Department of Community Health and Epidemiology, Queen's University, Kingston, Ontario, K7L3N6, Canada.
Mol Genet Metab. 2011 Apr;102(4):481-7. doi: 10.1016/j.ymgme.2010.12.015. Epub 2010 Dec 31.
DNA methylation plays a critical role in gene regulation and has been implicated in the etiology of chronic disease including atherosclerosis, neural degeneration and cancer. One-carbon metabolism serves two critically important functions: one concerning the production of purines and thymidine for DNA synthesis and the other related to the provision of methyl groups through the metabolism of methionine. Critical intermediates of methionine metabolism relevant to DNA methylation include S-adenosylmethionine (SAM), a universal methyl donor, and S-adenosylhomocysteine (SAH), a potent inhibitor of most methylation reactions. Thymidine synthesis, catalyzed by the crucial enzyme thymidylate synthase (TS), competes with methionine metabolism for a common substrate. Three functional polymorphisms in the TS gene have been identified including: (i) the thymidylate synthase enhancer region (TSER) tandem repeat polymorphism and (ii) the G to C single nucleotide polymorphism (G/C SNP) both of which occur in the 5'untranslated region (UTR) of the TS gene; and (iii) the 6-bp deletion at base pair 1494 (TS1494del6) located in the 3'UTR.
The purpose of this research was to investigate the relationship between TS polymorphisms and concentrations of SAM and SAH, markers of DNA methylation capacity.
The study population consisted of 395 healthy male and female volunteers from Kingston, Ontario and Halifax, Nova Scotia, Canada between 2006 and 2008. The effect of each TS polymorphism on SAM and SAH concentrations was investigated, and further analyses were conducted on categorization of polymorphisms based on 5' or 3'UTR. The combined effect of TS polymorphisms on SAM and SAH concentrations was also investigated, in addition to interactions between polymorphisms in TS and MTHFR 677C>T and interactions between TS polymorphisms and serum folate and vitamin B(12) status.
No associations were observed between TS polymorphisms and concentrations of SAM and SAH. Analysis of interaction between TS and MTHFR polymorphisms on SAH levels revealed a significant interaction with TS 3'polymorphism and MTHFR C677T (p=0.03). As well, interactions between TS 3'polymorphism and serum folate (p=0.03) and the combined effect of TS polymorphisms and serum folate on SAH levels (p=0.04) were found.
The findings of this research provide evidence that SAH, a marker of methylation capacity, is influenced by genetic and environmental factors and their interactions.
DNA 甲基化在基因调控中起着关键作用，并与包括动脉粥样硬化、神经退化和癌症在内的慢性疾病的病因有关。一碳代谢有两个非常重要的功能：一个是为 DNA 合成提供嘌呤和胸腺嘧啶，另一个是通过蛋氨酸代谢提供甲基。与 DNA 甲基化相关的蛋氨酸代谢的关键中间产物包括 S-腺苷甲硫氨酸（SAM），一种通用的甲基供体，和 S-腺苷同型半胱氨酸（SAH），一种大多数甲基化反应的有效抑制剂。由关键酶胸苷酸合成酶（TS）催化的胸苷合成与蛋氨酸代谢竞争共同的底物。在 TS 基因中已经确定了三个功能多态性，包括：（i）胸苷酸合成酶增强子区（TSER）串联重复多态性和（ii）G 到 C 的单核苷酸多态性（G/C SNP），它们都发生在 TS 基因的 5'非翻译区（UTR）；和（iii）位于 3'UTR 中的碱基对 1494 处的 6 个碱基缺失（TS1494del6）。
本研究旨在探讨 TS 多态性与 SAM 和 SAH 浓度的关系，SAM 和 SAH 是 DNA 甲基化能力的标志物。
本研究人群包括 2006 年至 2008 年间来自安大略省金斯顿和新斯科舍省哈利法克斯的 395 名健康男性和女性志愿者。研究了每个 TS 多态性对 SAM 和 SAH 浓度的影响，并进一步对基于 5'或 3'UTR 的多态性分类进行了分析。还研究了 TS 多态性对 SAM 和 SAH 浓度的综合影响，以及 TS 与 MTHFR677C>T 多态性之间的相互作用，以及 TS 多态性与血清叶酸和维生素 B(12)状态之间的相互作用。
未观察到 TS 多态性与 SAM 和 SAH 浓度之间存在相关性。对 SAH 水平上 TS 和 MTHFR 多态性之间相互作用的分析显示，与 TS3'多态性和 MTHFR C677T 之间存在显著相互作用（p=0.03）。此外，还发现了 TS3'多态性与血清叶酸之间的相互作用（p=0.03）以及 TS 多态性与血清叶酸的综合作用对 SAH 水平的影响（p=0.04）。
本研究结果表明，SAH 作为一种甲基化能力的标志物，受遗传和环境因素及其相互作用的影响。
