Department of Child and Adolescent Psychiatry/Psychology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands; The Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands.
Department of Child and Adolescent Psychiatry/Psychology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands; The Generation R Study Group, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands; Department of Clinical, Educational & Health Psychology, Division of Psychology & Language Sciences, Faculty of Brain Sciences, University College London, London, UK.
Brain Behav Immun. 2024 Nov;122:483-496. doi: 10.1016/j.bbi.2024.08.053. Epub 2024 Aug 29.
DNA methylation levels at specific sites can be used to proxy C-reactive protein (CRP) levels, providing a potentially more stable and accurate indicator of sustained inflammation and associated health risk. However, its use has been primarily limited to adults or preterm infants, and little is known about determinants for - or offspring outcomes of - elevated levels of this epigenetic proxy in cord blood. The aim of this study was to comprehensively map prenatal predictors and long-term neurobehavioral outcomes of neonatal inflammation, as assessed with an epigenetic proxy of inflammation in cord blood, in the general pediatric population.
Our study was embedded in the prospective population-based Generation R Study (n = 2,394). We created a methylation profile score of CRP (MPS-CRP) in cord blood as a marker of neonatal inflammation and validated it against serum CRP levels in mothers during pregnancy, as well as offspring at birth and in childhood. We then examined (i) which factors (previously associated with sustained inflammation) explain variability in MPS-CRP at birth, including a wide range of prenatal lifestyle and clinical conditions, pro-inflammatory exposures, as well as child genetic liability to elevated CRP levels; and (ii) whether MPS-CRP at birth associates with child neurobehavioral outcomes, including global structural MRI and DTI measures (child mean age 10 and 14 years) as well as psychiatric symptoms over time (Child Behavioral Checklist, at mean age 1.5, 3, 6, 10 and 14 years).
MPS-CRP at birth was validated with serum CRP in cord blood (cut-off > 1 mg/L) (AUC = 0.72). Prenatal lifestyle pro-inflammatory factors explained a small part (i.e., < 5%) of the variance in the MPS-CRP at birth. No other prenatal predictor or the polygenic score of CRP in the child explained significant variance in the MPS-CRP at birth. The MPS-CRP at birth prospectively associated with a reduction in global fractional anisotropy over time on mainly a nominal threshold (β = -0.014, SE = 0.007, p = 0.032), as well as showing nominal associations with structural differences (amygdala [(β = 0.016, SE = 0.006, p = 0.010], cerebellum [(β = -0.007, SE = 0.003, p = 0.036]). However, no associations with child psychiatric symptoms were observed.
Prenatal exposure to lifestyle-related pro-inflammatory factors was the only prenatal predictor that accounted for some of the individual variability in MPS-CRP levels at birth. Further, while the MPS-CRP prospectively associated with white matter alterations over time, no associations were observed at the behavioral level. Thus, the relevance and potential utility of using epigenetic data as a marker of neonatal inflammation in the general population remain unclear. In the future, the use of epigenetic proxies for a wider range of immune markers may lend further insights into the relationship between neonatal inflammation and adverse neurodevelopment within the general pediatric population.
特定部位的 DNA 甲基化水平可用于替代 C 反应蛋白（CRP）水平，为持续炎症及其相关健康风险提供更稳定和准确的指标。然而，其应用主要局限于成年人或早产儿，对于脐带血中这种表观遗传替代物升高的决定因素或后代结局知之甚少。本研究旨在全面描绘儿科人群中，以脐带血中炎症的表观遗传替代物评估的新生儿炎症的产前预测因子和长期神经行为结局。
我们的研究嵌入在前瞻性基于人群的 Generation R 研究（n=2394）中。我们在脐带血中创建了 CRP 的甲基化谱评分（MPS-CRP），作为新生儿炎症的标志物，并在怀孕期间、出生时和儿童期对其与母亲血清 CRP 水平以及后代进行了验证。然后，我们研究了（i）哪些因素（先前与持续炎症相关）可以解释出生时 MPS-CRP 的变异性，包括广泛的产前生活方式和临床状况、促炎暴露以及儿童 CRP 水平升高的遗传易感性；以及（ii）出生时的 MPS-CRP 是否与儿童神经行为结局相关，包括全球结构 MRI 和 DTI 测量（儿童平均年龄为 10 岁和 14 岁）以及随时间变化的精神症状（儿童行为检查表，平均年龄为 1.5 岁、3 岁、6 岁、10 岁和 14 岁）。
MPS-CRP 在出生时与脐带血中的 CRP 血清（cut-off>1mg/L）相验证（AUC=0.72）。产前生活方式促炎因素解释了出生时 MPS-CRP 变异性的一小部分（即<5%）。出生时 MPS-CRP 没有其他产前预测因子或儿童 CRP 的多基因评分可以解释。出生时的 MPS-CRP 与全球各向异性分数随时间的减少呈负相关（β=-0.014，SE=0.007，p=0.032），并且在名义阈值上与结构差异呈显著关联（杏仁核[β=0.016，SE=0.006，p=0.010]，小脑[β=-0.007，SE=0.003，p=0.036]）。然而，没有观察到与儿童精神症状的关联。
产前暴露于与生活方式相关的促炎因素是唯一可以解释出生时 MPS-CRP 水平个体差异的产前预测因子。此外，尽管 MPS-CRP 与随时间变化的白质改变呈负相关，但在行为水平上未观察到相关性。因此，在一般人群中使用表观遗传数据作为新生儿炎症标志物的相关性和潜在效用仍不清楚。未来，使用针对更广泛免疫标志物的表观遗传替代物可能会进一步深入了解新生儿炎症与一般儿科人群中不良神经发育之间的关系。
