Variation and expression of dihydrofolate reductase (DHFR) in relation to spina bifida

Linden, Ivon J. M. van der; Nguyen, Uyen Quynh; Heil, Sandra G.; Franke, Barbara; Vloet, Suzanne; Gellekink, Henkjan; Heijer, Martin den; Blom, Henk J.

doi:10.1016/j.ymgme.2007.01.009

Cited by 40 publications

(24 citation statements)

References 18 publications

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“…The association between this polymorphism and the NTD risk was inconsistent between the studies [61,90,120]. The DHFR in human liver-cell homogenates shows a wide range of activity between individual samples [3], suggesting large differences in an individual's ability to reduce FA.…”

Section: Genetic Polymorphisms Affect Folate Bioavailability Utilizamentioning

confidence: 99%

Is 5-methyltetrahydrofolate an alternative to folic acid for the prevention of neural tube defects?

Obeid

Holzgreve

Pietrzik

2013

Journal of Perinatal Medicine

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Women have higher requirements for folate during pregnancy. An optimal folate status must be achieved before conception and in the first trimester when the neural tube closes. Low maternal folate status is causally related to neural tube defects (NTDs). Many NTDs can be prevented by increasing maternal folate intake in the preconceptional period. Dietary folate is protective, but recommending increasing folate intake is ineffective on a population level particularly during periods of high demands. This is because the recommendations are often not followed or because the bioavailability of food folate is variable. Supplemental folate [folic acid (FA) or 5-methyltetrahydrofolate (5-methylTHF)] can effectively increase folate concentrations to the level that is considered to be protective. FA is a synthetic compound that has no biological functions unless it is reduced to dihydrofolate and tetrahydrofolate. Unmetabolized FA appears in the circulation at doses of > 200 μg. Individuals show wide variations in their ability to reduce FA. Carriers of certain polymorphisms in genes related to folate metabolism or absorption can better benefit from 5-methylTHF instead of FA. 5-MethylTHF [also known as (6S)-5-methylTHF] is the predominant natural form that is readily available for transport and metabolism. In contrast to FA, 5-methylTHF has no tolerable upper intake level and does not mask vitamin B 12 deficiency. Supplementation of the natural form, 5-methylTHF, is a better alternative to supplementation of FA, especially in countries not applying a fortification program. Supplemental 5-methylTHF can effectively improve folate biomarkers in young women in early pregnancy in order to prevent NTDs.

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Section: Genetic Polymorphisms Affect Folate Bioavailability Utilizamentioning

confidence: 99%

Is 5-methyltetrahydrofolate an alternative to folic acid for the prevention of neural tube defects?

Obeid

Holzgreve

Pietrzik

2013

Journal of Perinatal Medicine

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“…Individuals homozygous for the deletion (À/À) have lower mean plasma total homocysteine than those homozygous for the insertion ( þ / þ ), 40 with the (À/À) individuals also having been shown to have 4.8-fold greater DHFR mRNA expression in lymphocytes compared with ( þ / þ ) carriers. 42 The 5 0 -upstream 9-bp repeat polymorphism (homozygous 6R carriers) 43 and 3 0 -UTR SNP (rs34764978) (C/T and T/T carriers) 44 have also been associated with enhanced mRNA expression.…”

Section: Tymsmentioning

confidence: 99%

Investigation of inter-individual variability of the one-carbon folate pathway: a bioinformatic and genetic review

2009

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“…To date, four DHFR polymorphisms have been described. The most extensively studied is a 19 bp deletion (c.86 + 60_78) within intron 1 (Johnson et al 2004), which has been evaluated as a risk factor for NTDs in three studies (Johnson et al 2004;van der Linden et al 2007;Parle-McDermott et al 2007). The Wrst, a small case-control study (61 spina biWda cases and 50 mothers of spina biWda cases from the United States) provided evidence that the risk of having a child with spina biWda is higher for those with the del/del genotype than for those with the ins/del or ins/ins genotypes (Johnson et al 2004).…”

Section: Introductionmentioning

confidence: 99%

“…Interestingly, it has also been reported that individuals with the del/del genotype have lower homocysteine concentrations than individuals with genotypes that include the ins allele , which is consistent with the NTD protective eVect observed in the Irish study (Parle-McDermott et al 2007). Neither of the other two DHFR polymorphisms that have been identiWed in Caucasians has been found to be associated with the risk of NTDs (ParleMcDermott et al 2007;van der Linden et al 2007). …”

Section: Introductionmentioning

confidence: 99%

An insertion/deletion polymorphism of the dihydrofolate reductase (DHFR) gene is associated with serum and red blood cell folate concentrations in women

Stanisławska-Sachadyn

Brown

Mitchell

et al. 2008

Hum Genet

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A low serum folate and high homocysteine phenotype is associated with an increased risk of neural tube defects (NTDs), cardiovascular diseases and other pathologies. Thus defining both genetic and non-genetic factors that may impact folate/homocysteine metabolism will enhance our understanding of the etiologic mechanisms underlying these conditions and facilitate risk assessment. Dihydrofolate reductase catalyzes the reduction of folic acid to dihydrofolate and thereafter to tetrahydrofolate. The impact of the dihydrofolate reductase (DHFR) c.86 + 60_78 insertion/deletion (ins/del) polymorphism on folate and homocysteine concentrations was analyzed using data from healthy young adults from Northern Ireland, collected as part of visit three of the Young Hearts Project. Among men the DHFR c.86 + 60_78 polymorphism was not significantly associated with serum or red blood cell folate concentrations, or with homocysteine concentrations. Among women the DHFR c.86 + 60_78 polymorphism explained 2% of the variation in RBC folate levels and 5% of the variation in serum folate levels, but did not appear to have an independent effect on homocysteine. Relative to women with the DHFR c.86 + 60_78 ins/ins and ins/del genotypes, del/del homozygotes had increased serum and red blood cell folate concentrations and may therefore be at decreased risk of having offspring affected by NTDs and of other adverse reproductive and health outcomes attributable to low folate.

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Variation and expression of dihydrofolate reductase (DHFR) in relation to spina bifida

Cited by 40 publications

References 18 publications

Is 5-methyltetrahydrofolate an alternative to folic acid for the prevention of neural tube defects?

Is 5-methyltetrahydrofolate an alternative to folic acid for the prevention of neural tube defects?

Investigation of inter-individual variability of the one-carbon folate pathway: a bioinformatic and genetic review

An insertion/deletion polymorphism of the dihydrofolate reductase (DHFR) gene is associated with serum and red blood cell folate concentrations in women

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