Abstract
BackgroundRisk gene variants for celiac disease, identified in genome-wide linkage and association studies, might influence molecular pathways important for disease development. The aim was to examine expression levels of potential risk genes close to these variants in the small intestine and peripheral blood and also to test if the non-coding variants affect nearby gene expression levels in children with celiac disease.MethodsIntestinal biopsy and peripheral blood RNA was isolated from 167 children with celiac disease, 61 with potential celiac disease and 174 disease controls. Transcript levels for 88 target genes, selected from celiac disease risk loci, were analyzed in biopsies of a smaller sample subset by qPCR. Differentially expressed genes (3 from the pilot and 8 previously identified) were further validated in the larger sample collection (n = 402) of both tissues and correlated to nearby celiac disease risk variants.ResultsAll genes were significantly down- or up-regulated in the intestinal mucosa of celiac disease children, NTS being most down-regulated (Fold change 3.6, p < 0.001). In contrast, PPP1R12B isoform C was up-regulated in the celiac disease mucosa (Fold change 1.9, p < 0.001). Allele specific expression of GLS (rs6741418, p = 0.009), INSR (rs7254060, p = 0.003) and NCALD (rs652008, p = 0.005) was also detected in the biopsies. Two genes (APPL2 and NCALD) were differentially expressed in peripheral blood but no allele specific expression was observed in this tissue.ConclusionThe differential expression of NTS and PPP1R12B indicate a potential role for smooth muscle contractility and cell proliferation in celiac disease, whereas other genes like GLS, NCALD and INSR suggests involvement of nutrient signaling and energy homeostasis in celiac disease pathogenesis. A disturbance in any of these pathways might contribute to development of childhood celiac disease.Electronic supplementary materialThe online version of this article (doi:10.1186/s12881-015-0190-1) contains supplementary material, which is available to authorized users.
Highlights
Risk gene variants for celiac disease, identified in genome-wide linkage and association studies, might influence molecular pathways important for disease development
When including additional patients and controls we could not detect any significant difference in gene expression between potential celiac disease patients and controls in neither peripheral blood nor in the intestinal biopsies (Fig. 1, blood data not shown)
Seven genes were down-regulated in the biopsies of celiac disease patients, among them NTS down-regulated 3.6 fold and the INSR, APPL2, ADCY9, GLS, HSPB1 and KIF13A 1.52.2 fold in the patient group (p < 0.001)
Summary
Risk gene variants for celiac disease, identified in genome-wide linkage and association studies, might influence molecular pathways important for disease development. The odds ratios (OR) for monozygotic twins to be concordant for celiac disease was 17 compared to 1.4 for DQ identical dizygotic twins independent of the DQ at risk genotype [3]. This indicates that non-HLA genetic factors play a role in disease susceptibility. Genome wide association studies (GWASs) in celiac disease have identified altogether 58 non-HLA risk variants within 40 different loci [4,5,6,7].
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