Hierarchical order of distinct autoantibody spreading and progression to type 1 diabetes in the TEDDY Study
figure
posted on 2020-07-08, 20:25 authored by Kendra Vehik, Ezio Bonifacio, Ake Lernmark, Liping Yu, Alistair Williams, Desmond Schatz, Marian Rewers, Jin-Xiong She, Jorma Toppari, William Hagopian, Beena Akolkar, Anette G. Ziegler, Jeffrey P. Krischer, the TEDDY Study Group<b>Objective:</b>
The first-appearing β-cell
autoantibody has been shown to influence risk of type 1 diabetes. Here, we
assessed risk of autoantibody spreading to the second-appearing autoantibody
and further progression to clinical disease in the Environmental Determinants
of Diabetes in the Young study.
<p><b>Research Design and
Methods:</b> Eligible children with increased HLA-DR-DQ genetic
risk for type 1 diabetes were followed quarterly from age 3 months up to 15
years for development of a single first-appearing autoantibody (GADA, IAA or
IA-2A) and subsequent development of a single second-appearing autoantibody and
progression to type 1 diabetes. Autoantibody positivity was defined as
positivity for a specific autoantibody at two consecutive visits confirmed in
two laboratories. ZnT8A was measured in
children who developed another autoantibody.</p>
<p><b>Results:</b>
There were 608 children who developed a single first-appearing autoantibody (IAA,
n=282 or GADA, n=326) with a median follow-up of 12.5 years from birth. The
risk of a second-appearing autoantibody was independent of GADA versus IAA as a
first-appearing autoantibody (adjusted-HR=1.12, 95%CI=0.88-1.42, <i>P</i>=0.36). Second-appearing GADA, IAA, IA-2A or
ZnT8A conferred an increased risk of type 1 diabetes compared to children who remained single autoantibody
positive (IAA- or GADA-second: adjusted-HR=6.44 95%CI=3.78-10.98; IA-2A-second:
adjusted-HR=16.33 95%CI=9.10-29.29,<i> P</i><0.0001;
ZnT8A-second: adjusted-HR=5.35 95%CI=2.61-10.95, <i>P</i><0.0001). In children
who developed a distinct second autoantibody, IA-2A (adjusted-HR=3.08
95%CI=2.04-4.65, <i>P</i><0.0001)
conferred a greater risk of progression to type 1 diabetes as compared to GADA
or IAA. Additionally, both a younger initial age at seroconversion and shorter
time to the development of the second-appearing autoantibody increased the risk
for type 1 diabetes.</p>
<p><b>Conclusions:</b>
The hierarchical order of distinct autoantibody spreading was independent of
the first-appearing autoantibody type, age-dependent and augmented the risk of
progression to type 1 diabetes.<br>
</p>
Funding
Funded by U01 DK63829, U01 DK63861, U01 DK63821, U01 DK63865, U01 DK63863, U01 DK63836, U01 DK63790, UC4 DK63829, UC4 DK63861, UC4 DK63821, UC4 DK63865, UC4 DK63863, UC4 DK63836, UC4 DK95300, UC4 DK100238, UC4 DK106955, UC4 DK112243, UC4 DK117483, and Contract No. HHSN267200700014C from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institute of Allergy and Infectious Diseases (NIAID), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institute of Environmental Health Sciences (NIEHS), Juvenile Diabetes Research Foundation (JDRF), and Centers for Disease Control and Prevention (CDC). This work supported in part by the NIH/NCATS Clinical and Translational Science Awards to the University of Florida (UL1 TR000064) and the University of Colorado (UL1 TR001082).
History
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