title: No effect of folic acid supplementation on global DNA methylation in men and women with moderately elevated homocysteine.
abstract: A global loss of cytosine methylation in DNA has been implicated in a wide range of diseases. There is growing evidence that modifications in DNA methylation can be brought about by altering the intake of methyl donors such as folate. We examined whether long-term daily supplementation with 0.8 mg of folic acid would increase global DNA methylation compared with placebo in individuals with elevated plasma homocysteine. We also investigated if these effects were modified by MTHFR C677T genotype. Two hundred sixteen participants out of 818 subjects who had participated in a randomized double-blind placebo-controlled trial were selected, pre-stratified on MTHFR C677T genotype and matched on age and smoking status. They were allocated to receive either folic acid (0.8 mg/d; n = 105) or placebo treatment (n = 111) for three years. Peripheral blood leukocyte DNA methylation and serum and erythrocyte folate were assessed. Global DNA methylation was measured using liquid chromatography-tandem mass spectrometry and expressed as a percentage of 5-methylcytosines versus the total number of cytosine. There was no difference in global DNA methylation between those randomized to folic acid and those in the placebo group (difference = 0.008, 95%CI = -0.05,0.07, P = 0.79). There was also no difference between treatment groups when we stratified for MTHFR C677T genotype (CC, n = 76; CT, n = 70; TT, n = 70), baseline erythrocyte folate status or baseline DNA methylation levels. In moderately hyperhomocysteinemic men and women, long-term folic acid supplementation does not increase global DNA methylation in peripheral blood leukocytes.ClinicalTrials.gov NCT00110604.
authors.affiliation: Department of Epidemiology, Biostatistics, and HTA, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands. a.jung@ebh.umcn.nl
authors.forename: Audrey Y
authors.initials: AY
authors.lastname: Jung
authors.forename: Yvo
authors.initials: Y
authors.lastname: Smulders
authors.forename: Petra
authors.initials: P
authors.lastname: Verhoef
authors.forename: Frans J
authors.initials: FJ
authors.lastname: Kok
authors.forename: Henk
authors.initials: H
authors.lastname: Blom
authors.forename: Robert M
authors.initials: RM
authors.lastname: Kok
authors.forename: Ellen
authors.initials: E
authors.lastname: Kampman
authors.forename: Jane
authors.initials: J
authors.lastname: Durga
mesh_terms: D000368:Aged; D002853:Chromatography, Liquid / Q000379:methods; D019175:DNA Methylation; D019587:Dietary Supplements; D004311:Double-Blind Method; D005260:Female; D005492:Folic Acid / Q000627:therapeutic use*; D005838:Genotype; D006710:Homocysteine / Q000097:blood*; D006801:Humans; D007962:Leukocytes / Q000378:metabolism; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics*; D008875:Middle Aged; D015233:Models, Statistical; D010919:Placebos; D017698:Postmenopause; D012907:Smoking; D053719:Tandem Mass Spectrometry / Q000379:methods
chemical_list: D010919:Placebos; D006710:Homocysteine; D005492:Folic Acid; D042965:Methylenetetrahydrofolate Reductase (NADPH2)