title: Role of Type 1 Diabetes-Associated SNPs on Risk of Autoantibody Positivity in the TEDDY Study.
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 (GAD antibody, IA-2A, or micro insulin autoantibodies) and 84 of them progressed to T1D. We genotyped 5,164 Caucasian children for 41 non-HLA single nucleotide polymorphisms (SNPs) that achieved genome-wide significance for association with T1D in the genome-wide association scan meta-analysis 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 < 0.05), whereof four were significant after adjustment for multiple testing (P < 0.0012): rs2476601 in PTPN22 (hazard ratio [HR] 1.54 [95% CI 1.27-1.88]), rs2292239 in ERBB3 (HR 1.33 [95% CI 1.14-1.55]), rs3184504 in SH2B3 (HR 1.38 [95% CI 1.19-1.61]), and rs1004446 in INS (HR 0.77 [0.66-0.90]). These SNPs were also significantly associated with T1D in particular: rs2476601 (HR 2.42 [95% CI 1.70-3.44]). Although genes in the HLA region remain the most important genetic risk factors for T1D, other non-HLA genetic factors contribute to IA, a first step in the pathogenesis of T1D, and the progression of the disease.
authors.affiliation: Department of Clinical Sciences, Lund University/CRC, Malmö, Sweden carina.torn@med.lu.se.
authors.forename: Carina
authors.initials: C
authors.lastname: Törn
authors.affiliation: Pediatric Epidemiology Center, Department of Pediatrics, University of South Florida, Tampa, FL Division of Population Health Sciences and Education, St George's University of London, London, U.K.
authors.forename: David
authors.initials: D
authors.lastname: Hadley
authors.affiliation: Pediatric Epidemiology Center, Department of Pediatrics, University of South Florida, Tampa, FL.
authors.forename: Hye-Seung
authors.initials: HS
authors.lastname: Lee
authors.affiliation: Pacific Northwest Diabetes Research Institute, Seattle, WA.
authors.forename: William
authors.initials: W
authors.lastname: Hagopian
authors.affiliation: Department of Clinical Sciences, Lund University/CRC, Malmö, Sweden.
authors.forename: Åke
authors.initials: Å
authors.lastname: Lernmark
authors.affiliation: Department of Pediatrics, University of Turku, Turku, Finland.
authors.forename: Olli
authors.initials: O
authors.lastname: Simell
authors.affiliation: Barbara Davis Center for Childhood Diabetes, University of Colorado, Denver, Aurora, CO.
authors.forename: Marian
authors.initials: M
authors.lastname: Rewers
authors.affiliation: Department of Pediatrics, Diabetes Research Institute, Munich, Germany.
authors.forename: Anette
authors.initials: A
authors.lastname: Ziegler
authors.affiliation: Department of Pediatrics, University of Florida, Gainesville, FL.
authors.forename: Desmond
authors.initials: D
authors.lastname: Schatz
authors.affiliation: National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD.
authors.forename: Beena
authors.initials: B
authors.lastname: Akolkar
authors.affiliation: Center for Public Health Genomics, University of Virginia, Charlottesville, VA.
authors.forename: Suna
authors.initials: S
authors.lastname: Onengut-Gumuscu
authors.affiliation: Center for Public Health Genomics, University of Virginia, Charlottesville, VA.
authors.forename: Wei-Min
authors.initials: WM
authors.lastname: Chen
authors.affiliation: Department of Pediatrics, University of Turku, Turku, Finland.
authors.forename: Jorma
authors.initials: J
authors.lastname: Toppari
authors.affiliation: Department of Pediatrics, University of Turku, Turku, Finland.
authors.forename: Juha
authors.initials: J
authors.lastname: Mykkänen
authors.affiliation: Immunogenetics Laboratory, University of Turku, Turku, Finland Department of Clinical Microbiology, University of Eastern Finland, Kuopio, Finland.
authors.forename: Jorma
authors.initials: J
authors.lastname: Ilonen
authors.affiliation: Center for Public Health Genomics, University of Virginia, Charlottesville, VA.
authors.forename: Stephen S
authors.initials: SS
authors.lastname: Rich
authors.affiliation: Center for Biotechnology and Genomic Medicine, Georgia Regents University, Augusta, GA.
authors.forename: Jin-Xiong
authors.initials: JX
authors.lastname: She
authors.affiliation: Barbara Davis Center for Childhood Diabetes, University of Colorado, Denver, Aurora, CO.
authors.forename: Andrea K
authors.initials: AK
authors.lastname: Steck
authors.affiliation: Pediatric Epidemiology Center, Department of Pediatrics, University of South Florida, Tampa, FL.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Krischer
mesh_terms: D001323:Autoantibodies / Q000097:blood* / Q000378:metabolism; D015551:Autoimmunity / Q000235:genetics; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D005060:Europe; D020022:Genetic Predisposition to Disease; D016678:Genome; D005838:Genotype; D006680:HLA Antigens / Q000235:genetics / Q000276:immunology; D006801:Humans; D007231:Infant, Newborn; D007515:Islets of Langerhans / Q000276:immunology; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012307:Risk Factors; D014481:United States
chemical_list: D001323:Autoantibodies; D006680:HLA Antigens