TY - JOUR
T1 - Transcription factor 7-like 2 (TCF7L2) gene polymorphism and progression from single to multiple autoantibody positivity in individuals at risk for type 1 diabetes
AU - Type 1 Diabetes TrialNet Study Group
AU - Redondo, Maria J.
AU - Steck, Andrea K.
AU - Sosenko, Jay
AU - Anderson, Mark
AU - Antinozzi, Peter
AU - Michels, Aaron
AU - Wentworth, John M.
AU - Atkinson, Mark A.
AU - Pugliese, Alberto
AU - Geyer, Susan
N1 - Publisher Copyright:
© 2018 by the American Diabetes Association.
PY - 2018/12/1
Y1 - 2018/12/1
N2 - 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.
AB - 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.
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U2 - 10.2337/dc18-0861
DO - 10.2337/dc18-0861
M3 - Article
C2 - 30275285
AN - SCOPUS:85056803019
SN - 0149-5992
VL - 41
SP - 2480
EP - 2486
JO - Diabetes care
JF - Diabetes care
IS - 12
ER -