2097-P: Age at Type 1 Diabetes Diagnosis Is an Independent Risk Factor from HLA for Development of Type 1 Diabetes in First-Degree Relatives

Introduction and Objective: HLA genotype is the strongest genetic predictor of T1D risk. Highest risk HLA genotypes include DR3/DR4-DQB1*03:02 (DR3 and DR4). Islet autoantibodies are a marker of additional risk. This study aims to assess whether inclusion of age of onset for T1D in first-degree relatives (FDR) improves model prediction of risk for development of T1D beyond HLA and autoantibody status. Methods: This study analyzed cohort data obtained from the TrialNet Pathway to Prevention Study. Data was collected between March 14, 2004, and July 31, 2025. This study included 3,989 individuals with a single FDR with T1D who had available HLA genotypes and islet autoantibodies. A logistic regression to predict development of T1D was created utilizing DR3 and DR4 status, number of islet autoantibodies positive at initial screen, type of FDR with T1D, and age group at which FDR was diagnosed with T1D. Statistical analyses were performed using R version 4.4.2. Results: Even after controlling for the other variables described above, FDR onset age group remained an independent and statistically significant predictor for development of T1D (Likelihood-Ratio Chi-square = 32.32 (p < 0.001)). Individuals with an FDR diagnosed prior to age 5 (n = 1033) showed significantly increased odds to develop T1D compared to individuals with an FDR diagnosed between ages 6 and 10 (n = 1306, OR [95% CI] = 1.27 [1.05 - 1.53]), between ages 11 and 18 (n = 1052, OR = 1.53 [1.26 - 1.89]), or after age 18 (n = 598, OR = 2.21 [1.66 - 2.96]). Conclusion: Age of diagnosis at time of T1D in FDRs is an independent risk factor from HLA genotype and autoantibodies for development of T1D. Individuals with an FDR diagnosed prior to age 5 have significantly increased risk for development of T1D compared to individuals with an FDR diagnosed in older age groups. Disclosure G. Power: None. M. Tansey: Research Support; Current; Novo Nordisk, Diamyd, Provention Bio, Inc. Research Support; Ended; MannKind Corporation. Research Support; Current; Lumos Pharma, Inc., Ascendis Pharma A/S, Diurnal Ltd, Acadia Pharmaceuticals Inc., Eli Lilly and Company, BioMarin Pharmaceutical Inc. C. Pinnaro: None. A. Norris: None.