Kaisa M Kemppainen1, Kristian F Lynch2, Edwin Liu3, Maria Lönnrot4, Ville Simell5, Thomas Briese6, Sibylle Koletzko7, William Hagopian8, Marian Rewers3, Jin-Xiong She9, Olli Simell10, Jorma Toppari11, Anette-G Ziegler12, Beena Akolkar13, Jeffrey P Krischer2, Åke Lernmark14, Heikki Hyöty15, Eric W Triplett1, Daniel Agardh16. 1. Department of Microbiology and Cell Science, University of Florida, Gainesville, Florida. 2. Health Informatics Institute, University of South Florida, Tampa, Florida. 3. Digestive Health Institute, Children's Hospital Colorado, University of Colorado, Denver; Barbara Davis Center, University of Colorado Denver, Aurora, Colorado. 4. Department of Virology, School of Medicine, University of Tampere, Tampere, Finland; Department of Dermatology, Tampere University Hospital, Tampere, Finland. 5. MediCity Laboratory, University of Turku, Turku, Finland. 6. Center for Infection and Immunity, and Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, New York. 7. Dr von Hauner Children's Hospital, Ludwig Maximilian University, Munich, Germany. 8. Pacific Northwest Diabetes Research Institute, Seattle, Washington. 9. Center for Biotechnology and Genomic Medicine, Medical College of Georgia, Georgia Regents University, Augusta, Georgia. 10. Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland. 11. Department of Pediatrics, University of Turku, Turku, Finland; Departments of Physiology and Pediatrics, University of Turku, Turku, Finland. 12. Institute of Diabetes Research, Helmholtz Zentrum München, Klinikum Rechts der Isar, Technische Universität München, Forschergruppe Diabetes eV, Neuherberg, Germany. 13. National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland. 14. Department of Clinical Sciences, Lund University, Malmo, Sweden. 15. 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. 16. Department of Clinical Sciences, Lund University, Malmo, Sweden. Electronic address: daniel.agardh@med.lu.se.
Abstract
BACKGROUND & AIMS: 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.
BACKGROUND & AIMS: 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: Adina Welander; Anna Röckert Tjernberg; Scott M Montgomery; Johnny Ludvigsson; Jonas F Ludvigsson Journal: Pediatrics Date: 2010-02-22 Impact factor: 7.124
Authors: H Szajewska; R Shamir; A Chmielewska; M Pieścik-Lech; R Auricchio; A Ivarsson; S Kolacek; S Koletzko; I Korponay-Szabo; M L Mearin; C Ribes-Koninckx; R Troncone Journal: Aliment Pharmacol Ther Date: 2015-03-26 Impact factor: 8.171
Authors: M Olivares; A Neef; G Castillejo; G De Palma; V Varea; A Capilla; F Palau; E Nova; A Marcos; I Polanco; C Ribes-Koninckx; L Ortigosa; L Izquierdo; Y Sanz Journal: Gut Date: 2014-06-17 Impact factor: 23.059
Authors: William A Hagopian; Henry Erlich; Ake Lernmark; Marian Rewers; Anette G Ziegler; Olli Simell; Beena Akolkar; Robert Vogt; Alan Blair; Jorma Ilonen; Jeffrey Krischer; JinXiong She Journal: Pediatr Diabetes Date: 2011-05-12 Impact factor: 3.409
Authors: Edwin Liu; Fran Dong; Anna E Barón; Iman Taki; Jill M Norris; Brigitte I Frohnert; Edward J Hoffenberg; Marian Rewers Journal: Gastroenterology Date: 2017-02-07 Impact factor: 22.682
Authors: Carin Andrén Aronsson; Hye-Seung Lee; Elin M Hård Af Segerstad; Ulla Uusitalo; Jimin Yang; Sibylle Koletzko; Edwin Liu; Kalle Kurppa; Polly J Bingley; Jorma Toppari; Anette G Ziegler; Jin-Xiong She; William A Hagopian; Marian Rewers; Beena Akolkar; Jeffrey P Krischer; Suvi M Virtanen; Jill M Norris; Daniel Agardh Journal: JAMA Date: 2019-08-13 Impact factor: 56.272
Authors: Laura Kivelä; Alberto Caminero; Daniel A Leffler; Maria Ines Pinto-Sanchez; Jason A Tye-Din; Katri Lindfors Journal: Nat Rev Gastroenterol Hepatol Date: 2020-11-20 Impact factor: 46.802
Authors: Kaisa M Kemppainen; Kendra Vehik; Kristian F Lynch; Helena Elding Larsson; Ronald J Canepa; Ville Simell; Sibylle Koletzko; Edwin Liu; Olli G Simell; Jorma Toppari; Anette G Ziegler; Marian J Rewers; Åke Lernmark; William A Hagopian; Jin-Xiong She; Beena Akolkar; Desmond A Schatz; Mark A Atkinson; Martin J Blaser; Jeffrey P Krischer; Heikki Hyöty; Daniel Agardh; Eric W Triplett Journal: JAMA Pediatr Date: 2017-12-01 Impact factor: 16.193