Dissecting heterogeneity in paediatric Type 1 diabetes: association of TCF7L2 rs7903146 TT and low‐risk human leukocyte antigen (HLA) genotypes

• Published in: Diabetic medicine 2017-02, Vol.34 (2), p.286-290
• Main Authors: Redondo, M. J., Grant, S. F. A., Davis, A., Greenbaum, C.
• Format: Article
• Language: English
• Subjects: Adolescent; Alleles; Antigens; Autoantibodies; Autoantibodies - immunology; Autoimmunity; C-Peptide - metabolism; Child; Child, Preschool; Children; Cohort Studies; Diabetes; Diabetes mellitus; Diabetes mellitus (insulin dependent); Diabetes mellitus (non-insulin dependent); Diabetes Mellitus, Type 1 - genetics; Diabetes Mellitus, Type 1 - immunology; Drb1 protein; Female; Gene polymorphism; Genes; Genetic Predisposition to Disease; Genotypes; Glutamate decarboxylase; Glutamate Decarboxylase - immunology; Glutamic acid; Histocompatibility antigen HLA; HLA-DRB1 Chains - genetics; Humans; Hypotheses; ICA1 protein; Insulin; Male; Pediatrics; Polymorphism; Polymorphism, Single Nucleotide; Single-nucleotide polymorphism; Transcription Factor 7-Like 2 Protein - genetics; Zinc transporter; Zinc Transporter 8 - immunology
• ISSN: 0742-3071; 1464-5491
• DOI: 10.1111/dme.13123

Aims To test the hypothesis that non‐obese individuals with childhood‐onset Type 1 diabetes and the rs7903146 TT genotype would be less likely to have high‐risk human leukocyte antigen (HLA) genotypes and alleles. Methods We studied a cohort of 105 non‐obese participants in the T1D Exchange Biobank Residual Insulin Study who had childhood‐onset Type 1 diabetes [mean (sd) age at onset and recruitment, respectively, 9.9 (4.15) and 14.4 (4.13) years; 84.8% non‐Hispanic white]. We analysed islet autoantibodies (glutamic acid decarboxylase 65, islet cell autoantigen 512/islet antigen‐2 and zinc transporter 8), non‐fasting random C‐peptide levels, HLA type and TCF7L2 single nucleotide polymorphism rs7903146 in this cohort. Results None of the 13 individuals with the rs7903146 TT genotype carried the highest Type 1 diabetes risk HLA genotype, i.e. DRB1*03:01/DR4 (DRB1*0401, *04:05 or *04:02), compared with 29.4% (27/92) of those without it (P=0.023). The DRB1*03:01 allele was present in 15.4% (2/13) of individuals with the single nucleotide polymorphism, compared with 59.8% (55/92) of those without it (P=0.003). Analyses restricted to autoantibody‐positive individuals (n=80) yielded similar results. The HLA DRB1*15:01 allele, which affords dominant protection against Type 1 diabetes, was found in one participant, who had multiple islet autoantibodies and carried the rs7903146 TT genotype. Conclusions These findings further support the hypothesis that TCF7L2 gene variation contributes to diabetogenesis in a subset of young people with Type 1 diabetes, opening possible new pathways for therapy and prevention. What's new? Individuals with Type 1 diabetes who carry the Type 2 diabetes‐associated TCF7L2 single‐nucleotide polymorphism (SNP) genotype are less likely to carry human leukocyte antigen (HLA) genotypes that confer susceptibility to Type 1 diabetes. These findings support our previous report that children with fewer markers of islet autoimmunity are more likely to have the Type 2 diabetes‐associated TCF7L2 SNP genotype. These results also support disease heterogeneity and possibly open new pathways for treatment and prevention.