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Johnson, S.B.* ; Lynch, K.F.* ; Roth, R.* ; Lundgren, M.* ; Parikh, H.M.* ; Akolkar, B.* ; Hagopian, W.* ; Krischer, J.* ; Rewers, M.* ; She, J.X.* ; Toppari, J.* ; Ziegler, A.-G. ; Lernmark, Å.*

First-appearing islet autoantibodies for type 1 diabetes in young children: Maternal life events during pregnancy and the child’s genetic risk.

Diabetologia 64, 591-602 (2021)
Postprint DOI PMC
Open Access Green
Aims/hypothesis: Psychological stress has long been considered a possible trigger of type 1 diabetes, although prospective studies examining the link between psychological stress or life events during pregnancy and the child’s type 1 diabetes risk are rare. The objective of this study was to examine the association between life events during pregnancy and first-appearing islet autoantibodies (IA) in young children, conditioned by the child’s type 1 diabetes-related genetic risk. Methods: The IA status of 7317 genetically at-risk The Environmental Determinants of Diabetes in the Young (TEDDY) participants was assessed every 3 months from 3 months to 4 years, and bi-annually thereafter. Reports of major life events during pregnancy were collected at study inception when the child was 3 months of age and placed into one of six categories. Life events during pregnancy were examined for association with first-appearing insulin (IAA) (N = 222) or GAD (GADA) (N = 209) autoantibodies in the child until 6 years of age using proportional hazard models. Relative excess risk due to interaction (RERI) by the child’s HLA-DR and SNP profile was estimated. Results: Overall, 65% of mothers reported a life event during pregnancy; disease/injury (25%), serious interpersonal (28%) and job-related (25%) life events were most common. The association of life events during pregnancy differed between IAA and GADA as the first-appearing autoantibody. Serious interpersonal life events correlated with increased risk of GADA-first only in HLA-DR3 children with the BACH2-T allele (HR 2.28, p < 0.0001), an additive interaction (RERI 1.87, p = 0.0004). Job-related life events were also associated with increased risk of GADA-first among HLA-DR3/4 children (HR 1.53, p = 0.04) independent of serious interpersonal life events (HR 1.90, p = 0.002), an additive interaction (RERI 1.19, p = 0.004). Job-related life events correlated with reduced risk of IAA-first (HR 0.55, p = 0.004), particularly in children with the BTNL2-GG allele (HR 0.48; 95% CI 0.31, 0.76). Conclusions/interpretation: Specific life events during pregnancy are differentially related to IAA vs GADA as first-appearing IA and interact with different HLA and non-HLA genetic factors, supporting the concept of different endotypes underlying type 1 diabetes. However, the mechanisms underlying these associations remain to be discovered. Life events may be markers for other yet-to-be-identified factors important to the development of first-appearing IA. Graphical abstract: [Figure not available: see fulltext.]
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords Bach2 Single Nucleotide Polymorphism ; Btnl2 Single Nucleotide Polymorphism ; Gad Autoantibodies ; Hla-dr-dq Haplogenotype ; Insulin Autoantibodies ; Islet Autoimmunity ; Prenatal Life Events ; Psychosocial Stress ; Type 1 Diabetes; Genome-wide Association; Environmental Determinants; Rheumatoid-arthritis; Cell; Stress; Bach2; Autoimmunity; Experiences; Prediction; Btnl2
ISSN (print) / ISBN 0012-186X
e-ISSN 1432-0428
Journal Diabetologia
Quellenangaben Volume: 64, Issue: 3, Pages: 591-602 Article Number: , Supplement: ,
Publisher Springer
Publishing Place Berlin ; Heidelberg [u.a.]
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Diabetes Research Type 1 (IDF)
Grants NIH/NCATS Clinical and Translational Science Awards
JDRF
Centers for Disease Control and Prevention (CDC)
National Institute of Environmental Health Sciences (NIEHS)
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
National Institute of Allergy and Infectious Diseases (NIAID)
National Institute of Diabetes and Digestive and Kidney diseases (NIDDK)