title: Molecular genetic analysis of the human dihydrofolate reductase gene: relation with plasma total homocysteine, serum and red blood cell folate levels.
abstract: 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.
authors.affiliation: Laboratory of Paediatrics and Neurology, Department of Endocrinology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: Henkjan
authors.initials: H
authors.lastname: Gellekink
authors.forename: Henk J
authors.initials: HJ
authors.lastname: Blom
authors.forename: I J M
authors.initials: IJ
authors.lastname: van der Linden
authors.forename: Martin
authors.initials: M
authors.lastname: den Heijer
mesh_terms: D024506:5' Flanking Region; D001483:Base Sequence; D004912:Erythrocytes / Q000737:chemistry*; D005091:Exons; D005492:Folic Acid / Q000097:blood*; D006710:Homocysteine / Q000097:blood*; D006801:Humans; D007438:Introns; D008969:Molecular Sequence Data; D020641:Polymorphism, Single Nucleotide; D012091:Repetitive Sequences, Nucleic Acid; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics* / Q000378:metabolism*; D013763:Tetrahydrofolates / Q000378:metabolism
chemical_list: D013763:Tetrahydrofolates; D006710:Homocysteine; D005492:Folic Acid; D013762:Tetrahydrofolate Dehydrogenase