Sci Rep. 2024 Oct 26;14(1):25463. doi: 10.1038/s41598-024-75496-w.

Anna Eurén ¹, Kristian Lynch ², Katri Lindfors ¹, Hemang Parikh ², Sibylle Koletzko ^3 4, Edwin Liu ⁵, Beena Akolkar ⁶, William Hagopian ⁷, Jeffrey Krischer ², Marian Rewers ⁸, Jorma Toppari ^9 10, Anette Ziegler ^11 12 13, Daniel Agardh ¹⁴, Kalle Kurppa ^15 16 17; TEDDY Study Group

Collaborators

• TEDDY Study Group: 

Marian Rewers, Aaron Barbour, Kimberly Bautista, Judith Baxter, Daniel Felipe-Morales, Brigitte I Frohnert, Marisa Stahl, Patricia Gesualdo, Michelle Hoffman, Rachel Karban, Edwin Liu, Alondra Munoz, Jill Norris, Holly O'Donnell, Stesha Peacock, Hanan Shorrosh, Andrea Steck, Megan Stern, Kathleen Waugh, Jorma Toppari, Olli G Simell, Annika Adamsson, Suvi Ahonen, Mari Åkerlund, Sirpa Anttila, Leena Hakola, Anne Hekkala, Tiia Honkanen, Heikki Hyöty, Jorma Ilonen, Sanna Jokipuu, Taru Karjalainen, Leena Karlsson, Jukka Kero, Jaakko J Koskenniemi, Miia Kähönen, Mikael Knip, Minna-Liisa Koivikko, Katja Kokkonen, Merja Koskinen, Mirva Koreasalo, Kalle Kurppa, Salla Kuusela, Jutta Laiho, Tiina Latva-Aho, Laura Leppänen, Katri Lindfors, Maria Lönnrot, Elina Mäntymäki, Markus Mattila, Maija Miettinen, Teija Mykkänen, Tiina Niininen, Sari Niinistö, Sami Oikarinen, Hanna-Leena Oinas, Paula Ollikainen, Zhian Othmani, Aino Pitkänen, Sirpa Pohjola, Jenna Rautanen, Anne Riikonen, Minna Romo, Nelli Rönkä, Satu Simell, Päivi Tossavainen, Mari Vähä-Mäkilä, Eeva Varjonen, Riitta Veijola, Irene Viinikangas, Silja Vilmi, Suvi M Virtanen, Richard McIndoe, Desmond Schatz, Diane Hopkins, Michael Haller, Risa Bernard, Melissa Gardiner, Ashok Sharma, Laura Jacobsen, Ashley DePeiza, Jennifer Hosford, Kennedy Petty, Leah Myers, Anette Ziegler, Ezio Bonifacio, Cigdem Gezginci, Willi Grätz, Anja Heublein, Eva Hohoff, Sandra Hummel, Annette Knopff, Melanie Köger, Sibylle Koletzko, Claudia Ramminger, Roswith Roth, Jennifer Schmidt, Marlon Scholz, Joanna Stock, Katharina Warncke, Lorena Wendel, Christiane Winkler, Åke Lernmark, Daniel Agardh, Carin Andrén Aronsson, Rasmus Bennet, Corrado Cilio, Susanne Dahlberg, Ulla Fält, Malin Goldman Tsubarah, Emelie Ericson-Hallström, Lina Fransson, Thomas Gard, Emina Halilovic, Gunilla Holmén, Susanne Hyberg, Berglind Jonsdottir, Naghmeh Karimi, Helena Elding Larsson, Marielle Lindström, Markus Lundgren, Marlena Maziarz, Jessica Melin, Caroline Nilsson, Yohanna Nordh, Kobra Rahmati, Anita Ramelius, Falastin Salami, Anette Sjöberg, Evelyn Tekum Amboh Carina Törn, Ulrika Ulvenhag, Terese Wiktorsson, Åsa Wimar, William A Hagopian, Michael Killian, Claire Cowen Crouch, Jennifer Skidmore, Luka-Sophia Bowen, Mikeil Metcalf, Arlene Meyer, Jocelyn Meyer, Denise Mulenga, Nole Powell, Jared Radtke, Shreya Roy, Davey Schmitt, Preston Tucker, Dorothy Becker, Margaret Franciscus, MaryEllen Dalmagro-Elias Smith, Ashi Daftary, Mary Beth Klein, Chrystal Yates, Jeffrey Krischer, Rajesh Adusumali, Sarah Austin-Gonzalez, Maryouri Avendano, Sandra Baethke, Brant Burkhardt, Martha Butterworth, Nicholas Cadigan, Joanna Clasen, Kevin Counts, Laura Gandolfo, Jennifer Garmeson, Veena Gowda, Christina Karges, Shu Liu, Xiang Liu, Kristian Lynch, Jamie Malloy, Lazarus Mramba, Cristina McCarthy, Jose Moreno, Hemang Parikh, Cassandra Remedios, Chris Shaffer, Susan Smith, Noah Sulman, Roy Tamura, Dena Tewey, Henri Thum

Author information

¹Celiac Disease Research Center, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.

²Health Informatics Institute, Morsani College of Medicine, University of South Florida, Tampa, FL, USA.

³Dr. von Hauner Children's Hospital, Department of Pediatrics, University Hospital, LMU Munich, Munich, Germany.

⁴Department of Pediatrics, Gastroenterology and Nutrition, School of Medicine Collegium Medicum University of Warmia and Mazury, Olsztyn, Poland.

⁵Digestive Health Institute, Children's Hospital, Anschutz Medical Campus, University of Colorado, Denver, CO, USA.

⁶National Institute of Diabetes & Digestive & Kidney Diseases, Bethesda, MD, USA.

⁷Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA.

⁸Barbara Davis Center for Childhood Diabetes, University of Colorado, Denver, CO, USA.

⁹Institute of Biomedicine, Research Centre for Integrative Physiology and Pharmacology, and Centre for Population Health Research, University of Turku, Turku, Finland.

¹⁰Department of Pediatrics, Turku University Hospital, 20520, Turku, Finland.

¹¹Institute of Diabetes Research, Helmholtz Zentrum München, Munich, Germany.

¹²Klinikum Rechts der Isar, Technische Universität München, Munich, Germany.

¹³Forschergruppe Diabetes e.V., Neuherberg -Munich, Germany.

¹⁴Lund University, Lund, Sweden.

¹⁵Celiac Disease Research Center, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland. kalle.kurppa@tuni.fi.

¹⁶Faculty of Medicine and Health Technology, Tampere Center for Child, Adolescent, and Maternal Health Research, Tampere University and Tampere University Hospital, Arvo Ylpön Katu 34, 33520, Tampere, Finland. kalle.kurppa@tuni.fi.

¹⁷Seinäjoen yliopistokeskus, Seinäjoki, Finland. kalle.kurppa@tuni.fi.

Abstract

Season of birth, viral infections, HLA haplogenotypes and non-HLA variants are implicated in the development of celiac disease and celiac disease autoimmunity, suggesting a combined role of genes and environmental exposures. The aim of the study was to further decipher the biological pathways conveying the season of birth effect in celiac disease autoimmunity to gain novel insights into the early pathogenesis of celiac disease. Interactions between season of birth, genetics, and early-life environmental factors on the risk of celiac autoimmunity were investigated in the multicenter TEDDY birth cohort study. Altogether 6523 genetically predisposed children were enrolled to long-term follow-up with prospective sampling and data collection at six research centers in the USA, Germany, Sweden and Finland. Celiac disease autoimmunity was defined as positive tissue transglutaminase antibodies in two consecutive serum samples. There was a significant season of birth effect on the risk of celiac autoimmunity. The effect was dependent on polymorphisms in CD247 gene encoding for CD3ζ chain of TCR-CD3 complex. In particular, children with major alleles for SNP rs864537A > G, in CD247 (AA genotype) had an excess risk of celiac autoimmunity when born March-August as compared to other months. The interaction of CD247 with season of birth on autoimmunity risk was accompanied by interactions with febrile infections between the ages of 3-6 months. Considering the important role of TCR-CD3 complex in the adaptive immune response and our findings here, CD247 variants and their possible effect of subgroups in autoimmunity development could be of interest in the design of future gene-environment studies of celiac disease. ClinicalTrials.gov Identifier: NCT00279318.