The causal effect of red blood cell folate on genome-wide methylation in cord blood: a Mendelian randomization approach
The causal effect of red blood cell folate on genome-wide methylation in cord blood: a Mendelian randomization approach
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DOI：
10.1186/1471-2105-14-353
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发表时间：
2013-12-04
影响因子：
3
通讯作者：
Michels, Karin B.
中科院分区：
文献类型：
--
作者：
Binder, Alexandra M.;Michels, Karin B.
背景：研究叶酸影响胎儿发育的生物学机制可以为预期益处的评估和风险管理提供信息。鉴于叶酸强化产品在美国无处不在，这项研究在伦理上是必要的。考虑到叶酸是为DNA甲基化提供甲基的单碳代谢途径的重要组成部分，表观遗传修饰提供了一种假定的分子机制，介导叶酸补充对新生儿和儿童预后的影响。结果：在这项研究中，我们使用孟德尔随机化方法来评估红细胞叶酸对脐带血全基因组DNA甲基化的影响。使用Illumina Infinium Human Methylation27 Bead Chip对来自波士顿布莱根妇女医院表观遗传出生队列的50名婴儿进行了大约14,500个基因近端启动子区域的位点特异性CpG甲基化分析。以亚甲基四氢叶酸还原酶基因型为工具，孟德尔随机化方法确定了7个CpG位点，这些位点在红细胞叶酸和甲基化水平之间具有显著（主要是正）相关性。在最接近CpG位点这一重要亚群的基因中，几个富集的生物过程参与了核酸运输和代谢过程。与标准的普通最小二乘回归方法相比，我们的估计对未测量的混杂更为稳健。结论：据作者所知，这是叶酸对甲基化模式影响的最大的全基因组分析，也是第一次使用孟德尔随机化来评估暴露对表观遗传修饰的影响。这些结果可以帮助指导未来分析孕周叶酸水平对候选途径的因果影响。
Background: Investigation of the biological mechanism by which folate acts to affect fetal development can inform appraisal of expected benefits and risk management. This research is ethically imperative given the ubiquity of folic acid fortified products in the US. Considering that folate is an essential component in the one-carbon metabolism pathway that provides methyl groups for DNA methylation, epigenetic modifications provide a putative molecular mechanism mediating the effect of folic acid supplementation on neonatal and pediatric outcomes.Results: In this study we use a Mendelian Randomization Unnecessary approach to assess the effect of red blood cell (RBC) folate on genome-wide DNA methylation in cord blood. Site-specific CpG methylation within the proximal promoter regions of approximately 14,500 genes was analyzed using the Illumina Infinium Human Methylation27 Bead Chip for 50 infants from the Epigenetic Birth Cohort at Brigham and Women's Hospital in Boston. Using methylenetetrahydrofolate reductase genotype as the instrument, the Mendelian Randomization approach identified 7 CpG loci with a significant (mostly positive) association between RBC folate and methylation level. Among the genes in closest proximity to this significant subset of CpG loci, several enriched biologic processes were involved in nucleic acid transport and metabolic processing. Compared to the standard ordinary least squares regression method, our estimates were demonstrated to be more robust to unmeasured confounding.Conclusions: To the authors' knowledge, this is the largest genome-wide analysis of the effects of folate on methylation pattern, and the first to employ Mendelian Randomization to assess the effects of an exposure on epigenetic modifications. These results can help guide future analyses of the causal effects of periconceptional folate levels on candidate pathways.