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Diabetes
Role of Type 1 diabetes associated SNPs on risk of autoantibody positivity in the TEDDY Study Carina Törn1, David Hadley2, Hye-Seung Lee2, William Hagopian3, Åke Lernmark1, Olli Simell4, Marian Rewers5, Anette Ziegler6, Desmond Schatz7, Beena Akolkar8, Suna Onengut-Gumuscu9, Wei-Min Chen9, Jorma Toppari4, Juha Mykkänen4, Jorma Ilonen10, Stephen S Rich9, Jin-Xiong She11, Andrea K Steck5, Jeffrey Krischer2 and the TEDDY Study Group
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Department of Clinical Sciences, Lund University/CRC, Malmö, Sweden
Pediatric Epidemiology Center, Department of Pediatrics, University of South Florida, Tampa, FL, USA 3
Pacific Northwest Diabetes Research Institute, Seattle, WA, USA 4
5
Barbara Davis Center for Childhood Diabetes, University of Colorado, Denver, Aurora, CO, USA 6
Department of Pediatrics, Diabetes Research Institute, Munich, Germany 7
8
Department of Pediatrics, University of Turku, Turku, Finland
Department of Pediatrics, University of Florida, Gainesville, FL, USA
National Institutes of Diabetes and Digestive and Kidney Disorders, National Institutes of Health, Bethesda, MD, USA 9 10
Center for Public Health Genomic, University of Virginia, Charlottesville, VA, USA
Immunogenetics Laboratory, University of Turku, Turku, Finland and Department of Clinical Microbiology, University of Eastern Finland, Kuopio, Finland 11
Center for Biotechnology and Genomic Medicine, Georgia Regents University, Augusta, GA, USA Correspondence author: Carina Törn, PhD, Associate Professor Unit for Diabetes and Celiac Disease Department of Clinical Sciences Wallenberg Laboratory Inga Marie Nilssons g 53 205 02 Malmö, Sweden Phone: +46-40-391917 Fax: +46-40-391122 e-mail:
[email protected]
Short running title: SNPs on risk of autoantibody positivity Word count excluding title page, abstract, acknowledgements, references, tables and figures: 3873 (limit 4000) Number of tables: 6 Number of figures. 1 (3 panels) Pages: 34
Key words: autoantibodies, single nucleotide polymorphisms, type 1 diabetes, candidate genes, HLA, PTPN22
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Diabetes Publish Ahead of Print, published online November 24, 2014
Diabetes
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Abstract
The Environmental Determinants of Diabetes in the Young (TEDDY) study prospectively
follows 8,677 children enrolled from birth, who carry HLA-susceptibility genotypes for development of islet autoantibodies (IA) and type 1 diabetes (T1D). During the median follow-up time of 57 months, 350 children developed at least one persistent IA (GADA, IA-2A or mIAA) and 84 of them progressed to T1D. We genotyped 5,164 Caucasian children for 41 non-HLA SNPs that achieved genome-wide significance for association with T1D in the GWAS metaanalysis conducted by the Type 1 Diabetes Genetics Consortium. In TEDDY-participants carrying high-risk HLA-genotypes, eight SNPs achieved significant association to development of IA using time-to-event analysis (p
