Long-Term Follow-Up Incidence of Type 1 Diabetes and Associated Autoimmune Diseases in First-Degree Relatives

First-degree relatives (FDRs) of individuals with type 1 diabetes (T1D) carry a significantly elevated risk of developing autoimmune diseases, including celiac disease (CD) and autoimmune thyroid disease (AITD). The DiaUnion 1.0 study aimed to characterize one-time autoantibodies, genetic risk profiles and long-term progression to T1D, CD or AITD in siblings of children newly diagnosed with T1D.

Between 1997 and 2010, 1427 Danish siblings provided plasma and DNA samples to the DanDiabKids biobank. Autoantibodies associated with T1D (GADA, IAA, IA2A, ZnT8A), CD (tTGA) and AITD (TPOA) were measured using ADAP technology and confirmed by radiobinding assays. Genotyping was performed to compute a T1D Genetic Risk Score (GRS). National registry data were used to track disease incidence up to year 2024.

Out of 1417 screened samples, 7.8% were positive for islet autoantibodies (IAab), and 4.6% had multiple IAab. Disease incidence rate increased substantially with IAab positivity: 0.11 per 100 person-years in IAab-negative siblings, 2.46 in single-IAab positive and 8.10 in those with multiple IAab. Similarly, 1.97 per 100 person-years of tTGA-positive siblings developed CD, and 0.69 per 100 person-years of TPOA-positive individuals developed AITD. Higher GRS and HLA DR3/DR4 haplotypes were associated with autoantibody positivity (p < 0.0001).

A single screening for T1D, CD and AITD autoantibodies combined with genetic risk scoring stratified long-term risk of clinically diagnosed autoimmune disease. These findings support further evaluation of targeted screening and follow-up strategies in FDRs to enable surveillance and potential early intervention before clinical onset.