Gastrointestinal Infections Modulate the Risk for Insulin Autoantibodies as the First-Appearing Autoantibody in the TEDDY Study
Maria Lönnrot, Kristian Lynch, Marian Rewers, Åke Lernmark, Kendra Vehik, Beena Akolkar, William Hagopian, Jeffrey P. Krischer, Rickhard A. McIndoe, Jorma Toppari, Anette‐G. Ziegler, Joseph F. Petrosino, Richard E. Lloyd, Heikki Hyöty, TEDDY Study Group, Marian Rewers, Kimberly Bautista, Judith Baxter, Daniel Felipe-Morales, Brigitte I. Frohnert, Marisa Stahl, Isabel Flores Garcia, Patricia Gesualdo, Sierra Hays, Michelle Hoffman, Rachel Karban, Edwin Liu, Leila Loaiza, Jill M. Norris, Holly O’Donnell, Loana Thorndahl, Andrea K. Steck, Kathleen Waugh, Jorma Toppari, Olli Simell, Annika Adamsson, Suvi Ahonen, Iris Erlund, Sirpa Anttila, Leena Hakola, Anne Hekkala, Tiia Honkanen, Heikki Hyöty, Jorma Ilonen, Sanna Jokipuu, Taru Karjalainen, Leena Eklund Karlsson, Jukka Kero, Jaakko J. Koskenniemi, Miia Kähönen, Mikael Knip, Minna-Liisa Koivikko, Katja Kokkonen, Merja Koskinen, Mirva Koreasalo, Kalle Kurppa, Salla Kuusela, Jarita Kytölä, Jutta E. Laiho, Tiina Latva-aho, Siiri Leisku, Laura Leppänen, Katri Lindfors, Maria Lönnrot, Elina Mäntymäki, Markus Mattila, Maija E. Miettinen, Teija Mykkänen, Tiina Niininen, Sari Niisistö, Noora Nurminen, Sami Oikarinen, Hanna-Leena Oinas, Paula Ollikainen, Zhian Othmani, Sirpa Pohjola, Solja Raja-Hanhela, Jenna Rautanen, Anne Riikonen, Minna Romo, Juulia Rönkä, Nelli Rönkä, Satu Simell, Päivi Tossavainen, Mari Vähä-Mäkilä, Eeva Varjonen, Riitta Veijola, Irene Viinikangas, Silja Vilmi, Suvi Μ. Virtanen, Richard McIndoe, Desmond Schatz, Diane Hopkins, Michael J. Haller, Risa Bernard, Melissa Gardiner, Ashok Sharma, Laura M. Jacobsen, Jennifer Hosford, Kennedy Petty
Abstract
OBJECTIVE: To investigate gastrointestinal infection episodes (GIEs) in relation to the appearance of islet autoantibodies in The Environmental Determinants of Diabetes in the Young (TEDDY) cohort. RESEARCH DESIGN AND METHODS: GIEs on risk of autoantibodies against either insulin (IAA) or GAD (GADA) as the first-appearing autoantibody were assessed in a 10-year follow-up of 7,867 children. Stool virome was characterized in a nested case-control study. RESULTS: GIE reports (odds ratio [OR] 2.17 [95% CI 1.39-3.39]) as well as Norwalk viruses found in stool (OR 5.69 [1.36-23.7]) at <1 year of age were associated with an increased IAA risk at 2-4 years of age. GIEs reported at age 1 to <2 years correlated with a lower risk of IAA up to 10 years of age (OR 0.48 [0.35-0.68]). GIE reports at any other age were associated with an increase in IAA risk (OR 2.04 for IAA when GIE was observed 12-23 months prior [1.41-2.96]). Impacts on GADA risk were limited to GIEs <6 months prior to autoantibody development in children <4 years of age (OR 2.16 [1.54-3.02]). CONCLUSIONS: Bidirectional associations were observed. GIEs were associated with increased IAA risk when reported before 1 year of age or 12-23 months prior to IAA. Norwalk virus was identified as one possible candidate factor. GIEs reported during the 2nd year of life were associated with a decreased IAA risk.