Circulating miRNAs as Potential Biomarkers for Celiac Disease Development
Frontiers in Immunology, vol. 12, pp. 734763
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: 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.
Authors 25
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University Medical Center Groningen · University of Groningen
Affiliation as printed
Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Groningen, Netherlands
Department of Genetics, University of Groningen and University Medical Center Groningen, Groningen, Netherlands
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Rodrigo Coutinho de Almeida Aachen Department of Biomedical Data Sciences Section Molecular Epidemiology
Leiden University Medical Center
Affiliation as printed
Department of Biomedical Data Sciences, Section Molecular Epidemiology, Leiden University Medical Center, Leiden, Netherlands
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University Medical Center Groningen · University of Groningen
Affiliation as printed
Department of Genetics, University of Groningen and University Medical Center Groningen, Groningen, Netherlands
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University Medical Center Groningen · University of Groningen
Affiliation as printed
Department of Genetics, University of Groningen and University Medical Center Groningen, Groningen, Netherlands
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University Medical Center Groningen · University of Groningen
Affiliation as printed
Center of Development and Innovation, University of Groningen and University Medical Center Groningen, Groningen, Netherlands
Department of Genetics, University of Groningen and University Medical Center Groningen, Groningen, Netherlands
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Affiliation as printed
School of Medicine and Surgery, University of Milano-Bicocca, Monza, Italy
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Leiden University Medical Center
Affiliation as printed
Department of Pediatrics, Leiden University Medical Center, Leiden, Netherlands
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Hospital Universitari i Politècnic La Fe · Instituto de Investigación Sanitaria La Fe
Affiliation as printed
Celiac Disease and Digestive Immunopathology Unit, Instituto de Investigación Sanitaria La Fe, La Fe University Hospital, Valencia, Spain
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Instituto de Investigación Sanitaria La Fe
Affiliation as printed
Celiac Disease and Digestive Immunopathology Unit, Instituto de Investigación Sanitaria La Fe, La Fe University Hospital, Madrid, Spain
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Tel Aviv University · Schneider Children's Medical Center
Affiliation as printed
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
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University of Naples Federico II
Affiliation as printed
Department of Medical Translational Sciences and European Laboratory for the Investigation of Food Induced Diseases, University Federico II, Naples, Italy
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University of Debrecen · Heim Pál Országos Gyermekgyógyászati Intézet
Affiliation as printed
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
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Institut de Recerca Biomèdica Catalunya Sud · Hospital Universitari Sant Joan de Reus · Universitat Rovira i Virgili
Affiliation as printed
Unitat de gastroenterologia pediàtrica, Hospital Universitari Sant Joan de Reus, Universitat Rovira i virgili, Institut d'Investigació Sanitària Pere Virgili (IISPV), Reus, Spain
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Affiliation as printed
Department of Paediatrics, The Medical University of Warsaw, Warsaw, Poland
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LMU Klinikum · University of Warmia and Mazury in Olsztyn · Ludwig-Maximilians-Universität München
Affiliation as printed
Department of Pediatric Gastroenterology and Nutrition, School of Medicine Collegium Medicum University of Warmia and Mazury, Olsztyn, Poland
Department of Pediatrics, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-Universität München (LMU) Klinikum Munich, Munich, Germany
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University Medical Center Groningen · University of Groningen
Affiliation as printed
Department of Genetics, University of Groningen and University Medical Center Groningen, Groningen, Netherlands
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University Medical Center Groningen · Radboud University Nijmegen · University of Groningen · Radboud University Medical Center
Affiliation as printed
Department of Genetics, University of Groningen and University Medical Center Groningen, Groningen, Netherlands
Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, Netherlands
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University Medical Center Groningen · University of Groningen · Radboud University Medical Center · Medizinische Hochschule Hannover · Radboud Institute for Molecular Life Sciences · Helmholtz Centre for Infection Research · Centre for Individualised Infection Medicine · Center for Experimental and Clinical Infection Research
Affiliation as printed
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 Genetics, University of Groningen and University Medical Center Groningen, Groningen, Netherlands
Department of Internal Medicine and Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands
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University Medical Center Groningen · University of Groningen
Affiliation as printed
Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Groningen, Netherlands
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University Medical Center Groningen · University of Groningen
Affiliation as printed
Department of Gastroenterology and Hepatology, University of Groningen and University Medical Center Groningen, Groningen, Netherlands
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University of Naples Federico II
Affiliation as printed
Department of Medical Translational Sciences and European Laboratory for the Investigation of Food Induced Diseases, University Federico II, Naples, Italy
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Leiden University Medical Center
Affiliation as printed
Department of Pediatrics, Leiden University Medical Center, Leiden, Netherlands
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University Medical Center Groningen · University of Groningen
Affiliation as printed
Department of Genetics, University of Groningen and University Medical Center Groningen, Groningen, Netherlands
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University Medical Center Groningen · University of Groningen
Affiliation as printed
Department of Genetics, University of Groningen and University Medical Center Groningen, Groningen, Netherlands
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Sebo Withoff corresponding
University Medical Center Groningen · University of Groningen
Affiliation as printed
Department of Genetics, University of Groningen and University Medical Center Groningen, Groningen, Netherlands
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