PMID- 27027642 OWN - NLM STAT- MEDLINE DCOM- 20180213 LR - 20180409 IS - 1464-5491 (Electronic) IS - 0742-3071 (Linking) VI - 34 IP - 2 DP - 2017 Feb TI - Dissecting heterogeneity in paediatric Type 1 diabetes: association of TCF7L2 rs7903146 TT and low-risk human leukocyte antigen (HLA) genotypes. PG - 286-290 LID - 10.1111/dme.13123 [doi] AB - 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. CI - (c) 2016 Diabetes UK. FAU - Redondo, M J AU - Redondo MJ AD - Department of Pediatrics, Section of Diabetes and Endocrinology, Texas Children's Hospital, Baylor College of Medicine, Houston, TX, USA. FAU - Grant, S F A AU - Grant SF AD - Divisions of Human Genetics and Endocrinology, The Children's Hospital of Philadelphia, Philadelphia, PA, USA. AD - Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. FAU - Davis, A AU - Davis A AD - Diabetes Clinical Research Program, Benaroya Research Institute, Seattle, WA, USA. FAU - Greenbaum, C AU - Greenbaum C AD - Diabetes Clinical Research Program, Benaroya Research Institute, Seattle, WA, USA. CN - T1D Exchange Biobank LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20160420 PL - England TA - Diabet Med JT - Diabetic medicine : a journal of the British Diabetic Association JID - 8500858 RN - 0 (Autoantibodies) RN - 0 (C-Peptide) RN - 0 (HLA-DRB1 Chains) RN - 0 (ICA512 autoantibody) RN - 0 (SLC30A8 protein, human) RN - 0 (TCF7L2 protein, human) RN - 0 (Transcription Factor 7-Like 2 Protein) RN - 0 (Zinc Transporter 8) RN - EC 4.1.1.15 (Glutamate Decarboxylase) RN - EC 4.1.1.15 (glutamate decarboxylase 2) SB - IM MH - Adolescent MH - Autoantibodies/immunology MH - C-Peptide/metabolism MH - Child MH - Child, Preschool MH - Cohort Studies MH - Diabetes Mellitus, Type 1/*genetics/immunology MH - Female MH - Genetic Predisposition to Disease MH - Glutamate Decarboxylase/immunology MH - HLA-DRB1 Chains/genetics MH - Humans MH - Male MH - Polymorphism, Single Nucleotide MH - Transcription Factor 7-Like 2 Protein/genetics MH - Zinc Transporter 8/immunology EDAT- 2016/03/31 06:00 MHDA- 2018/02/14 06:00 CRDT- 2016/03/31 06:00 PHST- 2016/03/29 00:00 [accepted] PHST- 2016/03/31 06:00 [pubmed] PHST- 2018/02/14 06:00 [medline] PHST- 2016/03/31 06:00 [entrez] AID - 10.1111/dme.13123 [doi] PST - ppublish SO - Diabet Med. 2017 Feb;34(2):286-290. doi: 10.1111/dme.13123. Epub 2016 Apr 20.