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Genetic Effects on Age-Dependent Onset and Islet Cell Autoantibody Markers in Type 1 Diabetes

¹ Department of Statistics and Actuarial Science, Simon Fraser University, Burnaby, Canada
² Pacific Northwest Research Institute, Seattle, Washington
³ Karolinska Institute, Department of Molecular Medicine, Stockholm, Sweden
⁴ Department of Medicine, University of Washington, Seattle, Washington
⁵ Department of Medicine, University of Lund, Lund, Sweden
⁶ Institute for Systems Biology, Seattle, Washington
⁷ Department of Endocrinology, University Hospital Malmö, University of Lund, Lund, Sweden
⁸ Department of Biostatistics, University of Washington, Seattle, Washington
⁹ Department of Paediatrics, Umeå University, Umeå, Sweden
¹⁰ Diabetes Center, Södersjukhuset, Stockholm, Sweden

Age-dependent associations between type 1 diabetes risk genes HLA, INS VNTR, and CTLA-4 and autoantibodies to GAD65 (GADAs), ICA512/IA-2, insulin, and islet cells were determined by logistic regression analysis in 971 incident patients with type 1 diabetes and 702 control subjects aged 0–34 years. GADAs were associated with HLA-DQ2 in young but not in older patients (P = 0.009). Autoantibodies to insulin were negatively associated with age (P < 0.0001) but positively associated with DQ8 (P = 0.03) and with INS VNTR (P = 0.04), supporting possible immune tolerance induction. ICA512/IA-2 were negatively associated with age (P < 0.0001) and with DQ2 (P < 0.0001) but positively associated with DQ8 (P = 0.04). Males were more likely than females to be negative for GADA (P < 0.0001), autoantibodies to islet cells (P = 0.04), and all four autoantibody markers (P = 0.004). The CTLA-4 3' end microsatellite marker was not associated with any of the autoantibodies. We conclude that age and genetic factors such as HLA-DQ and INS VNTR need to be combined with islet autoantibody markers when evaluating the risk for type 1 diabetes development.

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