OBJECTIVE:
To combine prospective cohort
studies, by including HLA harmonization, and to estimate risk of islet
autoimmunity and progression to clinical diabetes.
<p>RESEARCH
DESIGN AND METHODS: Prospective cohorts in Finland, Germany, Sweden and the US
have followed 24,662 children at increased genetic risk for development of
islet autoantibodies and type 1 diabetes. Following harmonization, the outcomes
were analyzed in 16,709 infants-toddlers enrolled by age 2.5 years.</p>
<p>RESULTS:
In
the infant-toddler cohort, 1413 (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 single
autoantibody, their status two years after seroconversion predicted diabetes
risk: 12% (10-25%) if reverting to autoantibody negative, 30% (20-40%) if
retaining 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. Their 15-year diabetes incidence for higher
vs. 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%/year to 6%/year in children developing multi-positivity ≤2 years or
>7.4 years, respectively. </p>
<p>CONCLUSIONS: The
number of islet autoantibodies at seroconversion reliably predicts 15-year type
1 diabetes risk. In children retaining single autoantibody, HLA-DR-DQ genotypes
can further refine risk of progression.</p>
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.
