Molecular genetic analysis of the human dihydrofolate reductase gene: relation with plasma total homocysteine, serum and red blood cell folate levels
Molecular genetic analysis of the human dihydrofolate reductase gene: relation with plasma total homocysteine, serum and red blood cell folate levels
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DOI：
10.1038/sj.ejhg.5201713
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发表时间：
2007-01-01
影响因子：
5.2
通讯作者：
den Heijer, Martin
中科院分区：
文献类型：
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作者：
Gellekink, Henkjan;Blom, Henk J.;den Heijer, Martin
叶酸代谢紊乱可能会增加某些恶性肿瘤、先天性缺陷和心血管疾病的风险。二氢叶酸还原酶 (DHFR) 基因主要参与将胸苷酸合成过程中产生的二氢叶酸还原为四氢叶酸，以维持足够量的叶酸用于 DNA 合成和同型半胱氨酸再甲基化。为了揭示可能影响血浆总同型半胱氨酸 (tHcy)、血清叶酸和红细胞 (RBC) 叶酸水平的可能变异，我们对 20 个白人个体的 DHFR 编码区以及内含子-外显子边界和 DHFR 侧翼区进行了测序。我们在 50 个上游区域中发现了一个 9 bp 的重复序列，该重复区域与 50 个非翻译区域部分重叠，并且在非编码区域中发现了几个单核苷酸多态性。我们筛选了受试者的 9 bp 重复序列 (n = 417)，以及最近报道的内含子 1 中的 19 bp 缺失 (n = 330)，并评估了它们与血浆 tHcy、血清和红细胞叶酸水平的关联。与野生型基因型相比，19-bp del/del 基因型与较低的血浆 tHcy 相关（-14.4% [95% 置信区间：-23.5 至 -4.5]，P = 0.006）。这可能表明细胞内叶酸水平受到影响。
Disturbances in folate metabolism may increase the risk of certain malignancies, congenital defects and cardiovascular diseases. The gene dihydrofolate reductase (DHFR) is primarily involved in the reduction of dihydrofolate, generated during thymidylate synthesis, to tetrahydrofolate in order to maintain adequate amounts of folate for DNA synthesis and homocysteine remethylation. In order to reveal possible variation that may affect plasma total homocysteine (tHcy), serum folate and red blood cell (RBC) folate levels, we sequenced the DHFR coding region as well as the intron-exon boundaries and DHFR flanking regions from 20 Caucasian individuals. We identified a 9-bp repeat in the 50-upstream region that partially overlapped with the 50-untranslated region, and several single-nucleotide polymorphisms, all in non-coding regions. We screened subjects for the 9-bp repeat (n = 417), as well as the recently reported 19-bp deletion in intron 1 (n = 330), and assessed their associations with plasma tHcy, serum and RBC folate levels. The 19-bp del/del genotype was associated with a lower plasma tHcy (-14.4% [95% confidence interval: -23.5 to -4.5], P = 0.006) compared with the wild-type genotype. This may suggest that intracellular folate levels are affected.