背景:怀孕期间的感染与后代的不良身心健康结局密切相关,然而,潜在的分子途径仍然很大程度上未知。这里,我们研究了子宫内常见感染暴露是否与出生时的DNA甲基化(DNAm)模式相关,以及这是否与普通人群的后代健康结局相关.
方法:使用来自荷兰基于人口的一代R研究的2,367名儿童的数据,我们首先进行了全表观基因组关联研究,以确定出生时与产前感染暴露相关的差异甲基化位点和区域.我们还通过使用每个妊娠中期的自我报告累积感染评分来检查感染时间的影响。第二,我们试图开发一个基于脐带血DNAm的总甲基化谱评分(MPS)作为产前感染暴露的表观遗传代表,并测试了该MPS是否与后代健康结果相关,包括精神症状,BMI,13-16岁的哮喘。第三,我们调查了产前感染暴露是否与后代表观遗传年龄加速相关-这是生物衰老的标志。在所有分析步骤中,我们测试了我们的发现是否在864名来自独立人群队列的参与者中复制(ALSPAC,英国)。
结果:我们观察到脐带血中没有与产前感染暴露有关的差异甲基化部位或区域,经过多次测试校正。33个DNAm位点显示出暗示性关联(p<5e10-5;其中一个在ALSPAC中也名义上相关),表明与免疫相关基因的潜在联系,神经发育,和心血管通路。虽然产前感染的MPS与产妇内部感染报告相关,但在第R代研究中保留了样本(R2增量=0.049),它没有在ALSPAC中复制(R2增量=0.001),在这两个队列中,其与后代健康结局均无前瞻性关联.此外,我们观察到,不同队列和时钟的产前感染暴露与表观遗传年龄加速之间没有关联.
结论:与之前的研究相比,报告了在子宫内暴露于严重感染的后代的DNAm差异,在普通儿科人群中,我们没有发现自我报告的妊娠期临床明显的常见感染与脐带血中DNAm或表观遗传衰老之间存在关联的证据.需要未来的研究来确定是否存在关联,但对于目前的样本量来说,关联太微妙而没有统计学意义。他们是否在感染评分与我们的发现队列更相似的队列中复制,它们是否发生在与脐带血不同的组织中,以及其他生物学途径是否可能与介导产前常见感染暴露对下游后代健康结局的影响更相关。
BACKGROUND: Infections during pregnancy have been robustly associated with adverse mental and physical health outcomes in offspring, yet the underlying molecular pathways remain largely unknown. Here, we examined whether exposure to common infections in utero associates with DNA methylation (DNAm) patterns at birth and whether this in turn relates to offspring health outcomes in the general population.
METHODS: Using data from 2,367 children from the Dutch population-based Generation R Study, we first performed an epigenome-wide association study to identify differentially methylated sites and regions at birth associated with prenatal infection exposure. We also examined the influence of infection timing by using self-reported cumulative infection scores for each trimester. Second, we sought to develop an aggregate methylation profile score (MPS) based on cord blood DNAm as an epigenetic proxy of prenatal infection exposure and tested whether this MPS prospectively associates with offspring health outcomes, including psychiatric symptoms, BMI, and asthma at ages 13-16 years. Third, we investigated whether prenatal infection exposure associates with offspring epigenetic age acceleration - a marker of biological aging. Across all analysis steps, we tested whether our findings replicate in 864 participants from an independent population-based cohort (ALSPAC, UK).
RESULTS: We observed no differentially methylated sites or regions in cord blood in relation to prenatal infection exposure, after multiple testing correction. 33 DNAm sites showed suggestive associations (p < 5e10 - 5; of which one was also nominally associated in ALSPAC), indicating potential links to genes associated with immune, neurodevelopmental, and cardiovascular pathways. While the MPS of prenatal infections associated with maternal reports of infections in the internal hold out sample in the Generation R Study (R2incremental = 0.049), it did not replicate in ALSPAC (R2incremental = 0.001), and it did not prospectively associate with offspring health outcomes in either cohort. Moreover, we observed no association between prenatal exposure to infections and epigenetic age acceleration across cohorts and clocks.
CONCLUSIONS: In contrast to prior studies, which reported DNAm differences in offspring exposed to severe infections in utero, we do not find evidence for associations between self-reported clinically evident common infections during pregnancy and DNAm or epigenetic aging in cord blood within the general pediatric population. Future studies are needed to establish whether associations exist but are too subtle to be statistically meaningful with present sample sizes, whether they replicate in a cohort with a more similar infection score as our discovery cohort, whether they occur in different tissues than cord blood, and whether other biological pathways may be more relevant for mediating the effect of prenatal common infection exposure on downstream offspring health outcomes.