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Circulating miRNAs as Potential Biomarkers for Celiac Disease Development.

Department of Genetics, University of Groningen and University Medical Center Groningen, Groningen, Netherlands. Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Groningen, Netherlands. Department of Biomedical Data Sciences, Section Molecular Epidemiology, Leiden University Medical Center, Leiden, Netherlands. Center of Development and Innovation, University of Groningen and University Medical Center Groningen, Groningen, Netherlands. School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy. Department of Pediatrics, Leiden University Medical Center, Leiden, Netherlands. Celiac Disease and Digestive Immunopathology Unit, Instituto de Investigación Sanitaria La Fe, La Fe University Hospital, Valencia, Spain. Celiac Disease and Digestive Immunopathology Unit, Instituto de Investigación Sanitaria La Fe, La Fe University Hospital, Madrid, Spain. Institute of Pediatric Gastroenterology, Nutrition, and Liver Diseases, Schneider Children's Medical Center, Petach Tikva, Israel. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. Department of Medical Translational Sciences and European Laboratory for the Investigation of Food Induced Diseases, University Federico II, Naples, Italy. Coeliac Disease Center, Heim Pál National Paediatric Institute, Budapest, Hungary and Dept. of Paediatrics, Faculty of Medicine and Clinical Center, University of Debrecen, Debrecen, Hungary. Unitat de gastroenterologia pediàtrica, Hospital Universitari Sant Joan de Reus, Universitat Rovira i virgili, Institut d'Investigació Sanitària Pere Virgili (IISPV), Reus, Spain. Department of Paediatrics, The Medical University of Warsaw, Warsaw, Poland. Department of Pediatrics, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-Universität München (LMU) Klinikum Munich, Munich, Germany. Department of Pediatric Gastroenterology and Nutrition, School of Medicine Collegium Medicum University of Warmia and Mazury, Olsztyn, Poland. Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, Netherlands. Department of Computational Biology for Individualised Infection Medicine, Centre for Individualised Infection Medicine (CiiM) & TWINCORE, Joint Ventures Between the Helmholtz-Centre for Infection Research (HZI) and the Hannover Medical School (MHH), Hannover, Germany. Department of Internal Medicine and Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands.

Frontiers in immunology. 2021;:734763
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Abstract

BACKGROUND & AIMS Celiac 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. METHODS Using 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. RESULTS 53 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. CONCLUSIONS We 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.

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Publication Type : Meta-Analysis ; Multicenter Study

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