ImportanceExposure to war is associated with poor mental health outcomes. Adverse and traumatic experiences can lead to long-lasting DNA methylation changes, potentially mediating the link between adversity and mental health. To date, limited studies have investigated the impact of war on DNA methylation in children or adolescents, hampering our understanding of the biological impact of war exposure.ObjectiveTo identify salivary DNA methylation differences associated with war exposure in refugee children and adolescents.Design, Setting, and ParticipantsThis cohort study included Syrian refugee children and adolescents, and their primary caregiver were recruited from tented settlements in Lebanon. Data collection was carried out in 2 waves, 1 year apart, from October 2017 to January 2018 and October 2018 to January 2019. Children and their caregiver were interviewed, and children provided saliva samples for DNA extraction. Data analysis was conducted in 2022, 2023, and 2024.ExposureWar exposure assessed by interviewing children and their caregiver using the War Events Questionnaire.Main Outcomes and MeasuresSalivary DNA methylation levels were assayed with the Infinium MethylationEPIC BeadChip (Illumina). Epigenetic aging acceleration was estimated using a set of preexisting epigenetic aging clocks. A literature search was conducted to identify previously reported DNA methylation correlates of childhood trauma.ResultsThe study population included 1507 children and adolescents (mean [SD] age, 11.3 [2.4] years; age range, 6-19 years; 793 female [52.6%]). A total of 1449 children provided saliva samples for DNA extraction in year 1, and 872 children provided samples in year 2. Children who reported war events had a number of differentially methylated sites and regions. Enrichment analyses indicated an enrichment of gene sets associated with transmembrane transport, neurotransmission, and intracellular movement in genes that exhibited differential methylation. Sex-stratified analyses found a number of sex-specific DNA methylation differences associated with war exposure. Only 2 of 258 (0.8%) previously reported trauma-associated DNA methylation sites were associated with war exposure (B = −0.004; 95% CI, −0.005 to −0.003; Bonferroni P = .04 and B = −0.005; 95% CI, −0.006 to −0.004; Bonferroni P = .03). Any war exposure or bombardment was nominally associated with decreased epigenetic age using the Horvath multitissue clock (B = −0.39; 95% CI, −0.63 to −0.14; P = .007 and B = −0.42; 95% CI, −0.73 to −0.11; P = .002).Conclusions and RelevanceIn this cohort of Syrian refugee children and adolescents, war exposure was associated with a small number of distinct differences in salivary DNA methylation.

中文翻译：

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叙利亚难民儿童和青少年的战争暴露和 DNA 甲基化


重要性暴露于战争与不良的心理健康结果有关。不良和创伤经历会导致持久的 DNA 甲基化变化，从而可能介导逆境与心理健康之间的联系。迄今为止，有限的研究调查了战争对儿童或青少年 DNA 甲基化的影响，阻碍了我们对战争暴露的生物学影响的理解。目的确定难民儿童和青少年与战争暴露相关的唾液 DNA 甲基化差异。设计、设置和参与者该队列研究包括叙利亚难民儿童和青少年，他们的主要照顾者是从黎巴嫩的帐篷定居点招募的。数据收集分 2 波进行，间隔 1 年，分别从 2017 年 10 月到 2018 年 1 月和 2018 年 10 月至 2019 年 1 月。儿童及其照顾者接受了访谈，儿童提供了唾液样本用于 DNA 提取。数据分析于 2022 年、 2023 年和 2024 年进行。暴露通过使用战争事件问卷采访儿童及其看护人来评估战争暴露.主要结果和测量唾液 DNA 甲基化水平使用 Infinium 甲基化EPIC BeadChip （Illumina） 测定。使用一组预先存在的表观遗传衰老时钟估计表观遗传衰老加速。进行了文献检索，以确定先前报道的童年创伤的 DNA 甲基化相关性。结果研究人群包括 1507 名儿童和青少年 （平均 [SD] 年龄，11.3 [2.4] 岁;年龄范围，6-19 岁;793 名女性 [52.6%]）。共有 1449 名儿童在第 1 年提供了唾液样本用于 DNA 提取，第 2 年共有 872 名儿童提供了样本。报告战争事件的儿童具有许多差异甲基化位点和区域。 富集分析表明，在表现出差异甲基化的基因中，与跨膜转运、神经传递和细胞内运动相关的基因集富集。性别分层分析发现许多与战争暴露相关的性别特异性 DNA 甲基化差异。在 258 个先前报告的创伤相关 DNA 甲基化位点中，只有 2 个 （0.8%） 与战争暴露相关 （B = -0.004;95% CI，-0.005 至 -0.003;Bonferroni P = .04 和 B = −0.005;95% CI，-0.006 至 -0.004;Bonferroni P = .03）。任何战争暴露或轰炸名义上与使用 Horvath 多组织时钟的表观遗传年龄减少相关 （B = -0.39;95% CI，-0.63 至 -0.14;P = .007 和 B = −0.42;95% CI，-0.73 至 -0.11;P = .002）。结论和相关性在这组叙利亚难民儿童和青少年中，战争暴露与唾液 DNA 甲基化的少量明显差异相关。