10.1038/447655a · Cited by 1,352 · see citing works
Self-citationOtt, S. J., Musfeldt, M., Wenderoth, D. F., Hampe, J., Brant, O., Fölsch, U. R., Timmis, K. N., & Schreiber, S. (2004) · Gut · doi:10.1136/gut.2003.025403 · Cited by 1,311 · see citing works
Travassos, L. H., Carneiro, L. A. M., Ramjeet, M., Hussey, S., Kim, Y.-G., Magalhães, J. G., Yuan, L., Soares, F., Chea, E., Le Bourhis, L., et al. (2010) · Nature Immunology · doi:10.1038/ni.1823 · Cited by 1,306 · see citing works
Low counts of Faecalibacterium prausnitzii in colitis microbiota
Sokol, H., Seksik, P., Furet, J. P., Firmesse, O., Nion-Larmurier, I., Beaugerie, L., Cosnes, J., Corthier, G., Marteau, P., & Doré, J. (2009) · Inflammatory Bowel Diseases · doi:10.1002/ibd.20903 · Cited by 1,275 · see citing works
Paneth cells, antimicrobial peptides and maintenance of intestinal homeostasis
Bevins, C. L., & Salzman, N. H. (2011) · Nature Reviews Microbiology · doi:10.1038/nrmicro2546 · Cited by 1,238 · see citing works
Understanding and Preventing the Global Increase of Inflammatory Bowel Disease
Kaplan, G. G., & Ng, S. C. (2017) · Gastroenterology · doi:10.1053/j.gastro.2016.10.020 · Cited by 1,224 · see citing works
Mendelian randomization: prospects, potentials, and limitations
Smith, G. D. (2004) · International Journal of Epidemiology · doi:10.1093/ije/dyh132 · Cited by 1,222 · see citing works
Haplotype tagging for the identification of common disease genes
Johnson, G. C. L., Esposito, L., Barratt, B. J., Smith, A. N., Heward, J., Di Genova, G., Ueda, H., Cordell, H. J., Eaves, I. A., Dudbridge, F., et al. (2001) · Nature Genetics · doi:10.1038/ng1001-233 · Cited by 1,174 · see citing works
Epithelial-cell recognition of commensal bacteria and maintenance of immune homeostasis in the gut
Artis, D. (2008) · Nature reviews. Immunology · doi:10.1038/nri2316 · Cited by 1,136 · see citing works
Current Understanding of Dysbiosis in Disease in Human and Animal Models
DeGruttola, A. K., Low, D., Mizoguchi, A., & Mizoguchi, E. (2016) · Inflammatory Bowel Diseases · doi:10.1097/mib.0000000000000750 · Cited by 1,122 · see citing works
Candidate-gene approaches for studying complex genetic traits: practical considerations
Tabor, H. K., Risch, N. J., & Myers, R. M. (2002) · Nature Reviews Genetics · doi:10.1038/nrg796 · Cited by 1,076 · see citing works
Dysbiosis of the faecal microbiota in patients with Crohn’s disease and their unaffected relatives
Joossens, M., Huys, G., Cnockaert, M., De Preter, V., Verbeke, K., Rutgeerts, P., Vandamme, P., & Vermeire, S. (2011) · Gut · doi:10.1136/gut.2010.223263 · Cited by 1,063 · see citing works
Galectin 8 targets damaged vesicles for autophagy to defend cells against bacterial invasion
Thurston, T. L. M., Wandel, M. P., von Muhlinen, N., Foeglein, Á., & Randow, F. (2012) · Nature · doi:10.1038/nature10744 · Cited by 1,034 · see citing works
Tansey, M. G., & Goldberg, M. S. (2010) · Neurobiology of Disease · doi:10.1016/j.nbd.2009.11.004 · Cited by 1,045 · see citing works
Zaki, M. H., Boyd, K. L., Vogel, P., Kastan, M. B., Lamkanfi, M., & Kanneganti, T.-D. (2010) · Immunity · doi:10.1016/j.immuni.2010.03.003 · Cited by 989 · see citing works
Li, Y., Willer, C., Sanna, S., & Abecasis, G. (2009) · Annual Review of Genomics and Human Genetics · doi:10.1146/annurev.genom.9.081307.164242 · Cited by 990 · see citing works
The genetics and immunopathogenesis of inflammatory bowel disease
Cho, J. H. (2008) · Nature Reviews Immunology · doi:10.1038/nri2340 · Cited by 940 · see citing works
Interleukin-17 and its target genes: mechanisms of interleukin-17 function in disease
Onishi, R. M., & Gaffen, S. L. (2010) · Immunology · doi:10.1111/j.1365-2567.2009.03240.x · Cited by 894 · see citing works
NOD1 and NOD2: Signaling, Host Defense, and Inflammatory Disease
Caruso, R., Warner, N., Inohara, N., & Núñez, G. (2014) · Immunity · doi:10.1016/j.immuni.2014.12.010 · Cited by 830 · see citing works
Finding genes that underlie complex traits.
Glazier, A. M., Nadeau, J. H., & Aitman, T. J. (2002) · Science · doi:10.1126/science.1076641 · Cited by 855 · see citing works
Mapping complex disease traits with global gene expression
Cookson, W., Liang, L., Abecasis, G., Moffatt, M., & Lathrop, M. (2009) · Nature Reviews Genetics · doi:10.1038/nrg2537 · Cited by 849 · see citing works
Interleukin-23 drives innate and T cell–mediated intestinal inflammation
Hue, S., Ahern, P., Buonocore, S., Kullberg, M. C., Cua, D. J., McKenzie, B. S., Powrie, F., & Maloy, K. J. (2006) · The Journal of Experimental Medicine · doi:10.1084/jem.20061099 · Cited by 823 · see citing works
Tiede, I., Fritz, G., Strand, S., Poppe, D., Dvorsky, R., Strand, D., Lehr, H. A., Wirtz, S., Becker, C., Atreya, R., et al. (2003) · Journal of Clinical Investigation · doi:10.1172/jci16432 · Cited by 828 · see citing works
IBD—what role do Proteobacteria play?
Mukhopadhya, I., Hansen, R., El-Omar, E. M., & Hold, G. L. (2012) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/nrgastro.2012.14 · Cited by 810 · see citing works
National Institute of Diabetes and Digestive Kidney Diseases Inflammatory Bowel Disease Genetics Consortium (NIDDK IBDGC), Rivas, M. A., United Kingdom Inflammatory Bowel Disease Genetics Consortium, International Inflammatory Bowel Disease Genetics Consortium, Beaudoin, M., Gardet, A., Stevens, C., Sharma, Y., Zhang, C. K., Boucher, G., et al. (2011) · Nature Genetics · doi:10.1038/ng.952 · Cited by 771 · see citing works
Transforming growth factor-β in T-cell biology
Gorelik, L., & Flavell, R. A. (2002) · Nature Reviews Immunology · doi:10.1038/nri704 · Cited by 792 · see citing works
Khan, I., Ullah, N., Zha, L., Bai, Y., Khan, A., Zhao, T., Che, T., & Zhang, C. (2019) · Pathogens · doi:10.3390/pathogens8030126 · Cited by 771 · see citing works
The microbiome in infectious disease and inflammation
Honda, K., & Littman, D. R. (2012) · Annual Review of Immunology · doi:10.1146/annurev-immunol-020711-074937 · Cited by 791 · see citing works
A brief history of human disease genetics
Claussnitzer, M., Cho, J. H., Collins, R., Cox, N. J., Dermitzakis, E. T., Hurles, M. E., Kathiresan, S., Kenny, E. E., Lindgren, C. M., MacArthur, D. G., et al. (2020) · Nature · doi:10.1038/s41586-019-1879-7 · Cited by 697 · see citing works
The allelic architecture of human disease genes: common disease-common variant... or not?
Pritchard, J. K. (2002) · Human Molecular Genetics · doi:10.1093/hmg/11.20.2417 · Cited by 711 · see citing works
Michielan, A., & D’Incà, R. (2015) · Mediators of Inflammation · doi:10.1155/2015/628157 · Cited by 709 · see citing works
Martini, E., Krug, S. M., Siegmund, B., Neurath, M. F., & Becker, C. (2017) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2017.03.007 · Cited by 668 · see citing works
Bacterial flagellin is a dominant antigen in Crohn disease
Lodes, M. J., Cong, Y., Elson, C. O., Mohamath, R., Landers, C. J., Targan, S. R., Fort, M., & Hershberg, R. M. (2004) · Journal of Clinical Investigation · doi:10.1172/jci200420295 · Cited by 802 · see citing works
Bacterial translocation (BT) in cirrhosis†
Wiest, R., & Garcia‐Tsao, G. (2005) · Hepatology · doi:10.1002/hep.20632 · Cited by 677 · see citing works
NOD proteins: regulators of inflammation in health and disease
Philpott, D. J., Sorbara, M. T., Robertson, S. J., Croitoru, K., & Girardin, S. E. (2014) · Nature Reviews Immunology · doi:10.1038/nri3565 · Cited by 668 · see citing works
Innate immune recognition of the microbiota promotes host-microbial symbiosis
Chu, H., & Mazmanian, S. K. (2013) · Nature Immunology · doi:10.1038/ni.2635 · Cited by 630 · see citing works
Electrolyte transport in the mammalian colon: mechanisms and implications for disease
Kunzelmann, K., & Mall, M. (2002) · Physiological Reviews · doi:10.1152/physrev.00026.2001 · Cited by 655 · see citing works
Gene-microbiota interactions contribute to the pathogenesis of inflammatory bowel disease
Chu, H., Khosravi, A., Kusumawardhani, I. P., Kwon, A. H. K., Vasconcelos, A. C., Cunha, L. D., Mayer, A. E., Shen, Y., Wu, W.-L., Kambal, A., et al. (2016) · Science · doi:10.1126/science.aad9948 · Cited by 647 · see citing works
New IBD genetics: common pathways with other diseases
Lees, C. W., Barrett, J. C., Parkes, M., & Satsangi, J. (2011) · Gut · doi:10.1136/gut.2009.199679 · Cited by 635 · see citing works
Carvalho, F. A., Koren, O., Goodrich, J. K., Johansson, M. E. V., Nalbantoglu, I., Aitken, J. D., Su, Y., Chassaing, B., Walters, W. A., González, A., et al. (2012) · Cell Host & Microbe · doi:10.1016/j.chom.2012.07.004 · Cited by 548 · see citing works
Nod2 is required for the regulation of commensal microbiota in the intestine
Petnicki-Ocwieja, T., Hrncir, T., Liu, Y.-J., Biswas, A., Hudcovic, T., Tlaskalova-Hogenova, H., & Kobayashi, K. S. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0907722106 · Cited by 564 · see citing works
Human genetic variation and the gut microbiome in disease
Hall, A. B., Tolonen, A. C., & Xavier, R. J. (2017) · Nature Reviews Genetics · doi:10.1038/nrg.2017.63 · Cited by 517 · see citing works
Advances in inflammatory bowel disease pathogenesis: linking host genetics and the microbiome
Knights, D., Lassen, K. G., & Xavier, R. J. (2013) · Gut · doi:10.1136/gutjnl-2012-303954 · Cited by 468 · see citing works
Recent insights into the immunopathogenesis of psoriasis provide new therapeutic opportunities
Nickoloff, B. J., & Nestle, F. O. (2004) · Journal of Clinical Investigation · doi:10.1172/jci200422147 · Cited by 544 · see citing works
The Commensal Microbiota and Enteropathogens in the Pathogenesis of Inflammatory Bowel Diseases
Chassaing, B., & Darfeuille–Michaud, A. (2011) · Gastroenterology · doi:10.1053/j.gastro.2011.01.054 · Cited by 443 · see citing works
Influence of mode of delivery on gut microbiota composition in seven year old children: Table 1
Salminen, S., Gibson, G. R., McCartney, A. L., & Isolauri, E. (2004) · Gut · doi:10.1136/gut.2004.041640 · Cited by 435 · see citing works
Mutations in NOD2 are associated with fibrostenosing disease in patients with Crohn's disease
Abreu, M. T., Taylor, K. D., Lin, Y.-C., Hang, T., Gaiennie, J., Landers, C. J., Vasiliauskas, E. A., Kam, L. Y., Rojany, M., Papadakis, K. A., et al. (2002) · Gastroenterology · doi:10.1053/gast.2002.35393 · Cited by 428 · see citing works
Immune Responses to the Microbiota at the Intestinal Mucosal Surface
Duerkop, B. A., Vaishnava, S., & Hooper, L. V. (2009) · Immunity · doi:10.1016/j.immuni.2009.08.009 · Cited by 424 · see citing works
Zaki, M. H., Vogel, P., Body-Malapel, M., Lamkanfi, M., & Kanneganti, T.-D. (2010) · The Journal of Immunology · doi:10.4049/jimmunol.1002046 · Cited by 411 · see citing works
Salzman, N. H., Underwood, M. A., & Bevins, C. L. (2007) · Seminars in Immunology · doi:10.1016/j.smim.2007.04.002 · Cited by 414 · see citing works
Theory and practice in quantitative genetics
Posthuma, D., Beem, A. L., de Geus, E. J. C., van Baal, G. C. M., von Hjelmborg, J. B., Iachine, I., & Boomsma, D. I. (2003) · Twin Research · doi:10.1375/136905203770326367 · Cited by 416 · see citing works
Bacillary dysentery as a causative factor of irritable bowel syndrome and its pathogenesis
Wang, L.-H., Fang, X.-C., & Pan, G.-Z. (2004) · Gut · doi:10.1136/gut.2003.021154 · Cited by 387 · see citing works
Gut-associated bacterial microbiota in paediatric patients with inflammatory bowel disease
Conte, M. P., Schippa, S., Zamboni, I., Penta, M., Chiarini, F., Seganti, L., Osborn, J., Falconieri, P., Borrelli, O., & Cucchiara, S. (2006) · Gut · doi:10.1136/gut.2005.078824 · Cited by 383 · see citing works
Welte, T., Zhang, S. S. M., Wang, T., Zhang, Z., Hesslein, D. G. T., Yin, Z., Kano, A., Iwamoto, Y., Li, E., Craft, J. E., et al. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0237137100 · Cited by 381 · see citing works
Fernandez, E. M., Valenti, V., Rockel, C., Hermann, C., Pot, B., Boneca, I. G., & Grangette, C. (2011) · Gut · doi:10.1136/gut.2010.232918 · Cited by 376 · see citing works
Hold, G. L. (2014) · World Journal of Gastroenterology · doi:10.3748/wjg.v20.i5.1192 · Cited by 365 · see citing works
Interactions between Intestinal Microbiota and Host Immune Response in Inflammatory Bowel Disease
Zhang, M., Sun, K., Wu, Y., Yang, Y., Tso, P., & Wu, Z. (2017) · Frontiers in Immunology · doi:10.3389/fimmu.2017.00942 · Cited by 347 · see citing works
The genetics of multiple sclerosis: SNPs to pathways to pathogenesis
Oksenberg, J. R., Baranzini, S. E., Sawcer, S., & Hauser, S. L. (2008) · Nature Reviews Genetics · doi:10.1038/nrg2395 · Cited by 347 · see citing works
Modulation of inflammation by autophagy: Consequences for human disease
Netea-Maier, R. T., Plantinga, T. S., van de Veerdonk, F. L., Smit, J. W., & Netea, M. G. (2016) · Autophagy · doi:10.1080/15548627.2015.1071759 · Cited by 349 · see citing works
Inflammatory Bowel Disease as a Model for Translating the Microbiome
Huttenhower, C., Kostic, A. D., & Xavier, R. J. (2014) · Immunity · doi:10.1016/j.immuni.2014.05.013 · Cited by 332 · see citing works
Scanlan, P. D., Shanahan, F., O'Mahony, C., & Marchesi, J. R. (2006) · Journal of Clinical Microbiology · doi:10.1128/jcm.00312-06 · Cited by 330 · see citing works
Endosomes are specialized platforms for bacterial sensing and NOD2 signalling
Nakamura, N., Lill, J. R., Phung, Q., Jiang, Z., Bakalarski, C., de Mazière, A., Klumperman, J., Schlatter, M., Delamarre, L., & Mellman, I. (2014) · Nature · doi:10.1038/nature13133 · Cited by 313 · see citing works
Chen, L., Wilson, J. E., Koenigsknecht, M. J., Chou, W.-C., Montgomery, S. A., Truax, A. D., Brickey, W. J., Packey, C. D., Maharshak, N., Matsushima, G. K., et al. (2017) · Nature Immunology · doi:10.1038/ni.3690 · Cited by 310 · see citing works
Martín, R., Chain, F., Miquel, S., Lu, J., Gratadoux, J.-J., Sokol, H., Verdu, E. F., Bercik, P., Bermúdez-Humarán, L. G., & Langella, P. (2014) · Inflammatory Bowel Diseases · doi:10.1097/01.mib.0000440815.76627.64 · Cited by 284 · see citing works
A High-Density Screen for Linkage in Multiple Sclerosis
(2005) · The American Journal of Human Genetics · doi:10.1086/444547 · Cited by 297 · see citing works
Diverse Genome-wide Association Studies Associate the IL12/IL23 Pathway with Crohn Disease
Wang, K., Zhang, H., Kugathasan, S., Annese, V., Bradfield, J. P., Russell, R. K., Sleiman, P. M. A., Imielinski, M., Glessner, J., Hou, C., et al. (2009) · The American Journal of Human Genetics · doi:10.1016/j.ajhg.2009.01.026 · Cited by 291 · see citing works
The NLRP3 inflammasome: Contributions to intestinal homeostasis
Zaki, M. H., Lamkanfi, M., & Kanneganti, T.-D. (2011) · Trends in Immunology · doi:10.1016/j.it.2011.02.002 · Cited by 290 · see citing works
- 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
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › 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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