Genetic Risk and Transition Through Preclinical Stages of Type 1 Diabetes

作者：Andrea K. Steck, Hemang Parikh, Taylor M. Triolo, Lauric A. Ferrat, Lu You, Peter A. Gottlieb, Richard A. Oram, Suna Önengüt-Gümüşcü, Jeffrey P. Krischer, Stephen S. Rich, María J. Redondo · 发表于：The Journal of Clinical Endocrinology & Metabolism · 年份：2025 · DOI：10.1210/clinem/dgaf392 · 被引用次数：4 · 研究领域：Diabetes and associated disorders、Pancreatic function and diabetes、T-cell and B-cell Immunology

CONTEXT: The influence of genetic factors on the transition through preclinical stages of type 1 diabetes (T1D) has not been studied. OBJECTIVE: Our aim was to evaluate the influence of genetic factors on transition through T1D stages. METHODS: In TrialNet participants who have been genotyped with the TEDDY-T1DExomeChip array (Illumina HumanCoreExome Beadarray with custom content), we evaluated the influence of the overall T1D genetic risk score (GRS2), its human leukocyte antigen (HLA) and non-HLA components, HLA-DR3 and HLA-DR4 haplotypes, and 90 single-nucleotide variations previously associated with islet autoimmunity and/or T1D on 3 transitions between diabetes stages: from single confirmed autoantibody positive to stage 1 (N = 4314), from stage 1 to stage 2 (N = 3066), and from stage 2 to stage 3 (clinical) T1D (N = 2045). RESULTS: The T1D GRS2 was associated with all 3 transitions with hazard ratios (HRs) of 1.11 (1.09-1.14) for single-autoantibody positivity to stage 1, HR 1.05 (1.03-1.08) for stage 1 to 2, and HR 1.13 (1.09-1.17) for stage 2 to 3 T1D. The T1D GRS2 HLA and HLA class II components were associated with all 3 transitions. The HLA class I component and the HLA-DR4 haplotype were associated with the transition from single-autoantibody positivity to stage 1 and from stage 2 to stage 3 T1D, while HLA-DR3 was associated only with the latter. CONCLUSION: Genetics influence transitions through each stage of preclinical T1D, with main contributions from HLA clas...