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.
Highlights
Ileal Crohn’s disease (CD) belongs to the group of inflammatory bowel diseases characterized by chronic intestinal inflammation, ulceration and consequent diarrhoea [1]
In contrast to colonic CD and ulcerative colitis (UC), ileal CD is characterized by a specific reduction of two Paneth cell antimicrobial peptides (AMPs), the human defensins (HD) -5 and -6 [13,14,15,16]
We studied frequency distributions and linkage disequilibria of all single nucleotide polymorphisms (SNPs) reported in the NCBI SNPdatabase in the exonic regions of lipoprotein receptorrelated protein 6 (LRP6) (Figure 1 upper panel)
Summary
Ileal Crohn’s disease (CD) belongs to the group of inflammatory bowel diseases characterized by chronic intestinal inflammation, ulceration and consequent diarrhoea [1]. Since bacteria represent the main target of adaptive immune responses [8,9,10] and trigger mucosal inflammation in susceptible individuals [11], we have suggested that location specific antimicrobial immunity defects render the mucosa susceptible to microbial adhesion and invasion [12] Such defence impairments accommodate both, the inherited and the microbial component in the pathogenesis [13] and help to explain the stability of the specific disease locations. In contrast to colonic CD and ulcerative colitis (UC), ileal CD is characterized by a specific reduction of two Paneth cell antimicrobial peptides (AMPs), the human defensins (HD) -5 and -6 [13,14,15,16] These two Paneth cell a- defensins are the most abundant products of the specialized secretory cells residing at the base of small intestinal crypts of Lieberkuhn and the most prominent AMPs in the ileal mucosa [17,18]. Paneth cell antimicrobials are involved in the regulation of the Author Summary
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