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Genetic Composition and Autoantibody Titers Model the Probability of Detecting C-Peptide Following Type 1 Diabetes Diagnosis

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posted on 08.01.2021, 23:42 by MacKenzie D. Williams, Rhonda Bacher, Daniel J. Perry, C. Ramsey Grace, Kieran M. McGrail, Amanda L. Posgai, Andrew Muir, Srikar Chamala, Michael J. Haller, Desmond A. Schatz, Todd M. Brusko, Mark A. Atkinson, Clive H. Wasserfall
We and others previously demonstrated that a type 1 diabetes genetic risk score (GRS) improves the ability to predict disease progression and onset in at-risk subjects with islet autoantibodies. Here, we hypothesized that GRS and islet autoantibodies, combined with age at onset and disease duration, could serve as markers of residual β-cell function following type 1 diabetes diagnosis. Generalized estimating equations were used to investigate whether GRS along with insulinoma-associated protein-2 autoantibody (IA-2A), zinc transporter 8 autoantibody (ZnT8A) and GAD autoantibody (GADA) titers were predictive of C-peptide detection in a largely cross-sectional cohort of 401 subjects with type 1 diabetes (duration median = 4.5 years, range 0-60). Indeed, a combined model incorporating disease duration, age at onset, GRS, and titers of IA-2A, ZnT8A and GADA provided superior capacity to predict C-peptide detection (QIC=334.6) compared with disease duration, age at onset, and GRS as the sole parameters (QIC=359.2). These findings support the need for longitudinal validation of our combinatorial model. The ability to project the rate and extent of decline in residual C-peptide production for individuals with type 1 diabetes could critically inform enrollment and benchmarking for clinical trials seeking to preserve or restore endogenous β-cell function.


These studies were supported by funding from the National Institutes of Health (P01 AI042288), the JDRF (1-SRA-2019-764-A-N and 2-PDF-2016-207-A-N), endowments from the American Diabetes Association, the McJunkin Family Charitable Foundation, and the Jeffrey Keene Family Professorship.