DNA methylation as a mediator of the association between prenatal adversity and risk factors for metabolic disease in adulthood

Although it is assumed that epigenetic mechanisms, such as changes in DNA methylation (DNAm), underlie the relationship between adverse intrauterine conditions and adult metabolic health, evidence from human studies remains scarce. Therefore, we evaluated whether DNAm in whole blood mediated the association between prenatal famine exposure and metabolic health in 422 individuals exposed to famine in utero and 463 (sibling) controls. We implemented a two-step analysis, namely, a genome-wide exploration across 342,596 cytosine-phosphate-guanine dinucleotides (CpGs) for potential mediators of the association between prenatal famine exposure and adult body mass index (BMI), serum triglycerides (TG), or glucose concentrations, which was followed by formal mediation analysis. DNAm mediated the association of prenatal famine exposure with adult BMI and TG but not with glucose. DNAm at PIM3 (cg09349128), a gene involved in energy metabolism, mediated 13.4% [95% confidence interval (CI), 5 to 28%] of the association between famine exposure and BMI. DNAm at six CpGs, including TXNIP (cg19693031), influencing β cell function, and ABCG1 (cg07397296), affecting lipid metabolism, together mediated 80% (95% CI, 38.5 to 100%) of the association between famine exposure and TG. Analyses restricted to those exposed to famine during early gestation identified additional CpGs mediating the relationship with TG near PFKFB3 (glycolysis) and METTL8 (adipogenesis). DNAm at the CpGs involved was associated with gene expression in an external data set and correlated with DNAm levels in fat depots in additional postmortem data. Our data are consistent with the hypothesis that epigenetic mechanisms mediate the influence of transient adverse environmental factors in early life on long-term metabolic health. The specific mechanism awaits elucidation. Comparison of DNA methylation in human tissues

尽管学界普遍认为表观遗传机制（如DNA甲基化（DNA methylation，简称DNAm）改变）是宫内不良环境暴露与成年代谢健康之间关联的潜在基础，但目前来自人体研究的相关证据仍较为匮乏。为此，本研究纳入422名宫内暴露于饥荒的个体与463名同胞对照，旨在探究全血DNA甲基化是否介导产前饥荒暴露与成年代谢健康之间的关联。本研究采用两步分析法：首先针对342596个胞嘧啶-磷酸-鸟嘌呤二核苷酸（cytosine-phosphate-guanine dinucleotides，CpGs）开展全基因组扫描，以筛选产前饥荒暴露与成年体质量指数（BMI）、血清甘油三酯（TG）或血糖浓度之间关联的潜在中介因子；随后开展正式的中介分析。结果显示，DNAm可介导产前饥荒暴露与成年BMI及血清TG之间的关联，但无法介导其与血糖的关联。位于能量代谢相关基因PIM3（cg09349128）处的DNAm，可介导13.4%的饥荒暴露与BMI之间的关联[95%置信区间（CI）：5%~28%]。包括影响β细胞功能的TXNIP（cg19693031）以及参与脂质代谢的ABCG1（cg07397296）在内的6个CpGs位点的DNAm，可共同介导80%的饥荒暴露与血清TG之间的关联（95%CI：38.5%~100%）。针对妊娠早期暴露于饥荒的个体开展的亚组分析，还筛选到了糖酵解相关基因PFKFB3与脂肪生成相关基因METTL8附近的CpGs位点，这些位点可介导饥荒暴露与血清TG之间的关联。上述关联CpGs位点的DNAm水平在外部数据集当中与基因表达水平存在关联，且在额外的死后组织数据中，其与脂肪组织中的DNAm水平存在相关性。本研究数据支持如下假说：表观遗传机制可介导早期生命阶段短暂的不良环境暴露对长期代谢健康产生的影响，其具体作用机制尚待进一步阐明。对人体组织的DNA甲基化水平进行比较