Predictors of the Initiation of Islet Autoimmunity and Progression to Multiple Autoantibodies and Clinical Diabetes: The TEDDY Study
Jeffrey P. Krischer, Xiang Liu, Åke Lernmark, William Hagopian, Marian Rewers, Jin‐Xiong She, Jorma Toppari, Anette‐G. Ziegler, Beena Akolkar, 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 M. Norris, Holly O’Donnell, Stesha Peacock, Hanan Shorrosh, Andrea K. Steck, Megan Stern, Kathleen Waugh, Jorma Toppari, Olli Simell, Annika Adamsson, Sanna-Mari Aaltonen, Suvi Ahonen, Iris Erlund, Leena Hakola, Anne Hekkala, Henna Holappa, Heikki Hyöty, Anni Ikonen, Jorma Ilonen, Sanna Jokipuu, 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, Laura Leppänen, Katri Lindfors, Maria Lönnrot, Elina Mäntymäki, Markus Mattila, Maija E. Miettinen, Katja Multasuo, Teija Mykkänen, Tiina Niininen, Sari Niinistö, Mia Nyblom, Sami Oikarinen, Paula Ollikainen, Zhian Othmani, Sirpa Pohjola, Jenna Rautanen, Anne Riikonen, Minna Romo, Satu Simell, Päivi Tossavainen, Mari Vähä-Mäkilä, Eeva Varjonen, Riitta Veijola, Irene Viinikangas, Suvi Μ. Virtanen, Jin‐Xiong She, Desmond Schatz, Diane Hopkins, Leigh Steed, Jennifer Bryant, Katherine Silvis, Michael J. Haller, Melissa Gardiner, Richard McIndoe, Ashok Sharma, StephenW. Anderson, Laura M. Jacobsen, John Marks, P.D. Towe, Anette G. Ziegler, Ezio Bonifacio, Cigdem Gezginci, Anja Heublein, Eva Hohoff
Abstract
OBJECTIVE: To distinguish among predictors of seroconversion, progression to multiple autoantibodies and from multiple autoantibodies to type 1 diabetes in young children. RESEARCH DESIGN AND METHODS: Genetically high-risk newborns (n = 8,502) were followed for a median of 11.2 years (interquartile range 9.3-12.6); 835 (9.8%) developed islet autoantibodies and 283 (3.3%) were diagnosed with type 1 diabetes. Predictors were examined using Cox proportional hazards models. RESULTS: Predictors of seroconversion and progression differed, depending on the type of first appearing autoantibody. Male sex, Finnish residence, having a sibling with type 1 diabetes, the HLA DR4 allele, probiotic use before age 28 days, and single nucleotide polymorphism (SNP) rs689_A (INS) predicted seroconversion to IAA-first (having islet autoantibody to insulin as the first appearing autoantibody). Increased weight at 12 months and SNPs rs12708716_G (CLEC16A) and rs2292239_T (ERBB3) predicted GADA-first (autoantibody to GAD as the first appearing). For those having a father with type 1 diabetes, the SNPs rs2476601_A (PTPN22) and rs3184504_T (SH2B3) predicted both. Younger age at seroconversion predicted progression from single to multiple autoantibodies as well as progression to diabetes, except for those presenting with GADA-first. Family history of type 1 diabetes and the HLA DR4 allele predicted progression to multiple autoantibodies but not diabetes. Sex did not predict progression to multiple autoantibodies, but males progressed more slowly than females from multiple autoantibodies to diabetes. SKAP2 and MIR3681HG SNPs are newly reported to be significantly associated with progression from multiple autoantibodies to type 1 diabetes. CONCLUSIONS: Predictors of IAA-first versus GADA-first autoimmunity differ from each other and from the predictors of progression to diabetes.