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Consequence of functional Nod2 and Tlr4 mutations on gene transcription in Crohn’s disease patients

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Abstract

The concept that mutations in germ-line encoded pattern recognition receptors with immune activating functions are associated with an increased incidence in Crohn’s disease (CD) is gaining acceptance. Whether these mutations have similar or distinct effects on cellular physiology remains obscure. The incidence of three single nucleotide polymorphisms (SNPs) within the Nod2 gene and one functional SNP within both the Tlr4 and Tlr5 gene in a Dutch cohort of 637 patients with inflammatory bowel disease and 127 controls was investigated. The functional consequence of mutant NOD2 and TLR4 was investigated by comparing gene expression profiles after stimulation of monocyte-derived dendritic cells (DCs) from homozygous TLR4- and NOD2-mutant patients with lipopolysaccharides and peptidoglycan, respectively. We observed that the R702W and 1007fs Nod2 alleles and the A299G Tlr4 alleles were significantly more prevalent in patients with CD as compared to healthy controls or patients with ulcerative colitis. The phenotype of TLR4- and NOD2-mutant DCs is distinct, but a large number of genes are up- or down-regulated concordantly. These data provide a concept for the genetic basis of CD; mutations in innate immunity cause similar effects on gene transcription and finally result in comparable clinical disease presentation.

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Acknowledgements

This study was supported by an unrestricted educational grant from the Broad Medical Research Programme to H. Braat. D.W. Hommes is a clinical fellow of The Netherlands organization for Health Research and Development. The authors would like to thank Dr. A.A. van Bodegraven from the Vrije Universiteit Medical Center for providing patient material.

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Authors and Affiliations

  1. Department of Experimental Internal Medicine, Academic Medical Center, P.O. Box 22700, Meibergdreef 9, 1100 DE, Amsterdam, The Netherlands

    Henri Braat, Tijmen Hommes, Danny Cohn, Esther Vogels, Inge Pronk & Arnold Spek

  2. Department of Gastroenterology and Hepatology, Academic Medical Center, P.O. Box 22700, Meibergdreef 9, 1100 DE, Amsterdam, The Netherlands

    Pieter Stokkers, Sander van Deventer & Daan Hommes

  3. Bioinformatics Laboratory, Academic Medical Center, P.O. Box 22700, Meibergdreef 9, 1100 DE, Amsterdam, The Netherlands

    Antoine van Kampen

  4. Department of Cell Biology, University of Groningen, Antonius Deusinglaan 1, 9713 AV, Groningen, The Netherlands

    Maikel Peppelenbosch

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  1. Henri Braat
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Correspondence to Maikel Peppelenbosch.

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Braat, H., Stokkers, P., Hommes, T. et al. Consequence of functional Nod2 and Tlr4 mutations on gene transcription in Crohn’s disease patients. J Mol Med 83, 601–609 (2005). https://doi.org/10.1007/s00109-005-0685-x

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  • DOI: https://doi.org/10.1007/s00109-005-0685-x

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