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

Lynch, Kristian F. LU ; Lee, Hye-Seung; Törn, Carina LU ; Vehik, Kendra LU ; Krischer, Jeffrey P.; Larsson, Helena Elding LU ; Haller, Michael J; Hagopian, William A.; Rewers, Marian J. and She, Jin-Xiong, et al. (2018) In Journal of Autoimmunity 86. p.93-103
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... (More)

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.

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published
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keywords
Autoimmune diabetes, Autoimmunity, Glutamic acid decarboxylase, HLA, IA-2, Insulin, Type 1 diabetes, β-cell autoantibodies
in
Journal of Autoimmunity
volume
86
pages
93 - 103
publisher
Elsevier
external identifiers
  • scopus:85029634260
ISSN
0896-8411
DOI
10.1016/j.jaut.2017.09.005
language
English
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yes
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eb0dc24c-1c95-49fa-b51f-fe0d4ce3b840
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2017-10-10 13:10:13
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2018-01-29 14:03:12
@article{eb0dc24c-1c95-49fa-b51f-fe0d4ce3b840,
  abstract     = {<p>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.</p>},
  author       = {Lynch, Kristian F. and Lee, Hye-Seung and Törn, Carina and Vehik, Kendra 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 Toppari, Jorma and Ziegler, Anette G. and Akolkar, Beena and Hyöty, Heikki and Bonifacio, Ezio and Lernmark, Åke and , },
  issn         = {0896-8411},
  keyword      = {Autoimmune diabetes,Autoimmunity,Glutamic acid decarboxylase,HLA,IA-2,Insulin,Type 1 diabetes,β-cell autoantibodies},
  language     = {eng},
  pages        = {93--103},
  publisher    = {Elsevier},
  series       = {Journal of Autoimmunity},
  title        = {Gestational respiratory infections interacting with offspring HLA and CTLA-4 modifies incident β-cell autoantibodies},
  url          = {http://dx.doi.org/10.1016/j.jaut.2017.09.005},
  volume       = {86},
  year         = {2018},
}