The presence of ≥2 islet autoantibodies in unaffected first degree relatives of individuals with type 1 diabetes (T1D) is associated with >25% risk of diabetes within 5 years. In some multiple islet autoantibody positive individuals however, progression is delayed for decades. The aim of this study was to characterize slow progressors participating in the Bart’s Oxford (BOX) study who have been positive for ≥2 islet autoantibodies for more than 10 years but remain diabetes-free.
Materials and methods
The population-based BOX study has identified >95% of children with T1D in the Oxford region, U.K, since 1985. Genetic and islet autoantibody characteristics of fast and slow progressors were compared. IAA, GADA and IA-2A were detected by radio-immunoassay, HLA class II by PCR-SSP and T1D-associated SNPs (IFIH1, CTLA4, PTPN22, IL18RAP, SH2B3, KIAA0350, COBL and ERBB3) by Taqman genotyping. For genetic studies, an additional 108 UK children diagnosed <2yrs also represented rapid progressors.
Of 4,888 first-degree relatives, 97 were identified with ≥2 islet autoantibodies. 40 (41%) developed diabetes after study entry (range 0.5-18.9 years); 32 within 10 years and 57 remained diabetes free. Of those who progressed within 10 years, 28% had the high risk HLA DRB1*03-DQB1*02/ DRB1*04-DQB1*0302 genotype compared with 18% who had not progressed (p=0.2). IA-2A were more common in progressors (p= 0.01).When rapid (diagnosed < 2 years) were compared with slow progressors, both HLA class II and SNP risk scores for 8 T1D associated genes1,2 discriminated rates of progression (p=0.007).
A subset of first degree relatives remain diabetes-free more than a decade after first islet autoantibody detection. Positivity for IA-2A discriminates rapid and slow progressors as does genetic risk scores. We hypothesise that regulatory T cell function may be enhanced in this protected population and are seeking to identify larger cohorts of well characterised slow progressors.