title: Genomic DNA methylation changes in response to folic acid supplementation in a population-based intervention study among women of reproductive age.
abstract: Folate is a source of one-carbons necessary for DNA methylation, a critical epigenetic modification necessary for genomic structure and function. The use of supplemental folic acid is widespread however; the potential influence on DNA methylation is unclear. We measured global DNA methylation using DNA extracted from samples from a population-based, double-blind randomized trial of folic acid supplementation (100, 400, 4000 µg per day) taken for 6 months; including a 3 month post-supplementation sample. We observed no changes in global DNA methylation in response to up to 4,000 µg/day for 6 months supplementation in DNA extracted from uncoagulated blood (approximates circulating blood). However, when DNA methylation was determined in coagulated samples from the same individuals at the same time, significant time, dose, and MTHFR genotype-dependent changes were observed. The baseline level of DNA methylation was the same for uncoagulated and coagulated samples; marked differences between sample types were observed only after intervention. In DNA from coagulated blood, DNA methylation decreased (-14%; P<0.001) after 1 month of supplementation and 3 months after supplement withdrawal, methylation decreased an additional 23% (P<0.001) with significant variation among individuals (max+17%; min-94%). Decreases in methylation of ≥25% (vs. <25%) after discontinuation of supplementation were strongly associated with genotype: MTHFR CC vs. TT (adjusted odds ratio [aOR] 12.9, 95%CI 6.4, 26.0). The unexpected difference in DNA methylation between DNA extracted from coagulated and uncoagulated samples in response to folic acid supplementation is an important finding for evaluating use of folic acid and investigating the potential effects of folic acid supplementation on coagulation.
authors.affiliation: Division of Birth Defects and Developmental Disabilities, National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention, Atlanta, Georgia, United States of America. kcrider@cdc.gov
authors.forename: Krista S
authors.initials: KS
authors.lastname: Crider
authors.forename: Eoin P
authors.initials: EP
authors.lastname: Quinlivan
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Berry
authors.forename: Ling
authors.initials: L
authors.lastname: Hao
authors.forename: Zhu
authors.initials: Z
authors.lastname: Li
authors.forename: David
authors.initials: D
authors.lastname: Maneval
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Yang
authors.forename: Sonja A
authors.initials: SA
authors.lastname: Rasmussen
authors.forename: Quanhe
authors.initials: Q
authors.lastname: Yang
authors.forename: Jiang-Hui
authors.initials: JH
authors.lastname: Zhu
authors.forename: Dale J
authors.initials: DJ
authors.lastname: Hu
authors.forename: Lynn B
authors.initials: LB
authors.lastname: Bailey
mesh_terms: D000328:Adult; D001777:Blood Coagulation; D019175:DNA Methylation; D019587:Dietary Supplements; D004311:Double-Blind Method; D044127:Epigenesis, Genetic; D005260:Female; D005492:Folic Acid / Q000627:therapeutic use*; D015972:Gene Expression Regulation, Neoplastic; D014644:Genetic Variation; D005838:Genotype; D006454:Hemoglobins / Q000378:metabolism; D006801:Humans; D045102:Methylenetetrahydrofolate Dehydrogenase (NAD+) / Q000235:genetics; D016017:Odds Ratio; D013997:Time Factors; D014805:Vitamin B 12 / Q000378:metabolism
chemical_list: D006454:Hemoglobins; D005492:Folic Acid; D045102:Methylenetetrahydrofolate Dehydrogenase (NAD+); D014805:Vitamin B 12