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J Autoimmun. 2018 Jan;86:93-103. doi: 10.1016/j.jaut.2017.09.005. Epub 2017 Sep 21.

Gestational respiratory infections interacting with offspring HLA and CTLA-4 modifies incident β-cell autoantibodies.

Author information

1
Health Informatics Institute, Morsani College of Medicine, University of South Florida, Tampa, FL, USA. Electronic address: Kristian.Lynch@epi.usf.edu.
2
Health Informatics Institute, Morsani College of Medicine, University of South Florida, Tampa, FL, USA.
3
Department of Clinical Sciences Malmö, Lund University/CRC, Skåne University Hospital SUS, Malmö, Sweden.
4
Department of Pediatrics, University of Florida Gainesville, Gainesville, FL, USA.
5
Pacific Northwest Diabetes Research Institute, Seattle, WA, USA.
6
Barbara Davis Center for Childhood Diabetes, University of Colorado, Aurora, CO, USA.
7
Center for Biotechnology and Genomic Medicine, Medical College of Georgia, Augusta University, Augusta, GA, USA.
8
Department of Pediatrics, Turku University Hospital, Turku, Finland.
9
Department of Pediatrics, Turku University Hospital, Turku, Finland; Department of Physiology, Institute of Biomedicine, University of Turku, Turku, Finland.
10
Institute of Diabetes Research, Helmholtz Zentrum München, Neuherberg, Germany; Klinikum rechts der Isar, Technische Universität München, Neuherberg, Germany; Forschergruppe Diabetes e.V., Neuherberg, Germany.
11
National Institute of Diabetes & Digestive & Kidney Diseases, Bethesda, MD, USA.
12
Department of Virology, Faculty of Medicine and Lifesciences, University of Tampere, Tampere, Finland; Fimlab Laboratories, Pirkannmaa Hospital District, Tampere, Finland.
13
Center for Regenerative Therapies Dresden, Dresden University of Technology, Dresden, Germany.

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

PMID:
28941965
PMCID:
PMC5747989
[Available on 2019-01-01]
DOI:
10.1016/j.jaut.2017.09.005

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