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Hierarchical Order of Distinct Autoantibody Spreading and Progression to Type 1 Diabetes in the TEDDY Study

Vehik, Kendra LU ; Bonifacio, Ezio ; Lernmark, Ake LU ; Yu, Liping ; Williams, Alistair ; Schatz, Desmond ; Rewers, Marian ; She, Jin-Xiong ; Toppari, Jorma and Hagopian, William , et al. (2020) In Diabetes Care 43(9). p.2066-2073
Abstract

OBJECTIVE: The first-appearing β-cell autoantibody has been shown to influence risk of type 1 diabetes (T1D). Here, we assessed the 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.

RESEARCH DESIGN AND METHODS: Eligible children with increased HLA-DR-DQ genetic risk for T1D were followed quarterly from age 3 months up to 15 years for development of a single first-appearing autoantibody (GAD antibody [GADA], insulin autoantibody [IAA], or IA2 autoantibody [IA-2A]) and subsequent development of a single second-appearing autoantibody and progression to T1D. Autoantibody positivity was defined as positivity... (More)

OBJECTIVE: The first-appearing β-cell autoantibody has been shown to influence risk of type 1 diabetes (T1D). Here, we assessed the 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.

RESEARCH DESIGN AND METHODS: Eligible children with increased HLA-DR-DQ genetic risk for T1D were followed quarterly from age 3 months up to 15 years for development of a single first-appearing autoantibody (GAD antibody [GADA], insulin autoantibody [IAA], or IA2 autoantibody [IA-2A]) and subsequent development of a single second-appearing autoantibody and progression to T1D. Autoantibody positivity was defined as positivity for a specific autoantibody at two consecutive visits confirmed in two laboratories. Zinc transporter 8 autoantibody (ZnT8A) was measured in children who developed another autoantibody.

RESULTS: 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 hazard ratio [HR] = 1.12, 95% CI = 0.88-1.42, P = 0.36). Second-appearing GADA, IAA, IA-2A, or ZnT8A conferred an increased risk of T1D compared with children who remained positive for a single autoantibody, e.g., 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; P < 0.0001), or ZnT8A second (adjusted HR 5.35; 95% CI 2.61-10.95; P < 0.0001). In children who developed a distinct second autoantibody, IA-2A (adjusted HR = 3.08; 95% CI = 2.04-4.65; P < 0.0001) conferred a greater risk of progression to T1D as compared with 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 T1D.

CONCLUSIONS: The hierarchical order of distinct autoantibody spreading was independent of the first-appearing autoantibody type and was age-dependent and augmented the risk of progression to T1D.

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type
Contribution to journal
publication status
published
subject
in
Diabetes Care
volume
43
issue
9
pages
2066 - 2073
publisher
American Diabetes Association
external identifiers
  • pmid:32641373
  • scopus:85090043666
ISSN
1935-5548
DOI
10.2337/dc19-2547
language
English
LU publication?
yes
additional info
© 2020 by the American Diabetes Association.
id
aa449e13-e9ee-49e9-839e-96524d91e9ae
date added to LUP
2020-07-10 18:09:06
date last changed
2020-09-25 11:14:16
@article{aa449e13-e9ee-49e9-839e-96524d91e9ae,
  abstract     = {<p>OBJECTIVE: The first-appearing β-cell autoantibody has been shown to influence risk of type 1 diabetes (T1D). Here, we assessed the 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><p>RESEARCH DESIGN AND METHODS: Eligible children with increased HLA-DR-DQ genetic risk for T1D were followed quarterly from age 3 months up to 15 years for development of a single first-appearing autoantibody (GAD antibody [GADA], insulin autoantibody [IAA], or IA2 autoantibody [IA-2A]) and subsequent development of a single second-appearing autoantibody and progression to T1D. Autoantibody positivity was defined as positivity for a specific autoantibody at two consecutive visits confirmed in two laboratories. Zinc transporter 8 autoantibody (ZnT8A) was measured in children who developed another autoantibody.</p><p>RESULTS: 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 hazard ratio [HR] = 1.12, 95% CI = 0.88-1.42, P = 0.36). Second-appearing GADA, IAA, IA-2A, or ZnT8A conferred an increased risk of T1D compared with children who remained positive for a single autoantibody, e.g., 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; P &lt; 0.0001), or ZnT8A second (adjusted HR 5.35; 95% CI 2.61-10.95; P &lt; 0.0001). In children who developed a distinct second autoantibody, IA-2A (adjusted HR = 3.08; 95% CI = 2.04-4.65; P &lt; 0.0001) conferred a greater risk of progression to T1D as compared with 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 T1D.</p><p>CONCLUSIONS: The hierarchical order of distinct autoantibody spreading was independent of the first-appearing autoantibody type and was age-dependent and augmented the risk of progression to T1D.</p>},
  author       = {Vehik, Kendra and Bonifacio, Ezio and Lernmark, Ake and Yu, Liping and Williams, Alistair and Schatz, Desmond and Rewers, Marian and She, Jin-Xiong and Toppari, Jorma and Hagopian, William and Akolkar, Beena and Ziegler, Anette G and Krischer, Jeffrey P},
  issn         = {1935-5548},
  language     = {eng},
  month        = {07},
  number       = {9},
  pages        = {2066--2073},
  publisher    = {American Diabetes Association},
  series       = {Diabetes Care},
  title        = {Hierarchical Order of Distinct Autoantibody Spreading and Progression to Type 1 Diabetes in the TEDDY Study},
  url          = {http://dx.doi.org/10.2337/dc19-2547},
  doi          = {10.2337/dc19-2547},
  volume       = {43},
  year         = {2020},
}