A1 Vertaisarvioitu alkuperäisartikkeli tieteellisessä lehdessä
Gestational respiratory infections interacting with offspring HLA and CTLA-4 modifies incident β-cell autoantibodies
Tekijät: Lynch KF, Lee HS, Torn C, Vehik K, Krischer JP, Larsson HE, Haller MJ, Hagopian WA, Rewers MJ, She JX, Simell OG, Toppari J, Ziegler AG, Akolkar B, Hyoty H, Bonifacio E, Lernmark A; on behalf of TEDDY Study Group
Kustantaja: ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
Julkaisuvuosi: 2018
Journal: Journal of Autoimmunity
Tietokannassa oleva lehden nimi: JOURNAL OF AUTOIMMUNITY
Lehden akronyymi: J AUTOIMMUN
Vuosikerta: 86
Aloitussivu: 93
Lopetussivu: 103
Sivujen määrä: 11
ISSN: 0896-8411
eISSN: 1095-9157
DOI: https://doi.org/10.1016/j.jaut.2017.09.005
Tiivistelmä
beta-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 beta-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 beta-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 beta-cell autoantibodies were included in a Cox regression analysis. IAA predominated as the first appearing beta-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 beta-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-DQ4-8/8-4 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 beta-cell autoantibody in early life. (C) 2017 Elsevier Ltd. All rights reserved.
beta-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 beta-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 beta-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 beta-cell autoantibodies were included in a Cox regression analysis. IAA predominated as the first appearing beta-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 beta-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-DQ4-8/8-4 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 beta-cell autoantibody in early life. (C) 2017 Elsevier Ltd. All rights reserved.
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