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

TEDDY study group

Research output: Contribution to journalArticle

6 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)93-103
Number of pages11
JournalJournal of Autoimmunity
Volume86
DOIs
StatePublished - Jan 1 2018

Fingerprint

HLA Antigens
Respiratory Tract Infections
Autoantibodies
Type 1 Diabetes Mellitus
Infection
Mothers
Genes
Alleles
Genotype
Regression Analysis
Insulin
Pregnancy
Incidence

Keywords

  • Autoimmune diabetes
  • Autoimmunity
  • Glutamic acid decarboxylase
  • HLA
  • IA-2
  • Insulin
  • Type 1 diabetes
  • β-cell autoantibodies

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

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

In: Journal of Autoimmunity, Vol. 86, 01.01.2018, p. 93-103.

Research output: Contribution to journalArticle

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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",
author = "{TEDDY study group} and Lynch, {Kristian F.} and Lee, {Hye Seung} and Carina T{\"o}rn and Kendra Vehik and Krischer, {Jeffrey P.} and Larsson, {Helena Elding} and Haller, {Michael J.} and Hagopian, {William A.} and Rewers, {Marian J.} and Jin-Xiong She and Simell, {Olli G.} and Jorma Toppari and Ziegler, {Anette G.} and Beena Akolkar and Heikki Hy{\"o}ty and Ezio Bonifacio and {\AA}ke Lernmark",
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T1 - Gestational respiratory infections interacting with offspring HLA and CTLA-4 modifies incident β-cell autoantibodies

AU - TEDDY study group

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

PY - 2018/1/1

Y1 - 2018/1/1

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.

AB - 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.

KW - Autoimmune diabetes

KW - Autoimmunity

KW - Glutamic acid decarboxylase

KW - HLA

KW - IA-2

KW - Insulin

KW - Type 1 diabetes

KW - β-cell autoantibodies

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