Genetic Associations with C-peptide Levels before Type 1 Diabetes Diagnosis in At-Risk Relatives

Objective We sought to determine whether the type 1 diabetes genetic risk score-2 (T1D-GRS2) and single nucleotide polymorphisms are associated with C-peptide preservation before type 1 diabetes diagnosis. Methods We conducted a retrospective analysis of 713 autoantibody-positive participants who developed type 1 diabetes in the TrialNet Pathway to Prevention Study who had T1DExomeChip data. We evaluated the relationships of 16 known single nucleotide polymorphisms and T1D-GRS2 with area under the curve (AUC) C-peptide levels during oral glucose tolerance tests conducted in the 9 months before diagnosis. Results Higher T1D-GRS2 was associated with lower C-peptide AUC in the 9 months before diagnosis in univariate (β = −.06, P < .0001) and multivariate (β = −.03, P = .005) analyses. Participants with the JAZF1 rs864745 T allele had lower C-peptide AUC in both univariate (β = −.11, P = .002) and multivariate (β = −.06, P = .018) analyses. Conclusion The type 2 diabetes-associated JAZF1 rs864745 T allele and higher T1D-GRS2 are associated with lower C-peptide AUC before diagnosis of type 1 diabetes, with implications for the design of prevention trials.