Transcription Factor 7-Like 2 (<i>TCF7L2</i>) Gene Polymorphism and Progression From Single to Multiple Autoantibody Positivity in Individuals at Risk for Type 1 Diabetes.

Abstract

The type 2 diabetes-associated alleles at the <i>TCF7L2</i> 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 <i>TCF7L2</i> locus influences progression of islet autoimmunity, from single to multiple (≥2) autoantibody positivity, in relatives of patients with type 1 diabetes. 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 <i>TCF7L2</i> 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. 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 <i>TCF7L2</i> locus did not significantly predict progression to multiple autoantibody positivity. However, among single GAD65 autoantibody-positive participants (<i>n</i> = 158), those who carried ≥1 risk allele had a lower rate of progression to multiple autoantibody positivity (hazard ratio [HR] 0.65, <i>P</i> = 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 <i>TCF7L2</i> 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, <i>P</i> = 0.016) even with adjustment for age. The type 2 diabetes-associated <i>TCF7L2</i> locus influences progression of islet autoimmunity, with differential effects by autoantibody specificity and interaction by obesity/overweight.