Gestational respiratory infections interacting with offspring HLA and CTLA-4 modifies incident β-cell autoantibodies
(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.
(Less)
- author
- author collaboration
- organization
- publishing date
- 2018
- type
- Contribution to journal
- publication status
- published
- subject
- 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
- pmid:28941965
- ISSN
- 0896-8411
- DOI
- 10.1016/j.jaut.2017.09.005
- language
- English
- LU publication?
- yes
- id
- eb0dc24c-1c95-49fa-b51f-fe0d4ce3b840
- date added to LUP
- 2017-10-10 13:10:13
- date last changed
- 2024-09-16 10:12:08
@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}}, issn = {{0896-8411}}, keywords = {{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}}, doi = {{10.1016/j.jaut.2017.09.005}}, volume = {{86}}, year = {{2018}}, }