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Public Release Type:
Journal
Publication Year: 2023
DOI:
https://doi.org/10.2337/db23-216-LB
Authors:
TAYLOR M. TRIOLO; HEMANG M. PARIKH; MUSTAFA TOSUR; LAURIC A. FERRAT; LU YOU; PETER GOTTLIEB; RICHARD A. ORAM; SUNA ONENGUT-GUMUSCU; JEFFREY KRISCHER; STEPHEN S. RICH; ANDREA STECK; MARIA J. REDONDO
Request IDs:
22822
Studies:
ATG-GCSF in New Onset Type 1 Diabetes
,
Hydroxychloroquine in Individuals At-risk for Type 1 Diabetes Mellitus
,
Oral Insulin for Prevention of Diabetes in Relatives at Risk for Type 1 Diabetes Mellitus
,
Preservation of Pancreatic Production of Insulin Through Immunosuppression
,
The Effects of Rituximab on the Progression of Type 1 Diabetes in New Onset Subjects
,
TN10 Anti-CD3 Prevention
,
TrialNet 08: Effects of Recombinant Human Glutamic Acid Decarboxylase (rhGAD65) Formulated in Alum (GAD-alum) on the Progression of Type 1 Diabetes in New Onset Subjects
,
TrialNet 09: Effects of CTLA-4 IG (Abatacept) on the Progression of Type 1 Diabetes in New Onset Subjects
,
TrialNet 14: Effects of Canakinumab on the Progression of Type 1 Diabetes in New Onset Subjects
,
TrialNet 18 -CTLA-4 Ig (Abatacept) for Prevention of abnormal glocose tolerance and diabetes in relatives at-risk for Type 1 Diabetes Mellitus
,
TrialNet Pathway To Prevention (formerly Natural History Study)
Autoimmune loss of beta-cell function (measured by C-peptide) is the hallmark of type 1 diabetes (T1D) targeted by interventions that aim to prevent T1D or its progression after onset. We sought to determine whether T1D genetic risk score-2 (T1D-GRS2) and single nucleotide polymorphisms (SNPs) that have been previously associated with C-peptide preservation after T1D diagnosis (e.g., SNPs in CLEC16A, G6CP2, INS, JAZF1, PTPN22, SLC30A8 and TCF7L2) influence C-peptide levels before diagnosis. We studied islet autoantibody (Ab)-positive participants in the TrialNet Pathway to Prevention Study who had T1DExomeChip data and assessed the influence of these 12 SNPs and the T1D-GRS2 on area under the curve (AUC) C-peptide levels during oral glucose tolerance tests conducted between 0-9 months prior to the diagnosis of T1D. Participants (n=702) had a mean age of 13.5±10.3 years, 47% were female, mean BMI was 20.7±6.0 kg/m2, and mean HbA1c 5.4±0.4%. The T1D high-risk HLA-DR3-DQ2 haplotype was present in 47% and the high-risk HLA-DR4-DQ8 haplotype was present in 67% of participants. We performed univariate and multivariate analyses adjusting for BMI, age, sex, number of positive Ab, and the first 3 principal components of ancestry. A higher T1D-GRS2 was associated with lower C-peptide AUC 0-9 months prior to T1D diagnosis in univariate (β=-0.06, P<0.0001) and multivariate (β=-0.03, p=0.008) analyses. Participants with the JAZF1 rs864745 G allele had lower C-peptide AUC 0-9 months prior to T1D diagnosis in univariate (β=-0.10, p=0.003) and multivariate (β=-0.05, p=0.047) analysis. In conclusion, the JAZF1 rs864745 G allele (which has also been associated with type 2 diabetes risk) and higher T1D-GRS2 predict lower C-peptide AUC prior to the diagnosis of T1D. Studies on their effect on response to trials to prevent or delay T1D onset are warranted.
