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. 2021 Jun 23;44(10):2269-2276.
doi: 10.2337/dc20-1836. Online ahead of print.

Islet Autoimmunity and HLA Markers of Presymptomatic and Clinical Type 1 Diabetes: Joint Analyses of Prospective Cohort Studies in Finland, Germany, Sweden, and the U.S

Vibha Anand  1 , Ying Li  2 , Bin Liu  2 , Mohamed Ghalwash  2   3 , Eileen Koski  2 , Kenney Ng  2 , Jessica L Dunne  4 , Josefine Jönsson  5 , Christiane Winkler  6   7   8 , Mikael Knip  9   10   11   12 , Jorma Toppari  13 , Jorma Ilonen  14 , Michael B Killian  15 , Brigitte I Frohnert  16 , Markus Lundgren  6 , Anette-Gabriele Ziegler  6   7   8 , William Hagopian  15 , Riitta Veijola  17 , Marian Rewers; T1DI Study Group
Affiliations

Islet Autoimmunity and HLA Markers of Presymptomatic and Clinical Type 1 Diabetes: Joint Analyses of Prospective Cohort Studies in Finland, Germany, Sweden, and the U.S

Vibha Anand et al. Diabetes Care. .

Abstract

Objective: To combine prospective cohort studies, by including HLA harmonization, and estimate risk of islet autoimmunity and progression to clinical diabetes.

Research design and methods: For prospective cohorts in Finland, Germany, Sweden, and the U.S., 24,662 children at increased genetic risk for development of islet autoantibodies and type 1 diabetes have been followed. Following harmonization, the outcomes were analyzed in 16,709 infants-toddlers enrolled by age 2.5 years.

Results: In the infant-toddler cohort, 1,413 (8.5%) developed at least one autoantibody confirmed at two or more consecutive visits (seroconversion), 865 (5%) developed multiple autoantibodies, and 655 (4%) progressed to diabetes. The 15-year cumulative incidence of diabetes varied in children with one, two, or three autoantibodies at seroconversion: 45% (95% CI 40-52), 85% (78-90), and 92% (85-97), respectively. Among those with a single autoantibody, status 2 years after seroconversion predicted diabetes risk: 12% (10-25) if reverting to autoantibody negative, 30% (20-40) if retaining a single autoantibody, and 82% (80-95) if developing multiple autoantibodies. HLA-DR-DQ affected the risk of confirmed seroconversion and progression to diabetes in children with stable single-autoantibody status. Their 15-year diabetes incidence for higher- versus lower-risk genotypes was 40% (28-50) vs. 12% (5-38). The rate of progression to diabetes was inversely related to age at development of multiple autoantibodies, ranging from 20% per year to 6% per year in children developing multipositivity in ≤2 years or >7.4 years, respectively.

Conclusions: The number of islet autoantibodies at seroconversion reliably predicts 15-year type 1 diabetes risk. In children retaining a single autoantibody, HLA-DR-DQ genotypes can further refine risk of progression.

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Figures

Figure 1
Figure 1
A: Cumulative incidence of confirmed seroconversion to a single islet autoantibody from birth by HLA risk group in the infant-toddler cohort. B: Cumulative incidence of confirmed seroconversion to multiple islet autoantibodies from birth by HLA risk group in the infant-toddler cohort. C: Cumulative incidence of type 1 diabetes from birth by HLA risk group in the infant-toddler cohort.
Figure 2
Figure 2
A: Cumulative incidence of type 1 diabetes by the number of positive islet autoantibodies (IA) (one, two, or three) at confirmed seroconversion in the infant-toddler cohort. B: Cumulative incidence of type 1 diabetes among subjects with a single autoantibody at confirmed seroconversion in the infant-toddler cohort. C: Cumulative incidence of type 1 diabetes by HLA risk group among subjects with a stable single autoantibody (S-S) 2 years postseroconversion in the infant-toddler cohort.
See this image and copyright information in PMC

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