Hierarchical Order of Distinct Autoantibody Spreading and Progression to Type 1 Diabetes in the TEDDY Study
Author:
Vehik Kendra1ORCID, Bonifacio Ezio23ORCID, Lernmark Åke4, Yu Liping5, Williams Alistair6, Schatz Desmond7ORCID, Rewers Marian5, She Jin-Xiong8, Toppari Jorma910, Hagopian William11, Akolkar Beena12, Ziegler Anette G.213, Krischer Jeffrey P.1, 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,
Affiliation:
1. Health Informatics Institute, Morsani College of Medicine, University of South Florida, Tampa, FL 2. Forschergruppe Diabetes e.V., Helmholtz Zentrum München, German Research Center for Environmental Health, Munich-Neuherberg, Germany 3. DFG Center for Regenerative Therapies Dresden, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany 4. Department of Clinical Sciences, Lund University/CRC, Skane University Hospital, Malmö, Sweden 5. Barbara Davis Center for Childhood Diabetes, University of Colorado, Aurora, CO 6. Diabetes and Metabolism, Translational Health Sciences, University of Bristol, Bristol, U.K. 7. Diabetes Center of Excellence, University of Florida, Gainesville, FL 8. Center for Biotechnology and Genomic Medicine, Augusta University, Augusta, GA 9. Research Centre for Integrative Physiology and Pharmacology, Institute of Biomedicine, University of Turku, Turku, Finland 10. Department of Pediatrics, Turku University Hospital, Turku, Finland 11. Pacific Northwest Diabetes Research Institute, Seattle, WA 12. National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD 13. Institute of Diabetes Research, Helmholtz Zentrum München, and Klinikum rechts der Isar, Technische Universität München, Neuherberg, Germany
Abstract
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 < 0.0001), or ZnT8A second (adjusted HR 5.35; 95% CI 2.61–10.95; P < 0.0001). In children who developed a distinct second autoantibody, IA-2A (adjusted HR 3.08; 95% CI 2.04–4.65; P < 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.
Funder
National Institute of Diabetes and Digestive and Kidney Diseases National Institute of Allergy and Infectious Diseases Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institute of Environmental Health Sciences JDRF Centers for Disease Control and Prevention National Institutes of Health/National Center for Advancing Translational Sciences
Publisher
American Diabetes Association
Subject
Advanced and Specialized Nursing,Endocrinology, Diabetes and Metabolism,Internal Medicine
Cited by
43 articles.
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