Abstract
Background & AimsCeliac disease (CeD), an immune-mediated disease with enteropathy triggered by gluten, affects ~1% of the general European population. Currently, there are no biomarkers to predict CeD development. MicroRNAs (miRNAs) are short RNAs involved in post-transcriptional gene regulation, and certain disease- and stage-specific miRNA profiles have been found previously. We aimed to investigate whether circulating miRNAs can predict the development of CeD.MethodsUsing next-generation miRNA-sequencing, we determined miRNAs in >200 serum samples from 53 participants of the PreventCD study, of whom 33 developed CeD during follow-up. Following study inclusion at 3 months of age, samples were drawn at predefined ages, diagnosis (first anti-transglutaminase antibody (TGA) positivity or diagnostic biopsy) and after the start of a gluten-free diet (GFD). This allowed identification of circulating miRNAs that are deregulated before TGA positivity. For validation of the biomarkers for CeD and GFD response, two additional cohorts were included in subsequent meta-analyses. Additionally, miRNAs were measured in duodenal biopsies in a case-control cohort.Results53 circulating miRNAs were increased (27) or decreased (26) in CeD versus controls. We assessed specific trends in these individual miRNAs in the PreventCD cohort by grouping the pre-diagnostic samples of the CeD patients (all had negative TGA) by how close to seroconversion (first sample positive TGA) the samples were taken. 8/53 miRNAs differed significantly between controls and samples taken <1 year before TGA positivity: miR-21-3p, miR-374a-5p, 144-3p, miR-500a-3p, miR-486-3p let-7d-3p, let-7e-5p and miR-3605-3p. 6/26 downregulated miRNAs reconstituted upon GFD, including miR-150-5p/-3p, whereas no upregulated miRNAs were downregulated upon GFD. 15/53 biomarker candidates also differed between CeD biopsies and controls, with a concordant direction, indicating that these circulating miRNAs might originate from the intestine.ConclusionsWe identified 53 circulating miRNAs that are potential early biomarkers for CeD, of which several can be detected more than a year before TGA positivity and some start to normalize upon GFD.
Highlights
In celiac disease (CeD), genetically susceptible individuals develop a small intestinal immune response to gluten, a group of storage proteins present in food items containing wheat, rye or barley [1]
Circulating microRNA profiles were generated from 250 serial serum samples obtained from 53 participants of whom 33 developed CeD during the course of the study (Table 1 shows the number of samples included in the final analyses after the quality control; Supplementary Table S4 shows the number of samples excluded in the quality control)
We used three cohorts to identify whether miRNAs in circulation could be indicative of CeD or change upon initiation of gluten-free diet (GFD)
Summary
In celiac disease (CeD), genetically susceptible individuals develop a small intestinal immune response to gluten, a group of storage proteins present in food items containing wheat, rye or barley [1]. Specific deamidated gluten peptides bind strongly to HLA-DQ2 or -DQ8, resulting in activation of gluten-specific CD4+ T cells, which initiate an immune response by secreting cytokines that activate CD8+ T cells [2, 3]. B cells interact with activated gluten-specific CD4+ T cells and secrete disease-specific autoantibodies against TG2 (TGA), of which the detection is the current mainstay of CeD diagnosis [3]. There are no biomarkers to predict CeD development. We aimed to investigate whether circulating miRNAs can predict the development of CeD
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