Department of Anesthesiology, Washington University School of Medicine, St Louis, Missouri, USA.
Pharmacogenet Genomics. 2011 Jul;21(7):426-31. doi: 10.1097/FPC.0b013e32834741ff.
Folate metabolism is an important target for drug therapy. Drug-induced inhibition of folate metabolism often causes an elevation of plasma total homocysteine (tHcy). Plasma tHcy levels are influenced by several nongenetic (e.g. folate intake, age, smoking) as well as genetic factors. Over the last decade, several countries have implemented a nationwide folate fortification program of all grain products. This investigation sought to determine the impact of folate fortification on the relative contribution of environmental and genetic factors to the variability of plasma tHcy.
Two cohorts were compared in this study, one from the United States (with folate fortification, n=281) and one from Austria (without folate fortification, n=139). Several environmental factors as well as previously identified gene variants important for tHcy levels (MTHFR C677T, MTHFR A1298C, MTRR A66G) were examined for their ability to predict plasma tHcy in a multiple linear regression model.
Nongenetic, environmental factors had a comparable influence on plasma tHcy between the two cohorts (R: approximately 0.19). However, after adjusting for other covariates, the tested gene variants had a substantially smaller impact among patients from the folate-fortified cohort (R=0.021) compared with the nonfolate-fortified cohort (R=0.095). The MTHFR C677T polymorphism was the single most important genetic factor. Male sex, smoking, and folate levels were important predictors for nonfolate-fortified patients; age was for folate-fortified patients.
Population wide folate fortification had a significant effect on the variability of plasma tHcy and reduced the influence of genetic factors, most importantly the MTHFR 677TT genotype, and may be an important confounder for a personalized drug therapy.
叶酸代谢是药物治疗的一个重要靶点。药物诱导的叶酸代谢抑制常导致血浆总同型半胱氨酸（tHcy）升高。血浆 tHcy 水平受多种非遗传（如叶酸摄入、年龄、吸烟）和遗传因素的影响。在过去的十年中，许多国家已经实施了所有谷物产品的全国性叶酸强化计划。本研究旨在确定叶酸强化对环境和遗传因素对血浆 tHcy 变异性的相对贡献的影响。
本研究比较了两个队列，一个来自美国（有叶酸强化，n=281），一个来自奥地利（无叶酸强化，n=139）。研究了几个环境因素以及先前确定的对 tHcy 水平有重要影响的基因变异（MTHFR C677T、MTHFR A1298C、MTRR A66G），以评估它们在多元线性回归模型中预测血浆 tHcy 的能力。
非遗传、环境因素对两个队列的血浆 tHcy 具有相似的影响（R：约 0.19）。然而，在调整其他协变量后，在叶酸强化队列的患者中，测试的基因变异的影响明显较小（R=0.021），而在非叶酸强化队列中则较大（R=0.095）。MTHFR C677T 多态性是唯一最重要的遗传因素。男性、吸烟和叶酸水平是非叶酸强化患者的重要预测因素；年龄是叶酸强化患者的重要预测因素。
人群叶酸强化对血浆 tHcy 的变异性有显著影响，并降低了遗传因素的影响，最重要的是 MTHFR 677TT 基因型，可能是个体化药物治疗的一个重要混杂因素。
