Gellekink Henkjan, Blom Henk J, van der Linden I J M, den Heijer Martin
Laboratory of Paediatrics and Neurology, Department of Endocrinology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Eur J Hum Genet. 2007 Jan;15(1):103-9. doi: 10.1038/sj.ejhg.5201713. Epub 2006 Sep 13.
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 5'-upstream region that partially overlapped with the 5'-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.
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，以维持足够的叶酸量用于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）叶酸水平的变异，我们对20名高加索个体的DHFR编码区以及内含子-外显子边界和DHFR侧翼区域进行了测序。我们在5'-上游区域发现了一个9碱基重复序列，该序列与5'-非翻译区部分重叠，以及几个单核苷酸多态性，均位于非编码区。我们对受试者进行了9碱基重复序列（n = 417）以及最近报道的内含子1中19碱基缺失（n = 330）的筛查，并评估了它们与血浆tHcy、血清和RBC叶酸水平的关联。与野生型基因型相比，19碱基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。
