@article{ef000953ceca4b7ca18201dbaddf57a1,
title = "Gestational respiratory infections interacting with offspring HLA and CTLA-4 modifies incident β-cell autoantibodies",
abstract = "β-cell autoantibodies against insulin (IAA), GAD65 (GADA) and IA-2 (IA-2A) precede onset of childhood type 1 diabetes (T1D). Incidence of the first appearing β-cell autoantibodies peaks at a young age and is patterned by T1D-associated genes, suggesting an early environmental influence. Here, we tested if gestational infections and interactions with child's human leukocyte antigen (HLA) and non-HLA genes affected the appearance of the first β-cell autoantibody. Singletons of mothers without diabetes (n = 7472) with T1D-associated HLA-DR-DQ genotypes were prospectively followed quarterly through the first 4 years of life, then semiannually until age 6 years, using standardized autoantibody analyses. Maternal infections during pregnancy were assessed via questionnaire 3–4.5 months post-delivery. Polymorphisms in twelve non-HLA genes associated with the first appearing β-cell autoantibodies were included in a Cox regression analysis. IAA predominated as the first appearing β-cell autoantibody in younger children (n = 226, median age at seroconversion 1.8 years) and GADA (n = 212; 3.2 years) in children aged ≥2 years. Gestational infections were not associated with the first appearing β-cell autoantibodies overall. However, gestational respiratory infections (G-RI) showed a consistent protective influence on IAA (HR 0.64, 95% CI 0.45–0.91) among CTLA4-(AG, GG) children (G-RI*CTLA4 interaction, p = 0.002). The predominant associations of HLA-DR-DQ 4-8/8-4 with IAA and HLA-DR-DQ 3-2/3-2 with GADA were not observed if a G-RI was reported (G-RI*HLA-DR-DQ interaction, p = 0.03). The role of G-RI may depend on offspring HLA and CTLA-4 alleles and supports a bidirectional trigger for IAA or GADA as a first appearing β-cell autoantibody in early life.",
keywords = "Autoimmune diabetes, Autoimmunity, Glutamic acid decarboxylase, HLA, IA-2, Insulin, Type 1 diabetes, β-cell autoantibodies",
author = "{on behalf of} and {TEDDY study group} and Lynch, {Kristian F.} and Lee, {Hye Seung} and Carina T{\"o}rn and Kendra Vehik and Krischer, {Jeffrey P.} and Larsson, {Helena Elding} and Haller, {Michael J.} and Hagopian, {William A.} and Rewers, {Marian J.} and She, {Jin Xiong} and Simell, {Olli G.} and Jorma Toppari and Ziegler, {Anette G.} and Beena Akolkar and Heikki Hy{\"o}ty and Ezio Bonifacio and {\AA}ke Lernmark",
note = "Funding Information: 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, and Contract No. HHSN267200700014C from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institute of Allergy and Infectious Diseases (NIAID), 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). Funding Information: 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 , and Contract No. HHSN267200700014C from the National Institute of Diabetes and Digestive and Kidney Diseases ( NIDDK ), National Institute of Allergy and Infectious Diseases ( NIAID ), 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 ). Publisher Copyright: {\textcopyright} 2017 Elsevier Ltd",
year = "2018",
month = jan,
doi = "10.1016/j.jaut.2017.09.005",
language = "English (US)",
volume = "86",
pages = "93--103",
journal = "Journal of Autoimmunity",
issn = "0896-8411",
publisher = "Academic Press Inc.",
}