Characteristics of slow progression to diabetes in multiple islet autoantibody-positive individuals from five longitudinal cohorts: the SNAIL study

Abstract

Aims/hypothesis: Multiple islet autoimmunity increases risk of diabetes, but not all individuals positive for two or more islet autoantibodies progress to disease within a decade. Major islet autoantibodies recognise insulin (IAA), GAD (GADA), islet antigen-2 (IA-2A) and zinc transporter 8 (ZnT8A). Here we describe the baseline characteristics of a unique cohort of 'slow progressors' (n = 132) who were positive for multiple islet autoantibodies (IAA, GADA, IA-2A or ZnT8A) but did not progress to diabetes within 10 years.

Methods: Individuals were identified from five studies (BABYDIAB, Germany; Diabetes Autoimmunity Study in the Young [DAISY], USA; All Babies in Southeast Sweden [ABIS], Sweden; Bart's Oxford Family Study [BOX], UK and the Pittsburgh Family Study, USA). Multiple islet autoantibody characteristics were determined using harmonised assays where possible. HLA class II risk was compared between slow progressors and rapid progressors (n = 348 diagnosed <5 years old from BOX) using the χ² test.

Results: In the first available samples with detectable multiple antibodies, the most frequent autoantibodies were GADA (92%), followed by ZnT8A (62%), IAA (59%) and IA-2A (41%). High risk HLA class II genotypes were less frequent in slow (28%) than rapid progressors (42%, p = 0.011), but only two slow progressors carried the protective HLA DQ6 allele.

Conclusion: No distinguishing characteristics of slow progressors at first detection of multiple antibodies have yet been identified. Continued investigation of these individuals may provide insights into slow progression that will inform future efforts to slow or prevent progression to clinical diabetes.

Keywords: HLA class II; Islet autoantibodies; Slow progression; Type 1 diabetes.

Fig. 1

Proportion of slow progressors positive for (a) IAA, (b) GADA, (c) IA-2A and (d) ZnT8A at the first available mAab-positive sample differed between the cohorts (p=0.001, p=0.018, p=0.007 and p=0.183, for each antibody, respectively). Black bars show overall percentage, white bars show percentage for slow progressors from each study. The ABIS participants were not tested for ZnT8A in their first mAab-positive sample

Fig. 2

HLA risks for (a) proportion of HLA class II high risk (black), intermediate risk (grey) or low risk (white) genotypes in BOX probands according to age at diagnosis (n=2075, including 348 rapid progressors diagnosed under 5 years of age) and slow progressors (SPs, n=121, p=0.011 for HLA class II risk in slow vs rapid progressors); and (b) proportion of participants carrying HLA class II DQ2 (white) or DQ8 (black) haplotypes in BOX (n=36), BABYDIAB (n=22), DAISY (n=30), Pittsburgh study (n=21) and ABIS (n=10)