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

Abstract

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. 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\u2009=\u2009222) or GAD (GADA) (N\u2009=\u2009209) 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. 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\u2009<\u20090.0001), an additive interaction (RERI 1.87, p\u2009=\u20090.0004). Job-related life events were also associated with increased risk of GADA-first among HLA-DR3/4 children (HR 1.53, p\u2009=\u20090.04) independent of serious interpersonal life events (HR 1.90, p\u2009=\u20090.002), an additive interaction (RERI 1.19, p\u2009=\u20090.004). Job-related life events correlated with reduced risk of IAA-first (HR 0.55, p\u2009=\u20090.004), particularly in children with the BTNL2-GG allele (HR 0.48; 95% CI 0.31, 0.76). 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.