title: Factors That Increase Risk of Celiac Disease Autoimmunity After a Gastrointestinal Infection in Early Life.
abstract: OBJECTIVE
  Little is known about the pathogenic mechanisms of gluten immunogenicity in patients with celiac disease. We studied temporal associations between infections and the development of celiac disease autoimmunity, and examined effects of HLA alleles, rotavirus vaccination status, and infant feeding.
  
  
  METHODS
  We monitored 6327 children in the United States and Europe carrying HLA risk genotypes for celiac disease from 1 to 4 years of age for presence of tissue transglutaminase autoantibodies (the definition of celiac disease autoimmunity), until March 31, 2015. Parental reports of gastrointestinal and respiratory infections were collected every third month from birth. We analyzed time-varying relationships among reported infections, rotavirus vaccination status, time to first introduction of gluten, breastfeeding, and risk of celiac disease autoimmunity using proportional hazard models.
  
  
  RESULTS
  We identified 13,881 gastrointestinal infectious episodes (GIE) and 79,816 respiratory infectious episodes. During the follow-up period, 732 of 6327 (11.6%) children developed celiac disease autoimmunity. A GIE increased the risk of celiac disease autoimmunity within the following 3 months by 33% (hazard ratio [HR], 1.33; 95% confidence interval [CI], 1.11-1.59). This risk increased 2-fold among children born in winter and introduced to gluten before age 6 months (HR, 2.08; 95% CI, 1.46-2.98), and increased 10-fold among children without HLA-DQ2 alleles and breastfed for fewer than 4 months (HR, 9.76; 95% CI, 3.87-24.8). Risk of celiac disease autoimmunity was reduced in children vaccinated against rotavirus and introduced to gluten before age 6 months (HR, 0.57; 95% CI, 0.36-0.88).
  
  
  CONCLUSIONS
  Gastrointestinal infections increase the risk of celiac disease autoimmunity in children with genetic susceptibility to this autoimmune disorder. The risk is modified by HLA genotype, infant gluten consumption, breastfeeding, and rotavirus vaccination, indicating complex interactions among infections, genetic factors, and diet in the etiology of celiac disease in early childhood.
authors.affiliation: Department of Microbiology and Cell Science, University of Florida, Gainesville, Florida.
authors.forename: Kaisa M
authors.initials: KM
authors.lastname: Kemppainen
authors.affiliation: Health Informatics Institute, University of South Florida, Tampa, Florida.
authors.forename: Kristian F
authors.initials: KF
authors.lastname: Lynch
authors.affiliation: Digestive Health Institute, Children's Hospital Colorado, University of Colorado, Denver; Barbara Davis Center, University of Colorado Denver, Aurora, Colorado.
authors.forename: Edwin
authors.initials: E
authors.lastname: Liu
authors.affiliation: Department of Virology, School of Medicine, University of Tampere, Tampere, Finland; Department of Dermatology, Tampere University Hospital, Tampere, Finland.
authors.forename: Maria
authors.initials: M
authors.lastname: Lönnrot
authors.affiliation: MediCity Laboratory, University of Turku, Turku, Finland.
authors.forename: Ville
authors.initials: V
authors.lastname: Simell
authors.affiliation: Center for Infection and Immunity, and Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, New York.
authors.forename: Thomas
authors.initials: T
authors.lastname: Briese
authors.affiliation: Dr von Hauner Children's Hospital, Ludwig Maximilian University, Munich, Germany.
authors.forename: Sibylle
authors.initials: S
authors.lastname: Koletzko
authors.affiliation: Pacific Northwest Diabetes Research Institute, Seattle, Washington.
authors.forename: William
authors.initials: W
authors.lastname: Hagopian
authors.affiliation: Digestive Health Institute, Children's Hospital Colorado, University of Colorado, Denver; Barbara Davis Center, University of Colorado Denver, Aurora, Colorado.
authors.forename: Marian
authors.initials: M
authors.lastname: Rewers
authors.affiliation: Center for Biotechnology and Genomic Medicine, Medical College of Georgia, Georgia Regents University, Augusta, Georgia.
authors.forename: Jin-Xiong
authors.initials: JX
authors.lastname: She
authors.affiliation: Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland.
authors.forename: Olli
authors.initials: O
authors.lastname: Simell
authors.affiliation: Department of Pediatrics, University of Turku, Turku, Finland; Departments of Physiology and Pediatrics, University of Turku, Turku, Finland.
authors.forename: Jorma
authors.initials: J
authors.lastname: Toppari
authors.affiliation: Institute of Diabetes Research, Helmholtz Zentrum München, Klinikum Rechts der Isar, Technische Universität München, Forschergruppe Diabetes eV, Neuherberg, Germany.
authors.forename: Anette-G
authors.initials: AG
authors.lastname: Ziegler
authors.affiliation: National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland.
authors.forename: Beena
authors.initials: B
authors.lastname: Akolkar
authors.affiliation: Health Informatics Institute, University of South Florida, Tampa, Florida.
authors.forename: Jeffrey P
authors.initials: JP
authors.lastname: Krischer
authors.affiliation: Department of Clinical Sciences, Lund University, Malmo, Sweden.
authors.forename: Åke
authors.initials: Å
authors.lastname: Lernmark
authors.affiliation: Department of Virology, School of Medicine, University of Tampere, Tampere, Finland; Department of Dermatology, Tampere University Hospital, Tampere, Finland; Fimlab Laboratories, Pirkanmaa Hospital District, Tampere, Finland.
authors.forename: Heikki
authors.initials: H
authors.lastname: Hyöty
authors.affiliation: Department of Microbiology and Cell Science, University of Florida, Gainesville, Florida.
authors.forename: Eric W
authors.initials: EW
authors.lastname: Triplett
authors.affiliation: Department of Clinical Sciences, Lund University, Malmo, Sweden. Electronic address: daniel.agardh@med.lu.se.
authors.forename: Daniel
authors.initials: D
authors.lastname: Agardh
mesh_terms: D000328:Adult; D002446:Celiac Disease / Q000453:epidemiology* / Q000209:etiology*; D002675:Child, Preschool; D004032:Diet / Q000379:methods; D004198:Disease Susceptibility; D005060:Europe / Q000453:epidemiology; D005260:Female; D005759:Gastroenteritis / Q000150:complications*; D005838:Genotype; D006680:HLA Antigens / Q000235:genetics; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D011446:Prospective Studies; D012141:Respiratory Tract Infections / Q000150:complications; D018570:Risk Assessment; D012401:Rotavirus / Q000276:immunology; D022243:Rotavirus Vaccines / Q000008:administration & dosage; D014481:United States / Q000453:epidemiology
chemical_list: D006680:HLA Antigens; D022243:Rotavirus Vaccines
keywords: Autoimmunity; Food; Gastroenteritis; Rotavirus