title: Association of a functional variant in the Wnt co-receptor LRP6 with early onset ileal Crohn's disease.
abstract: 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.
authors.affiliation: Dr. Margarete-Fischer-Bosch Institute for Clinical Pharmacology and University of Tübingen, Stuttgart, Germany.
authors.forename: Maureen J
authors.initials: MJ
authors.lastname: Koslowski
authors.forename: Zora
authors.initials: Z
authors.lastname: Teltschik
authors.forename: Julia
authors.initials: J
authors.lastname: Beisner
authors.forename: Elke
authors.initials: E
authors.lastname: Schaeffeler
authors.forename: Guoxing
authors.initials: G
authors.lastname: Wang
authors.forename: Irmgard
authors.initials: I
authors.lastname: Kübler
authors.forename: Michael
authors.initials: M
authors.lastname: Gersemann
authors.forename: Rachel
authors.initials: R
authors.lastname: Cooney
authors.forename: Derek
authors.initials: D
authors.lastname: Jewell
authors.forename: Walter
authors.initials: W
authors.lastname: Reinisch
authors.forename: Séverine
authors.initials: S
authors.lastname: Vermeire
authors.forename: Paul
authors.initials: P
authors.lastname: Rutgeerts
authors.forename: Matthias
authors.initials: M
authors.lastname: Schwab
authors.forename: Eduard F
authors.initials: EF
authors.lastname: Stange
authors.forename: Jan
authors.initials: J
authors.lastname: Wehkamp
mesh_terms: D000328:Adult; D000367:Age Factors; D003424:Crohn Disease / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007082:Ileum / Q000378:metabolism / Q000473:pathology; D060488:Low Density Lipoprotein Receptor-Related Protein-6 / Q000235:genetics* / Q000378:metabolism; D008297:Male; D019879:Paneth Cells / Q000378:metabolism / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D058118:Transcription Factor 7-Like 2 Protein / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism; D023084:alpha-Defensins / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
chemical_list: C555475:LRP6 protein, human; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D058118:Transcription Factor 7-Like 2 Protein; D051153:Wnt Proteins; D023084:alpha-Defensins; D051176:beta Catenin