Transcription factor 7-Like 2 (TCF7L2) gene polymorphism and progression from single to multiple autoantibody positivity in individuals at risk for type 1 diabetes

Redondo, MJ; Steck, AK; Sosenko, J; Anderson, M; Antinozzi, P; Michels, A; Wentworth, JM; Atkinson, MA; Pugliese, A; Geyer, S; Type 1 Diabetes TrialNet Study Group,

Author(s): Redondo, MJ; Steck, AK; Sosenko, J; Anderson, M; Antinozzi, P; Michels, A; Wentworth, JM; Atkinson, MA; Pugliese, A; Geyer, S; Type 1 Diabetes TrialNet Study Group,;
Details: Publication Year 2018-12,Volume 41,Issue #12,Page 2480-2486
Journal Title: Diabetes Care
Publication Type: Journal Article
Abstract: OBJECTIVE: The type 2 diabetes-associated alleles at the TCF7L2 locus mark a type 1 diabetes phenotype characterized by single islet autoantibody positivity as well as lower glucose and higher C-peptide measures. Here, we studied whether the TCF7L2 locus influences progression of islet autoimmunity, from single to multiple (>/=2) autoantibody positivity, in relatives of patients with type 1 diabetes. RESEARCH DESIGN AND METHODS: We evaluated 244 participants in the Type 1 Diabetes TrialNet Pathway to Prevention study with confirmed single autoantibody positivity at screening and Immunochip single nucleotide polymorphism data (47.5% male; median age 12.8 years, range 1.2-45.9; 90.2% white). We analyzed risk allele frequency at TCF7L2 rs4506565 (in linkage disequilibrium with rs7903146). Altogether, 62.6% participants carried >/=1 risk allele. Univariate and multivariable Cox proportional hazards models and Kaplan-Meier statistical methods were used. RESULTS: During follow-up (median 5.2 years, range 0.2-12.6), 62% of the single autoantibody-positive participants developed multiple autoantibody positivity. In the overall cohort, the TCF7L2 locus did not significantly predict progression to multiple autoantibody positivity. However, among single GAD65 autoantibody-positive participants (n = 158), those who carried >/=1 risk allele had a lower rate of progression to multiple autoantibody positivity (hazard ratio [HR] 0.65, P = 0.033) than those who did not, after adjustment for HLA risk haplotypes and age. Among subjects who were either IA-2 or insulin autoantibody positive only, carrying >/=1 TCF7L2 risk allele was not a significant factor overall, but in overweight or obese participants, it increased the risk of progression to multiple autoantibody positivity (HR 3.02, P = 0.016) even with adjustment for age. CONCLUSIONS: The type 2 diabetes-associated TCF7L2 locus influences progression of islet autoimmunity, with differential effects by autoantibody specificity and interaction by obesity/overweight.
Publisher: American DIabetes Association
Research Division(s): Population Health And Immunity
PubMed ID: 30275285
Publisher's Version: https://doi.org/10.2337/dc18-0861
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2018-12-18 02:54:31

Last Modified: 2018-12-18 04:13:54