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Diabetes. 2015 May;64(5):1818-29. doi: 10.2337/db14-1497. Epub 2014 Nov 24.

Role of Type 1 Diabetes-Associated SNPs on Risk of Autoantibody Positivity in the TEDDY Study.

Collaborators (238)

Rewers M, Bautista K, Baxter J, Bedoy R, Felipe-Morales D, Frohnert B, Gesualdo P, Hoffman M, Karban R, Liu E, Norris J, Samper-Imaz A, Steck A, Waugh K, Wright H, She JX, Schatz D, Hopkins D, Steed L, Thomas J, Silvis K, Haller M, Shankar M, Sheehan E, Gardiner M, McIndoe R, Liu H, Nechtman J, Sharma A, Williams J, Foghis G, Anderson SW, Ziegler AG, Beyerlein A, Bonifacio E, Hummel M, Hummel S, Foterek K, Kersting M, Knopff A, Koletzko S, Peplow C, Roth R, Stock J, Strauss E, Warncke K, Winkler C, Toppari J, Simell OG, Adamsson A, Hyöty H, Ilonen J, Kähönen M, Knip M, Koivu A, Koreasalo M, Kurppa K, Lönnrot M, Mäntymäki E, Multasuo K, Mykkänen J, Niininen T, Nyblom M, Rajala P, Rautanen J, Riikonen A, Romo M, Simell S, Simell T, Simell V, Sjöberg M, Stenius A, Varjonen E, Veijola R, Virtanen SM, Akerlund M, Lernmark A, Agardh D, Andrén Aronsson C, Ask M, Bremer J, Carlsson UM, Cilio C, Ekstrand C, Ericson-Hallström E, Fransson L, Gard T, Gerardsson J, Håkansson R, Hansen M, Hansson G, Hyberg S, Johansen F, Jonasdottir B, Jonsson L, Elding Larsson H, Lernmark B, Månsson-Martinez M, Markan M, Massadakis T, Melin J, Mestan Z, Rahmati K, Ramelius A, Salami F, Sedig Järvirova M, Sibthorpe S, Sjöberg B, Swartling U, Trulsson E, Törn C, Wallin A, Wimar A, Aberg S, Hagopian WA, Yan X, Killian M, Cowen Crouch C, Skidmore J, Ayres S, Dunson K, Heaney D, Hervey R, Johnson C, Lyons R, Meyer A, Mulenga D, Schulte E, Scott E, Stabbert J, Willis J, Becker D, Franciscus M, Dalmagro-Elias Smith ME, Daftary A, Klein MB, Yates C, Krischer JP, Abbondondolo M, Austin-Gonzalez S, Brown R, Burkhardt B, Butterworth M, Cuthbertson D, Eberhard C, Fiske S, Garcia D, Gowda V, Hadley D, Lee HS, Liu S, Liu X, Lynch K, Malloy J, McCarthy C, McLeod W, Shaffer C, Smith L, Smith S, Tamura R, Uusitalo U, Vehik K, Vijayakandipan P, Wood K, Yang J, Akolkar B, Bourcier K, Briese T, Bennett Johnson S, Oberste S, Triplett E, Yu L, Miao D, Bingley P, Williams A, Chandler K, Rokni S, Boldison J, Butterly J, Carreno G, Caygill C, Geoghan I, Long A, Payne M, Pearson J, Ridewood S, Wyatt R, Aardal Eriksson E, Lundgren IM, Lönn Karlsson E, Nezirevic Dernroth D, Erlund I, Salminen I, Sundvall J, Leiviskä J, Lehtonen M, Little RR, Tennill AL, Erlich H, Mack SJ, Erlich H, Mack SJ, Fear AL, Fiehn O, Wikoff B, Defelice B, Grapov D, Kind T, Palazoglu M, Valdiviez L, Wancewicz B, Wohlgemuth G, Wong J, Petrosino J, Marcovina SM, Gaur VP, Smith RD, Metz TO, Ansong C, Webb-Robertson BJ, Mitchell HD, Higgins H, Ke S, She JX, McIndoe R, Liu H, Nechtman J, Zhao Y, Jiang N, Rich SS, Chen WM, Onengut-Gumuscu S, Farber E, Roche Pickin R, Davis J, Gallo D, Bonnie J, Campolieto P.

Author information

1
Department of Clinical Sciences, Lund University/CRC, Malmö, Sweden carina.torn@med.lu.se.
2
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.
3
Pediatric Epidemiology Center, Department of Pediatrics, University of South Florida, Tampa, FL.
4
Pacific Northwest Diabetes Research Institute, Seattle, WA.
5
Department of Clinical Sciences, Lund University/CRC, Malmö, Sweden.
6
Department of Pediatrics, University of Turku, Turku, Finland.
7
Barbara Davis Center for Childhood Diabetes, University of Colorado, Denver, Aurora, CO.
8
Department of Pediatrics, Diabetes Research Institute, Munich, Germany.
9
Department of Pediatrics, University of Florida, Gainesville, FL.
10
National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD.
11
Center for Public Health Genomics, University of Virginia, Charlottesville, VA.
12
Immunogenetics Laboratory, University of Turku, Turku, Finland Department of Clinical Microbiology, University of Eastern Finland, Kuopio, Finland.
13
Center for Biotechnology and Genomic Medicine, Georgia Regents University, Augusta, GA.

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.

PMID:
25422107
PMCID:
PMC4407865
DOI:
10.2337/db14-1497
[Indexed for MEDLINE]
Free PMC Article

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