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.

WNT-Inflammasome Signaling Mediates NOD2-Induced Development of Acute Arthritis in Mice

“…Thus, a role for WNT signaling, if any, during NOD2-induced inflammasome activation was assessed. Inflammasome activation was analyzed by cleavage of caspase-1 and IL-1b from their pro forms to activated p 20 and p 17 products, respectively, as well as by estimating Il-1b mRNA expression and secreted levels of active IL1b. Interestingly, although MDP-stimulated macrophages displayed robust activation of inflammasomes, macrophages pretreated with b-catenin inhibitor (WNT signaling inhibitor) (Fig.…”

“…Several investigations implicated the close association of NOD2 and the WNT signaling pathway during the development of Crohn's disease (20)(21)(22). Canonical WNT signaling involves binding of the WNT ligands to Frizzled (Fzd) and LRP5/6 coreceptors to induce stabilization of b-catenin protein.…”

Increased Gut Permeability and Microbiota Change Associate with Mesenteric Fat Infl ammation and Metabolic Dysfunction in Diet-Induced Obese Mice

“…Supplementary, major proceedings in our understanding of the checks and balance systems within epithelial proliferative gut networks provide new views on different intestinal disorders. Our group could, for instance, elucidate an involvement of disturbed Wnt signalling, which is crucial for epithelial proliferation but also Paneth cell antimicrobial function, in chronic small intestinal inflammation (Koslowski et al, 2012;Wehkamp et al, 2007). Moreover, we also reported an influence of gut bacteria regarding the expression of transcription factors controlling epithelial secretory lineage decision making as well as Goblet cell differentiation (Becker et al, 2013).…”

“…Multiple studies could show a critical Paneth cell dependence on canonical Wnt (Andreu et al, 2005(Andreu et al, , 2008van Es et al, 2005van Es et al, , 2012. In small intestinal CD, reduced expression (Perminow et al, 2010;Wehkamp et al, 2007;Zilbauer et al, 2011) and a genetic association (Koslowski et al, 2009b) of TCF7L2 as well as an early onset associated coding variant in LRP6 and generally low mRNA level of the Wnt co-receptor (Koslowski et al, 2012), support an important role of the pathway in disease aetiology. Furthermore, E-cadherin (CDH1) which has also been introduced in the context of CD susceptibility provides an additional bridge to disturbed canonical Wnt activity (Muise et al, 2009).…”

Harnessing low-density lipoprotein receptor protein 6 (LRP6) genetic variation and Wnt signaling for innovative diagnostics in complex diseases

“…23 Besides, LRP6 rs2302685, predisposing people toward early-onset ileal Crohn's disease, may also turn into an attractive therapeutic target as an alternative to the current anti-inflammatory approaches in the therapy of Crohn' diseases. 80 Another variant, LRP6 rs6488507, may be associated with the increased risk of NSCLC in tobacco smokers, and thus the clinical diagnostic testing may be necessary for carriers with smoking history. 51 Hence, it is expected that further research in this field means a lot to the prediction or treatment of complex diseases.…”