Am J Gastroenterol. 2022 Dec 23. doi: 10.14309/ajg.0000000000002056. Online ahead of print.

Stahl Marisa ¹, Li Qian ², Lynch Kristian ³, Koletzko Sibylle ^4 5, Mehta Pooja ¹, Gragert Loren ⁶, Norris Jill M ⁷, Andrén Aronsson Carin ⁸, Lindfors Katri ⁹, Kurppa Kalle ^9 10, Ilonen Jorma ¹¹, Krischer Jeffrey ³, Alkolkar Beena ^12 13, Ziegler Annette-G ¹⁴, Toppari Jorma ¹⁵, Rewers Marian ¹⁶, Agardh Daniel ¹⁷, Hagopian William ¹⁸, Liu Edwin ¹; and the TEDDY Study Group

Author information

¹Digestive Health Institute, Department of Pediatrics, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States.

²Department of Biostatistics, St. Jude Children's Research Hospital, Memphis, TN, United States.

³Health Informatics Institute, Morsani College of Medicine, University of South Florida, Tampa, FL, United States.

⁴Department of Pediatrics, Dr von Hauner Kinderspital, LMU Klinikum, Munich, Germany.

⁵Department of Pediatrics, Gastroenterology and Nutrition, School of Medicine Collegium Medicum University of Warmia and Mazury, Olsztyn, Poland.

⁶Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA, United States.

⁷Department of Epidemiology, Colorado School of Public Health, University of Colorado Anschutz Medical Campus, Aurora, CO, United States.

⁸Department of Clinical Sciences, Malmo, Lund University, Malmo, Sweden.

⁹Celiac Disease Research Center, Tampere University and Tampere University Hospital.

¹⁰Tampere Center for Child, Adolescent and Maternal Health Research, Faculty of Medicine and Health Technology, Tampere University and Tampere University Hospital.

¹¹Immunogenetics Laboratory, Institute of Biomedicine, University of Turku, Turku, Finland.

¹²Department of Pediatrics, Turku University Hospital, Turku, Finland.

¹³National Institutes of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, United States.

¹⁴Forschergruppe Diabetes e.V. and Institute of Diabetes Research, Helmholtz Zentrum, Munich, Germany.

¹⁵Institute of Biomedicine, Centre for Integrative Physiology and Pharmacology, Univeristy of Turku, Turku, Finland.

¹⁶Barbara Davis Center for Diabetes, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States.

¹⁷Diabetes and Celiac Disease, Lund University, Malmo, Sweden.

¹⁸Department of Diabetes, Pacific Northwest Research Institute, Seattle, WA, United States.

Abstract

Objectives: The Environmental Determinants of Diabetes in the Young (TEDDY) study follows an HLA-risk selected birth cohort for celiac disease (CD) development using a uniform protocol. Children under investigation come from 6 different regions within Europe and the United States. Our aim was to identify regional differences in celiac disease autoimmunity (CDA) and CD cumulative incidence for children born between 2004 and 2010.

Methods: Children (n=6,628) with DQ2.5 and/or DQ8.1 were enrolled prospectively from birth in Georgia, Washington, Colorado, Finland, Germany, and Sweden. Children underwent periodic study screening for tissue transglutaminase antibodies (tTGA) and then CD evaluation per clinical care. Population-specific estimates were calculated by weighting the study-specific cumulative incidence with the population-specific haplogenotype frequencies obtained from large stem cell registries from each site.

Results: Individual haplogenotype risks for CDA and CD varied by region and affected the cumulative incidence within that region. The CD incidence by age 10 years was highest in Swedish children at 3%. Within the US, the incidence by age 10 in Colorado was 2.4%. In the HLA, sex, and family history-adjusted model, Colorado children had a 2.5-fold higher risk of CD compared to Washington. Likewise, Swedish children had a 1.4-fold and 1.8-fold higher risk of CD compared to Finland and Germany, respectively.

Conclusions: There is high regional variability in cumulative incidence of CD which suggests differential environmental, genetic, and epigenetic influences even within the United States. The overall high incidence warrants a low threshold for screening and further research on region-specific CD triggers.