title: Impact of folic acid fortification on global DNA methylation and one-carbon biomarkers in the Women's Health Initiative Observational Study cohort.
abstract: DNA methylation is an epigenetic mechanism that regulates gene expression and can be modified by one-carbon nutrients. The objective of this study was to investigate the impact of folic acid (FA) fortification of the US food supply on leukocyte global DNA methylation and the relationship between DNA methylation, red blood cell (RBC) folate, and other one-carbon biomarkers among postmenopausal women enrolled in the Women's Health Initiative Observational Study. We selected 408 women from the highest and lowest tertiles of RBC folate distribution matching on age and timing of the baseline blood draw, which spanned the pre- (1994-1995), peri- (1996-1997), or post-fortification (1998) periods. Global DNA methylation was assessed by liquid chromatography-tandem mass spectrometry and expressed as a percentage of total cytosine. We observed an interaction (P = 0.02) between fortification period and RBC folate in relation to DNA methylation. Women with higher (vs. lower) RBC folate had higher mean DNA methylation (5.12 vs. 4.99%; P = 0.05) in the pre-fortification period, but lower (4.95 vs. 5.16%; P = 0.03) DNA methylation in the post-fortification period. We also observed significant correlations between one-carbon biomarkers and DNA methylation in the pre-fortification period, but not in the peri- or post-fortification period. The correlation between plasma homocysteine and DNA methylation was reversed from an inverse relationship during the pre-fortification period to a positive relationship during the post-fortification period. Our data suggest that (1) during FA fortification, higher RBC folate status is associated with a reduction in leukocyte global DNA methylation among postmenopausal women and; (2) the relationship between one-carbon biomarkers and global DNA methylation is dependent on folate availability.
authors.affiliation: Division of Nutritional Sciences; Cornell University; Ithaca, NY USA.
authors.forename: Sajin
authors.initials: S
authors.lastname: Bae
authors.affiliation: Fred Hutchinson Cancer Research Center; Seattle, WA USA; German Cancer Research Center and National Center for Tumor Diseases; Heidelberg, Germany.
authors.forename: Cornelia M
authors.initials: CM
authors.lastname: Ulrich
authors.affiliation: Department of Foods and Nutrition; University of Georgia; Athens, GA USA.
authors.forename: Lynn B
authors.initials: LB
authors.lastname: Bailey
authors.affiliation: Division of Nutritional Sciences; Cornell University; Ithaca, NY USA.
authors.forename: Olga
authors.initials: O
authors.lastname: Malysheva
authors.affiliation: Fred Hutchinson Cancer Research Center; Seattle, WA USA.
authors.forename: Elissa C
authors.initials: EC
authors.lastname: Brown
authors.affiliation: Food Science and Human Nutrition Department; University of Florida; Gainesville, FL USA.
authors.forename: David R
authors.initials: DR
authors.lastname: Maneval
authors.affiliation: Fred Hutchinson Cancer Research Center; Seattle, WA USA.
authors.forename: Marian L
authors.initials: ML
authors.lastname: Neuhouser
authors.affiliation: Fred Hutchinson Cancer Research Center; Seattle, WA USA.
authors.forename: Ting-Yuan David
authors.initials: TY
authors.lastname: Cheng
authors.affiliation: Department of Nutritional Sciences; Rutgers University; New Brunswick, NJ USA; Department of Medical Pathology and Laboratory Medicine; University of California; Davis, CA USA.
authors.forename: Joshua W
authors.initials: JW
authors.lastname: Miller
authors.affiliation: Fred Hutchinson Cancer Research Center; Seattle, WA USA.
authors.forename: Yingye
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Fred Hutchinson Cancer Research Center; Seattle, WA USA.
authors.forename: Liren
authors.initials: L
authors.lastname: Xiao
authors.affiliation: Department of Preventive Medicine and Robert H. Lurie Comprehensive Cancer; Northwestern University; Chicago, IL USA.
authors.forename: Lifang
authors.initials: L
authors.lastname: Hou
authors.affiliation: Fred Hutchinson Cancer Research Center; Seattle, WA USA.
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Song
authors.affiliation: German Cancer Research Center and National Center for Tumor Diseases; Heidelberg, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Buck
authors.affiliation: Fred Hutchinson Cancer Research Center; Seattle, WA USA.
authors.forename: Shirley A A
authors.initials: SA
authors.lastname: Beresford
authors.affiliation: Division of Nutritional Sciences; Cornell University; Ithaca, NY USA.
authors.forename: Marie A
authors.initials: MA
authors.lastname: Caudill
mesh_terms: D000368:Aged; D015415:Biomarkers / Q000097:blood; D002794:Choline / Q000097:blood; D015331:Cohort Studies; D019175:DNA Methylation; D005260:Female; D005492:Folic Acid / Q000008:administration & dosage* / Q000097:blood; D005527:Food, Fortified; D006710:Homocysteine / Q000097:blood; D006801:Humans; D007962:Leukocytes / Q000378:metabolism; D008875:Middle Aged; D017698:Postmenopause
chemical_list: D015415:Biomarkers; D006710:Homocysteine; D005492:Folic Acid; D002794:Choline
keywords: DNA methylation; RBC folate; Women's Health Initiative; choline; folate; folic acid fortification; homocysteine; one-carbon biomarkers; postmenopausal women; vitamin B12