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Role of Type 1 diabetes associated SNPs on risk of autoantibody positivity in the TEDDY Study.

Author:
  • Carina Törn
  • David Hadley
  • Hye-Seung Lee
  • William Hagopian
  • Åke Lernmark
  • Olli Simell
  • Marian Rewers
  • Anette Ziegler
  • Desmond Schatz
  • Beena Akolkar
  • Suna Onengut-Gumuscu
  • Wei-Min Chen
  • Jorma Toppari
  • Juha Mykkänen
  • Jorma Ilonen
  • Stephen S Rich
  • Jin-Xiong She
  • Andrea K Steck
  • Jeffrey Krischer
Publishing year: 2015
Language: English
Pages: 1818-1829
Publication/Series: Diabetes
Volume: 64
Issue: 5
Document type: Journal article
Publisher: American Diabetes Association Inc.

Abstract english

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 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.

Keywords

  • Endocrinology and Diabetes

Other

Published
  • Diabetes and Celiac Unit
  • ISSN: 1939-327X
E-mail: ake [dot] lernmark [at] med [dot] lu [dot] se

Principal investigator

Diabetes and Celiac Unit

+46 40 39 19 01

+46 70 616 47 79

60:11:015

Jan Waldenströms gata 35, Malmö

33

Lund University Diabetes Centre, CRC, SUS Malmö, Jan Waldenströms gata 35, House 91:12. SE-214 28 Malmö. Telephone: +46 40 39 10 00