Genetic and environmental determinants of plasma total homocysteine levels: impact of population-wide folate fortification.
Genetic and environmental determinants of plasma total homocysteine levels: impact of population-wide folate fortification.
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DOI：
10.1097/fpc.0b013e32834741ff
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发表时间：
2011-07
影响因子：
2.6
通讯作者：
Saccone NL
中科院分区：
文献类型：
--
作者：
Nagele P;Meissner K;Francis A;Födinger M;Saccone NL
叶酸代谢是药物治疗的重要靶点。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水平受几种非遗传性（例如，叶酸摄入量、年龄、吸烟）以及遗传因素。在过去的十年中，一些国家已经实施了全国范围内所有谷物产品的叶酸强化计划。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（叶酸强化，n=281），一个来自奥地利（未强化叶酸，n=139）。在多元线性回归模型中，检测了几种环境因素以及先前鉴定的对tHcy水平重要的基因变体（MTHFR C677 T、MTHFR A1298 C、MTRR A66 G）预测血浆tHcy的能力。非遗传、环境因素对两个队列血浆tHcy的影响相当（R2 ~ 0.19）。然而，在调整其他协变量后，与非叶酸强化队列（R2 = 0.095）相比，测试的基因变异对叶酸强化队列患者的影响要小得多（R2 = 0.021）。MTHFR C677 T多态性是最重要的遗传因素。男性、吸烟和叶酸水平是非叶酸强化患者的重要预测因素;叶酸强化患者的年龄。人群范围内的叶酸强化对血浆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 677 TT基因型，可能是个性化药物治疗的重要混杂因素。
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 non-genetic (e.g., folate intake, age, smoking) as well as genetic factors. Over the last decade, several countries have implemented a nation-wide 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 U.S. (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. Non-genetic, environmental factors had a comparable influence on plasma tHcy between the two cohorts (R2 ~ 0.19). However, after adjusting for other covariates, the tested gene variants had a substantially smaller impact among patients from the folate fortified cohort (R2= 0.021) compared to the non-folate fortified cohort (R2= 0.095). The MTHFR C677T polymorphism was the single most important genetic factor. Male gender, smoking and folate levels were important predictors for non-folate fortified patients; age for folate fortified. 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.