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Association of a Functional Variant in the Wnt Co-Receptor LRP6 with Early Onset Ileal Crohn's Disease

Ileal Crohn's Disease (CD), a chronic small intestinal inflammatory disorder, is characterized by reduced levels of the antimicrobial peptides DEFA5 (HD-5) and DEFA6 (HD-6). Both of these α-defensins are exclusively produced in Paneth cells (PCs) at small intestinal crypt bases. Different ileal...

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Autores principales: Koslowski, Maureen J., Teltschik, Zora, Beisner, Julia, Schaeffeler, Elke, Wang, Guoxing, Kübler, Irmgard, Gersemann, Michael, Cooney, Rachel, Jewell, Derek, Reinisch, Walter, Vermeire, Séverine, Rutgeerts, Paul, Schwab, Matthias, Stange, Eduard F., Wehkamp, Jan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3285585/
https://www.ncbi.nlm.nih.gov/pubmed/22393312
http://dx.doi.org/10.1371/journal.pgen.1002523
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author Koslowski, Maureen J.
Teltschik, Zora
Beisner, Julia
Schaeffeler, Elke
Wang, Guoxing
Kübler, Irmgard
Gersemann, Michael
Cooney, Rachel
Jewell, Derek
Reinisch, Walter
Vermeire, Séverine
Rutgeerts, Paul
Schwab, Matthias
Stange, Eduard F.
Wehkamp, Jan
author_facet Koslowski, Maureen J.
Teltschik, Zora
Beisner, Julia
Schaeffeler, Elke
Wang, Guoxing
Kübler, Irmgard
Gersemann, Michael
Cooney, Rachel
Jewell, Derek
Reinisch, Walter
Vermeire, Séverine
Rutgeerts, Paul
Schwab, Matthias
Stange, Eduard F.
Wehkamp, Jan
author_sort Koslowski, Maureen J.
collection PubMed
description Ileal Crohn's Disease (CD), a chronic small intestinal inflammatory disorder, is characterized by reduced levels of the antimicrobial peptides DEFA5 (HD-5) and DEFA6 (HD-6). Both of these α-defensins are exclusively produced in Paneth cells (PCs) at small intestinal crypt bases. Different ileal CD–associated genes including NOD2, ATG16L1, and recently the β-catenin–dependant Wnt transcription factor TCF7L2 have been linked to impaired PC antimicrobial function. The Wnt pathway influences gut mucosal homeostasis and PC maturation, besides directly controlling HD-5/6 gene expression. The herein reported candidate gene study focuses on another crucial Wnt factor, the co-receptor low density lipoprotein receptor-related protein 6 (LRP6). We analysed exonic single nucleotide polymorphisms (SNPs) in a large cohort (Oxford: n = 1,893) and prospectively tested 2 additional European sample sets (Leuven: n = 688, Vienna: n = 1,628). We revealed an association of a non-synonymous SNP (rs2302685; Ile1062Val) with early onset ileal CD (OR 1.8; p = 0.00034; for homozygous carriers: OR 4.1; p = 0.00004) and additionally with penetrating ileal CD behaviour (OR 1.3; p = 0.00917). In contrast, it was not linked to adult onset ileal CD, colonic CD, or ulcerative colitis. Since the rare variant is known to impair LRP6 activity, we investigated its role in patient mucosa. Overall, LRP6 mRNA was diminished in patients independently from the genotype. Analysing the mRNA levels of PC product in biopsies from genotyped individuals (15 controls, 32 ileal, and 12 exclusively colonic CD), we found particularly low defensin levels in ileal CD patients who were carrying the variant. In addition, we confirmed a direct relationship between LRP6 activity and the transcriptional expression of HD-5 using transient transfection. Taken together, we identified LRP6 as a new candidate gene in ileal CD. Impairments in Wnt signalling and Paneth cell biology seem to represent pathophysiological hallmarks in small intestinal inflammation and should therefore be considered as interesting targets for new therapeutic approaches.
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spelling pubmed-32855852012-03-05 Association of a Functional Variant in the Wnt Co-Receptor LRP6 with Early Onset Ileal Crohn's Disease Koslowski, Maureen J. Teltschik, Zora Beisner, Julia Schaeffeler, Elke Wang, Guoxing Kübler, Irmgard Gersemann, Michael Cooney, Rachel Jewell, Derek Reinisch, Walter Vermeire, Séverine Rutgeerts, Paul Schwab, Matthias Stange, Eduard F. Wehkamp, Jan PLoS Genet Research Article Ileal Crohn's Disease (CD), a chronic small intestinal inflammatory disorder, is characterized by reduced levels of the antimicrobial peptides DEFA5 (HD-5) and DEFA6 (HD-6). Both of these α-defensins are exclusively produced in Paneth cells (PCs) at small intestinal crypt bases. Different ileal CD–associated genes including NOD2, ATG16L1, and recently the β-catenin–dependant Wnt transcription factor TCF7L2 have been linked to impaired PC antimicrobial function. The Wnt pathway influences gut mucosal homeostasis and PC maturation, besides directly controlling HD-5/6 gene expression. The herein reported candidate gene study focuses on another crucial Wnt factor, the co-receptor low density lipoprotein receptor-related protein 6 (LRP6). We analysed exonic single nucleotide polymorphisms (SNPs) in a large cohort (Oxford: n = 1,893) and prospectively tested 2 additional European sample sets (Leuven: n = 688, Vienna: n = 1,628). We revealed an association of a non-synonymous SNP (rs2302685; Ile1062Val) with early onset ileal CD (OR 1.8; p = 0.00034; for homozygous carriers: OR 4.1; p = 0.00004) and additionally with penetrating ileal CD behaviour (OR 1.3; p = 0.00917). In contrast, it was not linked to adult onset ileal CD, colonic CD, or ulcerative colitis. Since the rare variant is known to impair LRP6 activity, we investigated its role in patient mucosa. Overall, LRP6 mRNA was diminished in patients independently from the genotype. Analysing the mRNA levels of PC product in biopsies from genotyped individuals (15 controls, 32 ileal, and 12 exclusively colonic CD), we found particularly low defensin levels in ileal CD patients who were carrying the variant. In addition, we confirmed a direct relationship between LRP6 activity and the transcriptional expression of HD-5 using transient transfection. Taken together, we identified LRP6 as a new candidate gene in ileal CD. Impairments in Wnt signalling and Paneth cell biology seem to represent pathophysiological hallmarks in small intestinal inflammation and should therefore be considered as interesting targets for new therapeutic approaches. Public Library of Science 2012-02-23 /pmc/articles/PMC3285585/ /pubmed/22393312 http://dx.doi.org/10.1371/journal.pgen.1002523 Text en Koslowski et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Koslowski, Maureen J.
Teltschik, Zora
Beisner, Julia
Schaeffeler, Elke
Wang, Guoxing
Kübler, Irmgard
Gersemann, Michael
Cooney, Rachel
Jewell, Derek
Reinisch, Walter
Vermeire, Séverine
Rutgeerts, Paul
Schwab, Matthias
Stange, Eduard F.
Wehkamp, Jan
Association of a Functional Variant in the Wnt Co-Receptor LRP6 with Early Onset Ileal Crohn's Disease
title Association of a Functional Variant in the Wnt Co-Receptor LRP6 with Early Onset Ileal Crohn's Disease
title_full Association of a Functional Variant in the Wnt Co-Receptor LRP6 with Early Onset Ileal Crohn's Disease
title_fullStr Association of a Functional Variant in the Wnt Co-Receptor LRP6 with Early Onset Ileal Crohn's Disease
title_full_unstemmed Association of a Functional Variant in the Wnt Co-Receptor LRP6 with Early Onset Ileal Crohn's Disease
title_short Association of a Functional Variant in the Wnt Co-Receptor LRP6 with Early Onset Ileal Crohn's Disease
title_sort association of a functional variant in the wnt co-receptor lrp6 with early onset ileal crohn's disease
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3285585/
https://www.ncbi.nlm.nih.gov/pubmed/22393312
http://dx.doi.org/10.1371/journal.pgen.1002523
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