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Gestational respiratory infections interacting with offspring HLA and CTLA-4 modifies incident β-cell autoantibodies.
J Autoimmun. 2018 01; 86:93-103.JA

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.

Authors+Show Affiliations

Health Informatics Institute, Morsani College of Medicine, University of South Florida, Tampa, FL, USA. Electronic address: Kristian.Lynch@epi.usf.edu.Health Informatics Institute, Morsani College of Medicine, University of South Florida, Tampa, FL, USA.Department of Clinical Sciences Malmö, Lund University/CRC, Skåne University Hospital SUS, Malmö, Sweden.Health Informatics Institute, Morsani College of Medicine, University of South Florida, Tampa, FL, USA.Health Informatics Institute, Morsani College of Medicine, University of South Florida, Tampa, FL, USA.Department of Clinical Sciences Malmö, Lund University/CRC, Skåne University Hospital SUS, Malmö, Sweden.Department of Pediatrics, University of Florida Gainesville, Gainesville, FL, USA.Pacific Northwest Diabetes Research Institute, Seattle, WA, USA.Barbara Davis Center for Childhood Diabetes, University of Colorado, Aurora, CO, USA.Center for Biotechnology and Genomic Medicine, Medical College of Georgia, Augusta University, Augusta, GA, USA.Department of Pediatrics, Turku University Hospital, Turku, Finland.Department of Pediatrics, Turku University Hospital, Turku, Finland; Department of Physiology, Institute of Biomedicine, University of Turku, Turku, Finland.Institute of Diabetes Research, Helmholtz Zentrum München, Neuherberg, Germany; Klinikum rechts der Isar, Technische Universität München, Neuherberg, Germany; Forschergruppe Diabetes e.V., Neuherberg, Germany.National Institute of Diabetes & Digestive & Kidney Diseases, Bethesda, MD, USA.Department of Virology, Faculty of Medicine and Lifesciences, University of Tampere, Tampere, Finland; Fimlab Laboratories, Pirkannmaa Hospital District, Tampere, Finland.Center for Regenerative Therapies Dresden, Dresden University of Technology, Dresden, Germany.Department of Clinical Sciences Malmö, Lund University/CRC, Skåne University Hospital SUS, Malmö, Sweden.No affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

28941965

Citation

Lynch, Kristian F., et al. "Gestational Respiratory Infections Interacting With Offspring HLA and CTLA-4 Modifies Incident Β-cell Autoantibodies." Journal of Autoimmunity, vol. 86, 2018, pp. 93-103.
Lynch KF, Lee HS, Törn C, et al. Gestational respiratory infections interacting with offspring HLA and CTLA-4 modifies incident β-cell autoantibodies. J Autoimmun. 2018;86:93-103.
Lynch, K. F., Lee, H. S., Törn, C., Vehik, K., Krischer, J. P., Larsson, H. E., Haller, M. J., Hagopian, W. A., Rewers, M. J., She, J. X., Simell, O. G., Toppari, J., Ziegler, A. G., Akolkar, B., Hyöty, H., Bonifacio, E., & Lernmark, Å. (2018). Gestational respiratory infections interacting with offspring HLA and CTLA-4 modifies incident β-cell autoantibodies. Journal of Autoimmunity, 86, 93-103. https://doi.org/10.1016/j.jaut.2017.09.005
Lynch KF, et al. Gestational Respiratory Infections Interacting With Offspring HLA and CTLA-4 Modifies Incident Β-cell Autoantibodies. J Autoimmun. 2018;86:93-103. PubMed PMID: 28941965.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Gestational respiratory infections interacting with offspring HLA and CTLA-4 modifies incident β-cell autoantibodies. AU - Lynch,Kristian F, AU - Lee,Hye-Seung, AU - Törn,Carina, AU - Vehik,Kendra, AU - Krischer,Jeffrey P, AU - Larsson,Helena Elding, AU - Haller,Michael J, AU - Hagopian,William A, AU - Rewers,Marian J, AU - She,Jin-Xiong, AU - Simell,Olli G, AU - Toppari,Jorma, AU - Ziegler,Anette-G, AU - Akolkar,Beena, AU - Hyöty,Heikki, AU - Bonifacio,Ezio, AU - Lernmark,Åke, AU - ,, Y1 - 2017/09/21/ PY - 2017/08/13/received PY - 2017/09/06/revised PY - 2017/09/11/accepted PY - 2017/9/25/pubmed PY - 2019/4/9/medline PY - 2017/9/25/entrez KW - Autoimmune diabetes KW - Autoimmunity KW - Glutamic acid decarboxylase KW - HLA KW - IA-2 KW - Insulin KW - Type 1 diabetes KW - β-cell autoantibodies SP - 93 EP - 103 JF - Journal of autoimmunity JO - J Autoimmun VL - 86 N2 - 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. SN - 1095-9157 UR - https://www.unboundmedicine.com/medline/citation/28941965/Gestational_respiratory_infections_interacting_with_offspring_HLA_and_CTLA_4_modifies_incident_β_cell_autoantibodies_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0896-8411(17)30558-9 DB - PRIME DP - Unbound Medicine ER -