Department of Behavioral Sciences and Social Medicine, Florida State University, Tallahassee, FL, USA.
Health Informatics Institute, Morsani College of Medicine, University of South Florida, Tampa, FL, USA.
Diabetologia. 2021 Mar;64(3):591-602. doi: 10.1007/s00125-020-05344-9. Epub 2021 Jan 6.
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.
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.
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.
目的/假设：心理压力一直被认为是 1 型糖尿病的一个可能诱因，尽管很少有前瞻性研究检查怀孕期间的心理压力或生活事件与儿童 1 型糖尿病风险之间的联系。本研究的目的是检验怀孕期间生活事件与儿童早期出现的胰岛自身抗体（IA）之间的关联，同时考虑到儿童的 1 型糖尿病相关遗传风险。
在儿童 3 个月大时，通过每隔 3 个月到 4 年，此后每两年进行一次检查，对 7317 名有遗传风险的 TEDDY 参与者的 IA 状态进行评估。在研究开始时，当孩子 3 个月大时，收集了怀孕期间的重大生活事件报告，并将其归入六个类别之一。使用比例风险模型，在 6 岁之前，检查怀孕期间的生活事件与儿童首次出现胰岛素（IAA）（n=222）或 GAD（GADA）（n=209）自身抗体之间的关联。根据 HLA-DR 和 SNP 特征，估计儿童的相对超额风险比（RERI）。
总体而言，65%的母亲报告了怀孕期间的生活事件；疾病/伤害（25%）、严重人际（28%）和工作相关（25%）的生活事件最为常见。怀孕期间的生活事件与 IAA 和 GADA 作为首次出现的自身抗体之间的关联不同。在 HLA-DR3 儿童中，BACH2-T 等位基因与严重人际生活事件相关，增加了 GADA 首次出现的风险（HR 2.28，p<0.0001），表现出附加交互作用（RERI 1.87，p=0.0004）。在 HLA-DR3/4 儿童中，工作相关生活事件也与 GADA 首次出现的风险增加相关（HR 1.53，p=0.04），与严重人际生活事件无关（HR 1.90，p=0.002），表现出附加交互作用（RERI 1.19，p=0.004）。工作相关的生活事件与 IAA 首次出现的风险降低相关（HR 0.55，p=0.004），特别是在 BTNL2-GG 等位基因的儿童中（HR 0.48；95%CI 0.31，0.76）。
结论/解释：怀孕期间的特定生活事件与 IAA 与 GADA 作为首次出现的 IA 相关，与不同的 HLA 和非 HLA 遗传因素相互作用，支持了 1 型糖尿病存在不同表型的概念。然而，这些关联的机制仍有待发现。生活事件可能是尚未确定的其他对首次出现的 IA 发展很重要的因素的标志物。
