Department of Medical Informatics, Institute of Computer Science of the Academy of Sciences of the Czech Republic, Prague, Czech Republic.
J Nutr. 2012 Aug;142(8):1403-9. doi: 10.3945/jn.112.160549. Epub 2012 Jun 13.
The role of folates as coenzymes in 1-carbon metabolism and the clinical consequences of disturbed folate metabolism are widely known. Folate status is a complex trait determined by both exogenous and endogenous factors. This study analyzed the association between 12 genetic variants and folate status in a Czech population with no folate fortification program. These 12 genetic variants were selected from 56 variant alleles found by resequencing the coding sequences and adjacent intronic regions of 6 candidate genes involved in folate metabolism or transport (FOLR1, FOLR2, FOLR3, MTHFR, PCFT, and RFC) from 29 individuals with low plasma and erythrocyte folate concentrations. Regression analyses of a cohort of 511 Czech controls not taking folate supplements revealed that only 2 variants in the MTHFR gene were associated with altered folate concentrations in plasma and/or erythrocytes. In our previous study, we observed that the common variant MTHFR c.665C > T (known as c.677C > T; p.A222V) was associated with decreased plasma folate concentrations. In the present study, we show in addition that the rare variant MTHFR c.1958C > T (p.T653M) is associated with significantly increased erythrocyte folate concentrations (P = 0.02). Multivariate regression analysis revealed that this uncommon variant, which is present in 2% of Czech control chromosomes, explains 0.9% of the total variability of erythrocyte folate concentrations; the magnitude of this effect size was comparable with that of the common MTHFR c.665C > T variant. This result indicates that the rare genetic variants may determine folate status to a similar extent as the common allelic variant.
叶酸作为一碳代谢中的辅酶的作用以及叶酸代谢紊乱的临床后果是众所周知的。叶酸状态是一个复杂的特征，由外源性和内源性因素共同决定。本研究分析了在没有叶酸强化计划的捷克人群中，12 种遗传变异与叶酸状态之间的关联。这 12 种遗传变异是从参与叶酸代谢或转运的 6 个候选基因（FOLR1、FOLR2、FOLR3、MTHFR、PCFT 和 RFC）的编码序列和相邻内含子区域的 56 个变体等位基因中重新测序，在 29 名血浆和红细胞叶酸浓度较低的个体中发现。对 511 名未服用叶酸补充剂的捷克对照者进行的回归分析表明，只有 MTHFR 基因中的 2 个变异与血浆和/或红细胞中叶酸浓度的改变有关。在我们之前的研究中，我们观察到常见的 MTHFR c.665C > T 变体（称为 c.677C > T；p.A222V）与血浆叶酸浓度降低有关。在本研究中，我们还发现罕见的 MTHFR c.1958C > T 变体（p.T653M）与红细胞叶酸浓度显著升高有关（P = 0.02）。多元回归分析表明，这种在 2%的捷克对照染色体中存在的罕见变异解释了红细胞叶酸浓度总变异性的 0.9%；这种效应大小与常见的 MTHFR c.665C > T 变异相当。这一结果表明，罕见的遗传变异可能在一定程度上决定叶酸状态，与常见的等位基因变异相似。
