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The First Signs of ß-Cell Autoimmunity Appear in Infancy in Genetically Susceptible Children from the General Population: The Finnish Type 1 Diabetes Prediction and Prevention Study

The Juvenile Diabetes Research Foundation Center for Type 1 Diabetes Prevention in Finland (T.K., A.K., A.-M.H., M.Ku., P.Ku., K.S., T.S., P.Ke., J.I., O.S., M.Kn.), Department of Pediatrics, Medical School, University of Tampere (T.K., M.Ku., M.Kn.), and Tampere University Hospital, FIN-33014 Tampere; Department of Pediatrics (A.K., T.S., P.Ke., J.I., O.S.) and Department of Virology (J.I.), University of Turku, FIN-20520 Turku; University of Oulu (A.-M.H., P.Ku., K.S.), FIN-90220 Oulu; and Hospital for Children and Adolescents (M.Kn.), University of Helsinki, FIN-00029 Helsinki, Finland

Address all correspondence and requests for reprints to: Prof. Mikael Knip, Hospital for Children and Adolescents, University of Helsinki, P.O. Box 281, FIN-00029 HUCH, Finland. E-mail: mikael.knip{at}hus.fi

Abstract

Little is known about the timing of the etiological events and the preclinical process of type 1 diabetes during the first years of life in the general population. In this population-based prospective birth cohort study, the appearance of diabetes-associated autoantibodies as a sign of ß-cell autoimmunity and the development of type 1 diabetes were monitored from birth. Of 25,983 newborn infants, 2,448 genetically susceptible children were monitored for islet cell antibodies (ICA) at 3- to 6-month intervals. If an infant seroconverted to ICA positivity, all his/her samples were also analyzed for insulin autoantibodies (IAA), antibodies to the 65-kDa isoform of glutamic acid decarboxylase, and antibodies to the protein tyrosine phosphatase-related IA-2 molecule. Fifteen children of those who carried the high-risk genotype (2.7%) and 23 of those who carried the moderate-risk genotype (1.2%; P = 0.019) tested positive for ICA at least once. Among those who showed positivity for at least 2 antibodies during the observation period (25 of 38), IAA appeared as the first or among the first antibodies in 22 children (88%) and emerged earlier than the other antibodies (P < 0.019 or less). The first autoantibodies appeared in the majority of the children in the fall and winter (30 of 38 vs. 8 of 38 in the spring and summer, P < 0.001). These observations suggest that young children in the general population with a strong human-leukocyte-antigen-DQ-defined genetic risk of type 1 diabetes show signs of ß-cell autoimmunity proportionally more often than those with a moderate genetic risk. IAA emerge as the first detectable antibody more commonly than any other antibody specificity, implying that insulin may be the primary antigen in most cases of human type 1 diabetes associated with the DR4-DQB1*0302 haplotype. The seasonal variation in the emergence of the first signs of ß-cell autoimmunity suggests that infectious agents may play a role in the induction of such autoimmunity.

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