Jeffrey P Krischer1, Xiang Liu2, Åke Lernmark3, William A Hagopian4, Marian J Rewers5, Jin-Xiong She6, Jorma Toppari7,8, Anette-G Ziegler9, Beena Akolkar10. 1. Health Informatics Institute, Morsani College of Medicine, University of South Florida, Tampa, FL, USA. jeffrey.krischer@epi.usf.edu. 2. Health Informatics Institute, Morsani College of Medicine, University of South Florida, Tampa, FL, USA. 3. Department of Clinical Sciences, Lund University/CRC, Skåne University Hospital SUS, Malmo, Sweden. 4. Pacific Northwest Diabetes Research Institute, Seattle, WA, USA. 5. Barbara Davis Center for Childhood Diabetes, University of Colorado, Aurora, CO, USA. 6. Center for Biotechnology and Genomic Medicine, Augusta University, Augusta, GA, USA. 7. Department of Pediatrics, Turku University Hospital, Turku, Finland. 8. Institute of Biomedicine, Research Centre for Integrated Physiology and Pharmacology, and Population Research Centre, University of Turku, Turku, Finland. 9. Institute of Diabetes Research, Helmholtz Zentrum München, and Klinikum rechts der Isar, Technische Universität München, and Forschergruppe Diabetes e.V, Neuherberg, Germany. 10. National Institute of Diabetes & Digestive & Kidney Diseases, Bethesda, MD, USA.
Abstract
AIMS/HYPOTHESIS: Prognostic factors and characteristics of children diagnosed with type 1 diabetes before 6 years of age were compared with those diagnosed at 6-13 years of age in the TEDDY study. METHODS: Genetically high-risk children (n = 8502) were followed from birth for a median of 9.9 years; 328 (3.9%) were diagnosed with type 1 diabetes. Cox proportional hazard model was used to assess the association of prognostic factors with the risk of type 1 diabetes in the two age groups. RESULTS: Children in the younger group tended to develop autoantibodies earlier than those in the older group did (mean age 1.5 vs 3.5 years), especially insulin autoantibodies (IAA), which developed earlier than GAD autoantibodies (GADA). Children in the younger group also progressed to diabetes more rapidly than the children in the older group did (mean duration 1.9 vs 5.4 years). Children with autoantibodies first appearing against insulinoma antigen-2 (IA-2A) were found only in the older group. The significant diabetes risk associated with the country of origin in the younger group was no longer significant in the older group. Conversely, the diabetes risk associated with HLA genotypes was statistically significant also in the older group. Initial seroconversion after and before 2 years of age was associated with decreased risk for diabetes diagnosis in children positive for multiple autoantibodies, but the diabetes risk did not decrease further with increasing age if initial seroconversion occurred after age 2. Diabetes risk associated with the minor alleles of rs1004446 (INS) was decreased in both the younger and older groups compared with other genotypes (HR 0.67). Diabetes risk was significantly increased with the minor alleles of rs2476601 (PTPN22) (HR 2.04 and 1.72), rs428595 (PPIL2) (HR 2.13 and 2.10), rs113306148 (PLEKHA1) (HR 2.34 and 2.21) and rs73043122 (RNASET2) (HR 2.31 and 2.54) (HR values represent the younger and older groups, respectively). CONCLUSIONS/INTERPRETATIONS: Diabetes at an early age is likely to be preceded by IAA autoantibodies and is a more aggressive form of the disease. Among older children, once multiple autoantibodies have been observed there does not seem to be any association between progression to diabetes and the age of the child or family history. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00279318.
AIMS/HYPOTHESIS: Prognostic factors and characteristics of children diagnosed with type 1 diabetes before 6 years of age were compared with those diagnosed at 6-13 years of age in the TEDDY study. METHODS: Genetically high-risk children (n = 8502) were followed from birth for a median of 9.9 years; 328 (3.9%) were diagnosed with type 1 diabetes. Cox proportional hazard model was used to assess the association of prognostic factors with the risk of type 1 diabetes in the two age groups. RESULTS: Children in the younger group tended to develop autoantibodies earlier than those in the older group did (mean age 1.5 vs 3.5 years), especially insulin autoantibodies (IAA), which developed earlier than GAD autoantibodies (GADA). Children in the younger group also progressed to diabetes more rapidly than the children in the older group did (mean duration 1.9 vs 5.4 years). Children with autoantibodies first appearing against insulinoma antigen-2 (IA-2A) were found only in the older group. The significant diabetes risk associated with the country of origin in the younger group was no longer significant in the older group. Conversely, the diabetes risk associated with HLA genotypes was statistically significant also in the older group. Initial seroconversion after and before 2 years of age was associated with decreased risk for diabetes diagnosis in children positive for multiple autoantibodies, but the diabetes risk did not decrease further with increasing age if initial seroconversion occurred after age 2. Diabetes risk associated with the minor alleles of rs1004446 (INS) was decreased in both the younger and older groups compared with other genotypes (HR 0.67). Diabetes risk was significantly increased with the minor alleles of rs2476601 (PTPN22) (HR 2.04 and 1.72), rs428595 (PPIL2) (HR 2.13 and 2.10), rs113306148 (PLEKHA1) (HR 2.34 and 2.21) and rs73043122 (RNASET2) (HR 2.31 and 2.54) (HR values represent the younger and older groups, respectively). CONCLUSIONS/INTERPRETATIONS: Diabetes at an early age is likely to be preceded by IAA autoantibodies and is a more aggressive form of the disease. Among older children, once multiple autoantibodies have been observed there does not seem to be any association between progression to diabetes and the age of the child or family history. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00279318.
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