Genetic Risk and Transition Through Preclinical Stages of Type 1 Diabetes

Abstract

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 class II. These results increase our understanding of T1D development and support incorporating the T1D GRS2 to enhance the prediction of progression through the preclinical stages of T1D.

Keywords: early type 1 diabetes markers; genetic risk factors; genetic risk score; prediction of T1D; type 1 diabetes.