Predictors of the Initiation of Islet Autoimmunity and Progression to Multiple Autoantibodies and Clinical Diabetes: The TEDDY Study
Authors: Krischer Jeffrey P. , Liu Xiang , Lernmark Åke , Hagopian William A. , Rewers Marian J. , She Jin-Xiong , Toppari Jorma , Ziegler Anette-G. , Akolkar Beena ,   TEDDY Study Group, Rewers Marian , Barbour Aaron , Bautista Kimberly , Baxter Judith , Felipe-Morales Daniel , Frohnert Brigitte I. , Stahl Marisa , Gesualdo Patricia , Hoffman Michelle , Karban Rachel , Liu Edwin , Munoz Alondra , Norris Jill , O’Donnell Holly , Peacock Stesha , Shorrosh Hanan , Steck Andrea , Stern Megan , Waugh Kathleen , Toppari Jorma , Simell Olli G. , Adamsson Annika , Aaltonen Sanna-Mari , Ahonen Suvi , Åkerlund Mari , Hakola Leena , Hekkala Anne , Holappa Henna , Hyöty Heikki , Ikonen Anni , Ilonen Jorma , Jokipuu Sanna , Karlsson Leena , Kero Jukka , Koskenniemi Jaakko J. , Kähönen Miia , Knip Mikael , Koivikko Minna-Liisa , Kokkonen Katja , Koskinen Merja , Koreasalo Mirva , Kurppa Kalle , Kuusela Salla , Kytölä Jarita , Laiho Jutta , Latva-aho Tiina , Leppänen Laura , Lindfors Katri , Lönnrot Maria , Mäntymäki Elina , Mattila Markus , Miettinen Maija , Multasuo Katja , Mykkänen Teija , Niininen Tiina , Niinistö Sari , Nyblom Mia , Oikarinen Sami , Ollikainen Paula , Othmani Zhian , Pohjola Sirpa , Rautanen Jenna , Riikonen Anne , Romo Minna , Simell Satu , Tossavainen Päivi , Vähä-Mäkilä Mari , Varjonen Eeva , Veijola Riitta , Viinikangas Irene , Virtanen Suvi M. , She Jin-Xiong , Schatz Desmond , Hopkins Diane , Steed Leigh , Bryant Jennifer , Silvis Katherine , Haller Michael , Gardiner Melissa , McIndoe Richard , Sharma Ashok , Anderson StephenW. , Jacobsen Laura , Marks John , Towe P.D. , Ziegler Anette G. , Bonifacio Ezio , Gezginci Cigdem , Heublein Anja , Hohoff Eva , Hummel Sandra , Knopff Annette , Koch Charlotte , Koletzko Sibylle , Ramminger Claudia , Roth Roswith , Schmidt Jennifer , Scholz Marlon , Stock Joanna , Warncke Katharina , Wendel Lorena , Winkler Christiane , Lernmark Åke , Agardh Daniel , Aronsson Carin Andrén , Bennet Rasmus , Cilio Corrado , Dahlberg Susanne , Fält Ulla , Tsubarah Malin Goldman , Ericson-Hallström Emelie , Fransson Lina , Gard Thomas , Halilovic Emina , Holmén Gunilla , Hyberg Susanne , Jonsdottir Berglind , Karimi Naghmeh , Larsson Helena Elding , Lindström Marielle , Lundgren Markus , Maziarz Marlena , Martinez Maria Månsson , Melin Jessica , Mestan Zeliha , Nilsson Caroline , Nordh Yohanna , Rahmati Kobra , Ramelius Anita , Salami Falastin , Sjöberg Anette , Törn Carina , Ulvenhag Ulrika , Wiktorsson Terese , Wimar Åsa , Hagopian William A. , Killian Michael , Crouch Claire Cowen , Skidmore Jennifer , Bowen Luka-Sophia , Metcalf Mikeil , Meyer Arlene , Meyer Jocelyn , Mulenga Denise , Powell Nole , Radtke Jared , Roy Shreya , Schmitt Davey , Tucker Preston , Becker Dorothy , Franciscus Margaret , Dalmagro-EliasSmith MaryEllen , Daftary Ashi , Klein Mary Beth , Yates Chrystal , Krischer Jeffrey P. , Adusumali Rajesh , Austin-Gonzalez Sarah , Avendano Maryouri , Baethke Sandra , Burkhardt Brant , Butterworth Martha , Cadigan Nicholas , Clasen Joanna , Counts Kevin , Gandolfo Laura , Garmeson Jennifer , Gowda Veena , Karges Christina , Liu Shu , Liu Xiang , Lynch Kristian , Malloy Jamie , Mramba Lazarus , McCarthy Cristina , Moreno Jose , Parikh Hemang M. , Remedios Cassandra , Shaffer Chris , Smith Susan , Sulman Noah , Tamura Roy , Tewey Dena , Toth Michael , Uusitalo Ulla , Vehik Kendra , Vijayakandipan Ponni , Wroble Melissa , Yang Jimin , Young Kenneth , Abbondondolo Michael , Ballard Lori , Brown Rasheedah , Cuthbertson David , Dankyi Stephen , Eberhard Christopher , Fiske Steven , Hadley David , Heyman Kathleen , Hsiao Belinda , Laras Francisco Perez , Lee Hye-Seung , Li Qian , Maguire Colleen , McLeod Wendy , Merrell Aubrie , Meulemans Steven , Quigley Ryan , Smith Laura , Akolkar Beena , Yu Liping , Miao Dongmei , Gillespie Kathleen , Chandler Kyla , Kelland Ilana , Khoud Yassin Ben , Randell Matthew , Rich Stephen S. , Chen Wei-Min , Onengut-Gumuscu Suna , Farber Emily , Pickin Rebecca Roche , Davis Jonathan , Davis Jordan , Gallo Dan , Bonnie Jessica , Campolieto Paul , Hagopian William , Radtke Jared , Tucker Preston , WA Seattle , Ke Sandra , Mulholland Niveen , Briese Thomas , Brusko Todd , Johnson Suzanne Bennett , McKinney Eoin , Pastinen Tomi , Triplett Eric 
Published: September 2022

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.