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Genetic Modification of Risk Assessment Based on Staging of Preclinical Type 1 Diabetes in Siblings of Affected Children

Hospital for Children and Adolescents (S.M., H.K.A., M.K.), University of Helsinki, FIN-00029 Helsinki, Finland; Department of Pediatrics (K.S., P.K.), University of Oulu, FIN-90014 Oulu, Finland; Department of Virology and Turku Immunology Centre (H.R., J.I.), University of Turku, FIN-20520 Turku, Finland; and Department of Pediatrics (M.K.), Tampere University Hospital, FIN-33521 Tampere, Finland

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

We set out to study the association between human leukocyte antigen-defined genetic disease susceptibility and the stage of preclinical type 1 diabetes and whether genetic predisposition affects the natural course of preclinical diabetes in initially nondiabetic siblings of affected children. A total of 701 initially unaffected siblings were graded into four stages of preclinical type 1 diabetes based on the initial number of disease-associated autoantibodies detectable close to the time of diagnosis of the index case: no prediabetes (no antibodies), early (one antibody specificity), advanced (two antibodies), and late prediabetes (three or more antibodies). Another classification system covering 659 siblings was based on a combination of the initial number of antibodies and the first-phase insulin response (FPIR) to iv glucose: no prediabetes (no antibodies), early (one antibody specificity, normal FPIR), advanced (two or more antibodies, normal FPIR), and late prediabetes (at least one antibody, reduced FPIR). Genetic susceptibility to type 1 diabetes was defined by human leukocyte antigen identity and DR and DQ genotypes. There was a higher proportion of siblings with late prediabetes initially among those with strong genetic disease susceptibility than among those with decreased genetic predisposition (16.7% vs. 0.5%; P < 0.001 for DQB1 genotypes according to the first classification), whereas there was a higher proportion of siblings with no signs of prediabetes among those with genotypes conferring decreased risk (91.2% vs. 70.4% among those with high-risk DQB1 genotypes; P < 0.001 according to the first classification). Autoantibodies alone were more sensitive in the prediction of future diabetes in siblings than when combined with genetic susceptibility. Genetic susceptibility played a role in whether the initial prediabetic stage progressed (progression in 29.6% of the high-risk siblings compared with 6.6% of the siblings with DQB1 genotypes conferring decreased risk; P < 0.001 according to the first classification) and whether overt type 1 diabetes became manifest or not. Genetic susceptibility has an impact on both the initiation and progression of the autoimmune process leading to clinical diabetes in siblings of affected children.

This study was supported by grants from the Juvenile Diabetes Foundation International (Grant 197032), the Finnish Diabetes Research Foundation, the Medical Research Council, Academy of Finland (Grant 26109), the Päivikki and Sakari Sohlberg Foundation, and the Novo Nordisk Foundation. The Childhood Diabetes in Finland study has also been supported by grants from the Association of Finnish Life Insurance Companies, the Sigrid Jusélius Foundation, the National Institutes of Health (Grant DK 37957), the University of Helsinki, and the Finnish Medical Foundation.

Abbreviations: CI, Confidence interval(s); DiMe, Childhood Diabetes in Finland Study; FPIR, first-phase insulin response; GADA, antibodies to the 65 kDa isoform of glutamic acid decarboxylase; HLA, human leukocyte antigen; IA-2A, antibodies to the IA-2 protein; IAA, insulin autoantibodies; ICA, islet cell antibodies; IVGTT, iv glucose tolerance test; OR, odds ratio(s); RU, relative units.

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