Hierarchical Order of Distinct Autoantibody Spreading and Progression to Type 1 Diabetes in the TEDDY Study
Authors: Vehik Kendra , Bonifacio Ezio , Lernmark Åke , Yu Liping , Williams Alistair , Schatz Desmond , Rewers Marian , She Jin-Xiong , Toppari Jorma , Hagopian William , Akolkar Beena , Ziegler Anette G. , Krischer Jeffrey P. ,   The TEDDY Study Group, Rewers Marian , Barbour Aaron , Bautista Kimberly , Baxter Judith , Felipe-Morales Daniel , Driscoll Kimberly , Frohnert Brigitte I. , Stahl Marisa , Gesualdo Patricia , Hoffman Michelle , Karban Rachel , Liu Edwin , Norris Jill , Peacock Stesha , Shorrosh Hanan , Steck Andrea , Stern Megan , Villegas Erica , Waugh Kathleen , Toppari Jorma , . Simell Olli G , Adamsson Annika , Ahonen Suvi , Åkerlund Mari , Hakola Leena , Hekkala Anne , Holappa Henna , Hyöty Heikki , Ikonen Anni , Ilonen Jorma , Jäminki Sinikka , Jokipuu Sanna , Karlsson Leena , Kero Jukka , Kähönen Miia , Knip Mikael , Koivikko Minna-Liisa , Koskinen Merja , Koreasalo Mirva , Kurppa Kalle , Kytölä Jarita , Latva-aho Tiina , 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 , Rajala Petra , Rautanen Jenna , Riikonen Anne , Riski Eija , Pekkola Miia , Romo Minna , Ruohonen Satu , Simell Satu , Sjöberg Maija , Stenius Aino , Tossavainen Päivi , Vähä-Mäkilä Mari , Vainionpää Sini , 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 Stephen W. , 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 , Andrén Aronsson Carin , Ask Maria , Bennet Rasmus , Cilio Corrado , Dahlberg Susanne , Engqvist Helene , Ericson-Hallström Emelie , Björne Fors Annika , Fransson Lina , Gard Thomas , Hansen Monika , Jisser Hanna , Johansen Fredrik , Jonsdottir Berglind , Elding Larsson Helena , Lindström Marielle , Lundgren Markus , Maziarz Marlena , Månsson-Martinez Maria , Melin Jessica , Mestan Zeliha , Nilsson Caroline , Ottosson Karin , Rahmati Kobra , Ramelius Anita , Salami Falastin , Sjöberg Anette , Sjöberg Birgitta , Törn Carina , Wimar Åsa , Hagopian William A. , Killian Michael , Cowen Crouch Claire , Skidmore Jennifer , Chavoshi Masumeh , Meyer Arlene , Meyer Jocelyn , Mulenga Denise , Powell Nole , Radtke Jared , Romancik Matei , Roy Shreya , Schmitt Davey , Zink Sarah , Becker Dorothy , Franciscus Margaret , Dalmagro-Elias Smith MaryEllen , Daftary Ashi , Beth Klein Mary , Yates Chrystal , Krischer Jeffrey P. , Austin-Gonzalez Sarah , Avendano Maryouri , Baethke Sandra , Burkhardt Brant , Butterworth Martha , Clasen Joanna , Cuthbertson David , Eberhard Christopher , Fiske Steven , Garmeson Jennifer , Gowda Veena , Heyman Kathleen , Hsiao Belinda , Karges Christina , Perez Laras Francisco , Li Qian , Liu Shu , Liu Xiang , Lynch Kristian , Maguire Colleen , Malloy Jamie , McCarthy Cristina , Parikh Hemang , Remedios Cassandra , Shaffer Chris , Smith Laura , Smith Susan , Sulman Noah , Tamura Roy , Tewey Dena , Toth Michael , Uusitalo Ulla , Vehik Kendra , Vijayakandipan Ponni , Yang Jimin , Abbondondolo Michael , Ballard Lori , Brown Rasheedah , Dankyi Stephen , Hadley David , Lee Hye-Seung , McLeod Wendy , Merrell Aubrie , Meulemans Steven , Quigley Ryan , Akolkar Beena , Yu Liping , Miao Dongmei , Bingley Polly , Williams Alistair , Chandler Kyla , Kelland Ilana , Ben Khoud Yassin , Zahid Huma , Randell Matthew , Hagopian William , Chavoshi Masumeh , Radtke Jared , Zink Sarah , Erlich Henry , Mack Steven J. , Lisa Fear Anna , Rich Stephen S. , Chen Wei-Min , Onengut-Gumuscu Suna , Farber Emily , Roche Pickin Rebecca , Davis Jonathan , Davis Jordan , Gallo Dan , Bonnie Jessica , Campolieto Paul , Ke Sandra , Mulholland Niveen , Bourcier Kasia , Briese Thomas , Bennett Johnson Suzanne , Triplett Eric 
Published: July 2020

OBJECTIVE
The first-appearing β-cell autoantibody has been shown to influence risk of type 1 diabetes (T1D). Here, we assessed the risk of autoantibody spreading to the second-appearing autoantibody and further progression to clinical disease in The Environmental Determinants of Diabetes in the Young (TEDDY) study.

RESEARCH DESIGN AND METHODS
Eligible children with increased HLA-DR-DQ genetic risk for T1D were followed quarterly from age 3 months up to 15 years for development of a single first-appearing autoantibody (GAD antibody [GADA], insulin autoantibody [IAA], or insulinoma antigen-2 autoantibody [IA-2A]) and subsequent development of a single second-appearing autoantibody and progression to T1D. Autoantibody positivity was defined as positivity for a specific autoantibody at two consecutive visits confirmed in two laboratories. Zinc transporter 8 autoantibody (ZnT8A) was measured in children who developed another autoantibody.

RESULTS
There were 608 children who developed a single first-appearing autoantibody (IAA, n = 282, or GADA, n = 326) with a median follow-up of 12.5 years from birth. The risk of a second-appearing autoantibody was independent of GADA versus IAA as a first-appearing autoantibody (adjusted hazard ratio [HR] 1.12; 95% CI 0.88–1.42; P = 0.36). Second-appearing GADA, IAA, IA-2A, or ZnT8A conferred an increased risk of T1D compared with children who remained positive for a single autoantibody, e.g., IAA or GADA second (adjusted HR 6.44; 95% CI 3.78–10.98), IA-2A second (adjusted HR 16.33; 95% CI 9.10–29.29; P &lt; 0.0001), or ZnT8A second (adjusted HR 5.35; 95% CI 2.61–10.95; P &lt; 0.0001). In children who developed a distinct second autoantibody, IA-2A (adjusted HR 3.08; 95% CI 2.04–4.65; P &lt; 0.0001) conferred a greater risk of progression to T1D as compared with GADA or IAA. Additionally, both a younger initial age at seroconversion and shorter time to the development of the second-appearing autoantibody increased the risk for T1D.

CONCLUSIONS
The hierarchical order of distinct autoantibody spreading was independent of the first-appearing autoantibody type and was age-dependent and augmented the risk of progression to T1D.