216-LB: Genetic Influences on Beta-Cell Function before Type 1 Diabetes Diagnosis

• Published in: Diabetes (New York, N.Y.) Vol. 72; no. Supplement_1; p. 1
• Main Authors: TRIOLO, TAYLOR M., PARIKH, HEMANG M., TOSUR, MUSTAFA, FERRAT, LAURIC A., YOU, LU, GOTTLIEB, PETER, ORAM, RICHARD A., ONENGUT-GUMUSCU, SUNA, KRISCHER, JEFFREY, RICH, STEPHEN S., STECK, ANDREA, REDONDO, MARIA J.
• Format: Journal Article
• Language: English
• Published: New York American Diabetes Association 20-06-2023
• Subjects: Alleles; Autoantibodies; Beta cells; Diabetes; Diabetes mellitus (insulin dependent); Diabetes mellitus (non-insulin dependent); Diagnosis; Glucose tolerance; Haplotypes; Histocompatibility antigen HLA; Immunological tolerance; Medical diagnosis; Peptides; Protein-tyrosine-phosphatase; Single-nucleotide polymorphism
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/db23-216-LB

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.