Richmond Rebecca C, Sharp Gemma C, Herbert Georgia, Atkinson Charlotte, Taylor Caroline, Bhattacharya Sohinee, Campbell Doris, Hall Marion, Kazmi Nabila, Gaunt Tom, McArdle Wendy, Ring Susan, Davey Smith George, Ness Andy, Relton Caroline L
MRC Integrative Epidemiology Unit, University of Bristol, Bristol, UK.
Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
Int J Epidemiol. 2018 Jun 1;47(3):928-937. doi: 10.1093/ije/dyy032.
It has been proposed that maternal folic-acid supplement use may alter the DNA-methylation patterns of the offspring during the in-utero period, which could influence development and later-life health outcomes. Evidence from human studies suggests a role for prenatal folate levels in influencing DNA methylation in early life, but this has not been extended to consider persistent effects into adulthood.
To better elucidate the long-term impact of maternal folic acid in pregnancy on DNA methylation in offspring, we carried out an epigenome-wide association study (EWAS) nested within the Aberdeen Folic Acid Supplementation Trial (AFAST-a trial of two different doses: 0.2 and 5 mg, folic acid vs placebo). Offspring of the AFAST participants were recruited at a mean age of 47 years and saliva samples were profiled on the Illumina Infinium Human Methylation450 array. Both single-site and differentially methylated region analyses were performed.
We found an association at cg09112514 (p = 4.03×10-9), a CpG located in the 5' untranslated region of PDGFRA, in the main analysis comparing the intervention arms [low- (0.2 mg) and high-dose (5 mg) folic acid combined (N = 43)] vs placebo (N = 43). Furthermore, a dose-response reduction in methylation at this site was identified in relation to the intervention. In the regional approach, we identified 46 regions of the genome that were differentially methylated in response to the intervention (Sidak p-value <0.05), including HLA-DPB2, HLA-DPB1, PAX8 and VTRNA2-1. Whereas cg09112514 did not replicate in an independent EWAS of maternal plasma folate, there was suggested replication of differential methylation in PAX8.
The results of this study suggest that maternal folic-acid supplement use is associated with changes in the DNA methylation of the offspring that persist for many years after exposure in utero. These methylation changes are located in genes implicated in embryonic development, immune response and cellular proliferation. Further work to investigate whether these epigenetic changes translate into detectable phenotypic differences is required.
有人提出，孕期补充叶酸可能会改变胎儿在子宫内的DNA甲基化模式，这可能会影响其发育及日后的健康状况。来自人体研究的证据表明，产前叶酸水平在影响早期生命中的DNA甲基化方面发挥作用，但尚未扩展到考虑其对成年期的持续影响。
为了更好地阐明孕期母亲补充叶酸对后代DNA甲基化的长期影响，我们在阿伯丁叶酸补充试验（AFAST，一项针对两种不同剂量：0.2和5毫克叶酸与安慰剂对照的试验）中开展了一项全基因组关联研究（EWAS）。AFAST参与者的后代在平均年龄47岁时被招募，采集唾液样本并在Illumina Infinium Human Methylation450芯片上进行分析。进行了单位点和差异甲基化区域分析。
在主要分析中，比较干预组（低剂量（0.2毫克）和高剂量（5毫克）叶酸联合组（N = 43））与安慰剂组（N = 43）时，我们在cg09112514位点（p = 4.03×10 - 9）发现了关联，该位点是位于血小板衍生生长因子受体A（PDGFRA）5'非翻译区的一个CpG位点。此外，还发现该位点的甲基化随干预呈现剂量反应性降低。在区域分析中，我们鉴定出46个因干预而发生差异甲基化的基因组区域（Sidak p值<0.05），包括人类白细胞抗原DPB2（HLA - DPB2）、人类白细胞抗原DPB1（HLA - DPB1）、配对盒基因8（PAX8）和小核仁RNA宿主基因2 - 1（VTRNA2 - 1）。虽然cg09112514在一项关于母亲血浆叶酸的独立EWAS中未得到重复验证，但PAX8的差异甲基化有重复验证的迹象。
本研究结果表明，孕期母亲补充叶酸与后代DNA甲基化变化有关，这些变化在子宫内暴露多年后仍持续存在。这些甲基化变化位于与胚胎发育、免疫反应和细胞增殖相关的基因中。需要进一步研究这些表观遗传变化是否会转化为可检测到的表型差异。
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