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

OBJECTIVE: The type 2 diabetes-associated alleles at the 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 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 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 locus did not significantly predict progression to multiple autoantibody positivity. However, among single GAD65 autoantibody-positive participants ( = 158), those who carried ≥1 risk allele had a lower rate of progression to multiple autoantibody positivity (hazard ratio [HR] 0.65, = 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 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, = 0.016) even with adjustment for age.

CONCLUSIONS: The type 2 diabetes-associated locus influences progression of islet autoimmunity, with differential effects by autoantibody specificity and interaction by obesity/overweight.