Background: The transcription factor 7-like 2 (TCF7L2) gene has the strongest genetic association with type 2 diabetes. TCF7L2 also associates with latent autoimmune diabetes in adults, which often presents with a single islet autoantibody, but not with classical type 1 diabetes.
Methods: We aimed to test if TCF7L2 is associated with single islet autoantibody expression in pediatric type 1 diabetes. We studied 71 prospectively recruited children who had newly diagnosed type 1 diabetes and evidence of islet autoimmunity, that is, expressed ≥1 islet autoantibody to insulin, glutamic acid decarboxylase 65, islet cell autoantigen 512, or zinc transporter 8. TCF7L2 rs7903146 alleles were identified. Data at diagnosis were cross-sectionally analyzed.
Results: We found that 21.1% of the children with autoimmune type 1 diabetes expressed a single islet autoantibody. The distribution of TCF7L2 rs7903146 genotypes in children with a single autoantibody (n=15) was 40% CC, 26.7% CT and 33.3% TT, compared with children with ≥2 islet autoantibodies (50% CC, 42.9% CT and 7.1% TT, p=0.024). Furthermore, compared with children with ≥2 autoantibodies, single-autoantibody children had characteristics reflecting milder autoimmune destruction of β-cells. Restricting to lean children (body mass index<85th centile; n=36), 45.5% of those expressing a single autoantibody were rs7903146 TT homozygotes, compared with 0% of those with ≥2 autoantibodies (p<0.0001).
Conclusion: These results suggest that, in children with only mild islet autoimmunity, mechanisms associated with TCF7L2 genetic variation contribute to diabetogenesis, and this contribution is larger in the absence of obesity.
Keywords: Autoantibodies; LADA (Latent Autoimmune Diabetes in Adults); Pediatric Type 1 Diabetes; Transcription Factor.