Characterisation of rapid progressors to type 1 diabetes among children with HLA-conferred disease susceptibility

Abstract

Aims/hypothesis In this study, we aimed to characterise rapid progressors to type 1 diabetes among children recruited from the general population, on the basis of HLA-conferred disease susceptibility. Methods We monitored 7410 HLA-predisposed children participating in the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) study for the development of beta cell autoimmunity and type 1 diabetes from birth over a median follow-up time of 16.2 years (range 0.9-21.1 years). Islet cell antibodies (ICA) and autoantibodies to insulin (IAA), GAD (GADA) and islet antigen 2 (IA-2A) were assessed as markers of beta cell autoimmunity. Rapid progression was defined as progression to clinical type 1 diabetes within 1.5 years of autoantibody seroconversion. We analysed the association between rapid progression and demographic and autoantibody characteristics as well as genetic markers, including 25 non-HLA SNPs predisposing to type 1 diabetes. Results Altogether, 1550 children (21%) tested positive for at least one diabetes-associated autoantibody in at least two samples, and 248 (16%) of seroconverters progressed to type 1 diabetes by the end of 2015. The median time from seroconversion to diagnosis was 0.51 years in rapid progressors (n = 42, 17%) and 5.4 years in slower progressors. Rapid progression was observed both among young (<5 years) and early pubertal children (>7 years), resulting in a double-peak distribution of seroconversion age. Compared with slower progressors, rapid progressors had a higher frequency of positivity for multiple (≥2) autoantibodies and had higher titres of ICA, IAA and IA-2A at seroconversion, and there was a higher prevalence of the secretor genotype in the FUT2 gene among those carrying the high-risk HLA genotype. Compared with autoantibody-positive non-progressors, rapid progressors were younger, were more likely to carry the high-risk HLA genotype and a predisposing SNP in the PTPN22 gene, had higher frequency of ICA, IAA, GADA and IA-2A positivity and multipositivity, and had higher titres of all four autoantibodies at seroconversion. Conclusions/interpretation At seroconversion, individuals with rapid progression to type 1 diabetes were characterised by a younger age, higher autoantibody titres, positivity for multiple autoantibodies and higher prevalence of a FUT2 SNP. The double-peak profile for seroconversion age among the rapid progressors demonstrates for the first time that rapid progression may take place not only in young children but also in children in early puberty. Rapid progressors might benefit from careful clinical follow-up and early preventive measures.Heli Siljander and Mikael Knip are joint senior authors.Electronic supplementary material The online version of this article

Sex as a determinant of type 1 diabetes at diagnosis

“…20 The Finnish Type 1 Diabetes Prediction and Prevention study showed no sex differences in the development of any single or multiple autoantibodies 21 or in the disease progression after seroconversion. 22 In contrast, female sex was reported to be a clear risk factor for progression from multiple autoantibodies to T1D in the Environmental Determinants of Diabetes in the Young study. 23 Overall, there is limited information on potential sex differences in the autoantibody profile at the presentation of T1D.…”

“…In the prospective BABYDIAB study recruiting infants with at least 1 family member affected by T1D, the cumulative incidence of autoantibodies was similar in both sexes but the peak incidence was observed earlier in boys than in girls . The Finnish Type 1 Diabetes Prediction and Prevention study showed no sex differences in the development of any single or multiple autoantibodies or in the disease progression after seroconversion . In contrast, female sex was reported to be a clear risk factor for progression from multiple autoantibodies to T1D in the Environmental Determinants of Diabetes in the Young study .…”

The complexity and diversity of major histocompatibility complex challenge disease association studies

“…In addition, class I HLA genes have been associated with T1D. Young age, autoantibody profiles, and higher prevalence of non‐HLA FUT2 (fucosyltransferase 2) SNPs with predisposing HLA‐risk genes may characterize rapid disease progression in children . Aberrant T‐cell profiles are also linked to T1D.…”

Type 1 Diabetes: Disease Stratification

“…Faster rates of progression are observed with 3 or 4 versus 2 islet autoantibodies [25,70,71] . The presence of antibodies to IA-2 and ZnT8 as well as higher titers of antibody to Insulin and IA-2 are associated with a faster rate of progression [10,70,[72][73][74] . Islet autoantibody seroconversion at a young age is associated with a faster rate of progression [25] , and disease progression is also accelerated in children at stage 1 T1D with an increased BMI [75] and markedly accelerated in Hispanic children younger than 12 years of age who are overweight or obese [76] .…”

“…In contrast to genetics, environmental etiologies have not been validated and thus do not currently contribute to subject stratification in T1D prevention trials. However, some examples of gene-environment interactions include the interactions of the microbiome with the Fut-2 nonsecretor gene polymorphism, which increases risk of T1D and is associated with faster progression of presymptomatic T1D [10][11][12] , and interactions of picornaviruses, which include enteroviruses, with polymorphisms of the innate immunity viral RNA receptor gene region IFIH1(MDA-5) [13,14] .…”