Beach Steven R H, Lei Man Kit, Ong Mei Ling, Brody Gene H, Dogan Meeshanthini V, Philibert Robert A
Department of Psychology, University of Georgia, Athens, Georgia.
University of Georgia, Center for Family Research, Athens, Georgia.
Am J Med Genet B Neuropsychiatr Genet. 2017 Sep;174(6):608-618. doi: 10.1002/ajmg.b.32544. Epub 2017 Apr 24.
Smoking has been shown to have a large, reliable, and rapid effect on demethylation of AHRR, particularly at cg05575921, suggesting that methylation may be used as an index of cigarette consumption. Because the availability of methyl donors may also influence the degree of demethylation in response to smoking, factors that affect the activity of methylene tetrahydrofolate reductase (MTHFR), a key regulator of methyl group availability, may be of interest. In the current investigation, we examined the extent to which individual differences in methylation of MTHFR moderated the association between smoking and demethylation at cg05575921 as well as at other loci on AHRR associated with a main effect of smoking. Using a discovery sample (AIM, N = 293), and a confirmatory sample (SHAPE, N = 368) of young adult African Americans, degree of methylation of loci in the first exon of MTHFR was associated with amplification of the association between smoking and AHRR demethylation at cg05575921. However, genetic variation at a commonly studied MTHFR variant, C677T, did not influence cg05575921 methylation. The significant interaction between MTHFR methylation and the smoking-induced response at cg05575921 suggests a role for individual differences in methyl cycle regulation in understanding the effects of cigarette consumption on genome wide DNA methylation.
研究表明，吸烟对芳烃受体（AHRR）的去甲基化有显著、可靠且迅速的影响，尤其是在cg05575921位点，这表明甲基化可能被用作衡量香烟消费量的指标。由于甲基供体的可用性也可能影响吸烟引起的去甲基化程度，因此影响亚甲基四氢叶酸还原酶（MTHFR）活性的因素可能值得关注，MTHFR是甲基可用性的关键调节因子。在当前的研究中，我们考察了MTHFR甲基化的个体差异在多大程度上调节了吸烟与cg05575921位点以及AHRR上其他与吸烟主效应相关位点的去甲基化之间的关联。我们使用了一个发现样本（AIM，N = 293）和一个验证样本（SHAPE，N = 368），样本为年轻成年非裔美国人，MTHFR第一个外显子中位点的甲基化程度与吸烟和cg05575921位点AHRR去甲基化之间关联的增强有关。然而，一个常见的MTHFR变体C677T的基因变异并未影响cg05575921的甲基化。MTHFR甲基化与cg05575921位点吸烟诱导反应之间的显著相互作用表明，甲基循环调节的个体差异在理解香烟消费对全基因组DNA甲基化的影响中发挥了作用。
