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

• Published in: The journal of clinical endocrinology and metabolism
• Main Authors: Triolo, Taylor M, Parikh, Hemang M, Tosur, Mustafa, Ferrat, Lauric, You, Lu, Gottlieb, Peter A, Oram, Richard A, Onengut-Gumuscu, Suna, Krischer, Jeffrey P, Rich, Stephen S, Steck, Andrea K, Redondo, Maria J
• Format: Journal Article
• Language: English
• Published: United States 20-05-2024
• Subjects: epidemiology; type 1 diabetes; genetics; C-peptide; prediction; genetic risk score; prevention
• ISSN: 0021-972X; 1945-7197; 1945-7197
• DOI: 10.1210/clinem/dgae349

We sought to determine whether the type 1 diabetes genetic risk score-2 (T1D-GRS2) and single nucleotide polymorphisms (SNPs) are associated with C-peptide preservation before type 1 diabetes diagnosis.
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 SNPs and T1D-GRS2 with area under the curve (AUC) C-peptide levels during oral glucose tolerance tests conducted in the 9 months before diagnosis.
Higher T1D-GRS2 was associated with lower C-peptide AUC in the 9 months before diagnosis in univariate (β=-0.06, P<0.0001) and multivariate (β=-0.03, P=0.005) analyses. Participants with the JAZF1 rs864745 T allele had lower C-peptide AUC in both univariate (β=-0.11, P=0.002) and multivariate (β=-0.06, P=0.018) analyses.
The type 2 diabetes-associated JAZF1 rs864745 T allele and higher T1D-GRS2 are associated with lower C-peptide AUC prior to diagnosis of type 1 diabetes, with implications for the design of prevention trials.