title: Dissecting heterogeneity in paediatric Type 1 diabetes: association of TCF7L2 rs7903146 TT and low-risk human leukocyte antigen (HLA) genotypes.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Department of Pediatrics, Section of Diabetes and Endocrinology, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA.
authors.forename: M J
authors.initials: MJ
authors.lastname: Redondo
authors.affiliation: Divisions of Human Genetics and Endocrinology, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.|Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: S F A
authors.initials: SF
authors.lastname: Grant
authors.affiliation: Diabetes Clinical Research Program, Benaroya Research Institute, Seattle, WA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Davis
authors.affiliation: Diabetes Clinical Research Program, Benaroya Research Institute, Seattle, WA, USA.
authors.forename: C
authors.initials: C
authors.lastname: Greenbaum
mesh_terms: D000293:Adolescent; D001323:Autoantibodies / Q000276:immunology; D002096:C-Peptide / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology; D005260:Female; D020022:Genetic Predisposition to Disease; D005968:Glutamate Decarboxylase / Q000276:immunology; D059811:HLA-DRB1 Chains / Q000235:genetics; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide; D058118:Transcription Factor 7-Like 2 Protein / Q000235:genetics; D000075703:Zinc Transporter 8 / Q000276:immunology
chemical_list: D001323:Autoantibodies; D002096:C-Peptide; D059811:HLA-DRB1 Chains; C096322:ICA512 autoantibody; C492522:SLC30A8 protein, human; C544894:TCF7L2 protein, human; D058118:Transcription Factor 7-Like 2 Protein; D000075703:Zinc Transporter 8; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2