TY - JOUR
T1 - Co-occurrence of type 1 diabetes and celiac disease autoimmunity
AU - Hagopian, William
AU - Lee, Hye Seung
AU - Liu, Edwin
AU - Rewers, Marian
AU - She, Jin Xiong
AU - Ziegler, Anette G.
AU - Lernmark, Ake
AU - Toppari, Jorma
AU - Rich, Stephen S.
AU - Krischer, Jeffrey P.
AU - Erlich, Henry
AU - Akolkar, Beena
AU - Agardh, Daniel
N1 - Funding Information:
and supervise the single-nucleotide polymorphism genotyping effort, secured the funding, and reviewed and revised the manuscript; Dr Krischer helped conceptualize and design the study, secured funding, coordinated the study and its central data storage, and reviewed and revised the manuscript; Dr Erlich helped conceptualize, design, and conduct the HLA antigen genotyping effort and reviewed and revised the manuscript; Dr Akolkar helped conceptualize, design, and fund the study, coordinated the genetic typing parts of the study, and reviewed and revised the manuscript; each author has participated sufficiently in the work to take public responsibility for appropriate portions of the content; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work. doi: https://doi.org/10.1542/peds.2017-1305 Accepted for publication Aug 11, 2017 Address correspondence to William Hagopian, MD, PhD, Pacific Northwest Research Institute, 720 Broadway, Seattle, WA 98122. E-mail: wah@uw.edu PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Copyright © 2017 by the American Academy of Pediatrics FinanciaL discLosuRe: The authors have indicated they have no financial relationships relevant to this article to disclose. FundinG: Funded by DK 63829, 63861, 63821, 63865, 63863, 63836, 63790 and UC4DK095300 and Contract HHSN267200700014C from the National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Allergy and Infectious Diseases, National Institute of Child Health and Human Development, National Institute of Environmental Health Sciences, Juvenile Diabetes Research Foundation, and Centers for Disease Control and Prevention. 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. 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). Funded by the National Institutes of Health (NIH).
Publisher Copyright:
Copyright © 2017 by the American Academy of Pediatrics.
PY - 2017/11
Y1 - 2017/11
N2 - BACKGROUND AND OBJECTIVES: Few birth cohorts have prospectively followed development of type 1 diabetes (T1D) and celiac disease (CD) autoimmunities to determine timing, extent of co-occurrence, and associated genetic and demographic factors. METHODS: In this prospective birth cohort study, 8676 children at high genetic risk of both diseases were enrolled and 5891 analyzed in median follow-up of 66 months. Along with demographic factors and HLA-DR-DQ, genotypes for HLA-DPB1 and 5 non-HLA loci conferring risk of both T1D and CD were analyzed. RESULTS: Development of persistent islet autoantibodies (IAs) and tissue transglutaminase autoantibodies (tTGAs), as well as each clinical disease, was evaluated quarterly from 3 to 48 months of age and semiannually thereafter. IAs alone appeared in 367, tTGAs alone in 808, and both in 90 children. Co-occurrence significantly exceeded the expected rate. IAs usually, but not always, appeared earlier than tTGAs. IAs preceding tTGAs was associated with increasing risk of tTGAs (hazard ratio [HR]: 1.48; 95% confidence interval [CI]: 1.15- 1.91). After adjusting for country, sex, family history, and all other genetic loci, significantly greater co-occurrence was observed in children with a T1D family history (HR: 2.80), HLA-DR3/4 (HR: 1.94) and single-nucleotide polymorphism rs3184504 at SH2B3 (HR: 1.53). However, observed co-occurrence was not fully accounted for by all analyzed factors. CONCLUSIONS: In early childhood, T1D autoimmunity usually precedes CD autoimmunity. Preceding IAs significantly increases the risk of subsequent tTGAs. Co-occurrence is greater than explained by demographic factors and extensive genetic risk loci, indicating that shared environmental or pathophysiological mechanisms may contribute to the increased risk.
AB - BACKGROUND AND OBJECTIVES: Few birth cohorts have prospectively followed development of type 1 diabetes (T1D) and celiac disease (CD) autoimmunities to determine timing, extent of co-occurrence, and associated genetic and demographic factors. METHODS: In this prospective birth cohort study, 8676 children at high genetic risk of both diseases were enrolled and 5891 analyzed in median follow-up of 66 months. Along with demographic factors and HLA-DR-DQ, genotypes for HLA-DPB1 and 5 non-HLA loci conferring risk of both T1D and CD were analyzed. RESULTS: Development of persistent islet autoantibodies (IAs) and tissue transglutaminase autoantibodies (tTGAs), as well as each clinical disease, was evaluated quarterly from 3 to 48 months of age and semiannually thereafter. IAs alone appeared in 367, tTGAs alone in 808, and both in 90 children. Co-occurrence significantly exceeded the expected rate. IAs usually, but not always, appeared earlier than tTGAs. IAs preceding tTGAs was associated with increasing risk of tTGAs (hazard ratio [HR]: 1.48; 95% confidence interval [CI]: 1.15- 1.91). After adjusting for country, sex, family history, and all other genetic loci, significantly greater co-occurrence was observed in children with a T1D family history (HR: 2.80), HLA-DR3/4 (HR: 1.94) and single-nucleotide polymorphism rs3184504 at SH2B3 (HR: 1.53). However, observed co-occurrence was not fully accounted for by all analyzed factors. CONCLUSIONS: In early childhood, T1D autoimmunity usually precedes CD autoimmunity. Preceding IAs significantly increases the risk of subsequent tTGAs. Co-occurrence is greater than explained by demographic factors and extensive genetic risk loci, indicating that shared environmental or pathophysiological mechanisms may contribute to the increased risk.
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U2 - 10.1542/peds.2017-1305
DO - 10.1542/peds.2017-1305
M3 - Article
C2 - 29018046
AN - SCOPUS:85033597277
SN - 0031-4005
VL - 140
JO - Pediatrics
JF - Pediatrics
IS - 5
M1 - e20171305
ER -
