Molecular Genetic Analysis Of The Human Dihydrofolate Reductase Gene: Relation With Plasma Total Homocysteine, Serum And Red Blood Cell Folate Levels
Henkjan Gellekink, Henk J Blom, I J M van der Linden and Martin den Heijer
Published in European Journal of Human Genetics (2007) 15, 103-109.
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.
Correspondence: Dr M den Heijer, Department of Endocrinology (471), Radboud University Nijmegen Medical Centre, PO Box 9101, Nijmegen 6500 HB, The Netherlands. E-mail: email@example.com
Full article available online.
(C) European Journal of Human Genetics.
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