title: Genetic variation in one-carbon metabolism in relation to genome-wide DNA methylation in breast tissue from heathy women.
abstract: Single nucleotide polymorphisms (SNPs) in one-carbon metabolism genes and lifestyle factors (alcohol drinking and breast folate) may be determinants of whole-genome methylation in the breast. DNA methylation profiling was performed using the Illumina Infinium HumanMethylation450 BeadChip in 81 normal breast tissues from women undergoing reduction mammoplasty and no history of cancer. ANCOVA, adjusting for age, race and BMI, was used to identify differentially-methylated (DM) CpGs. Gene expression, by the Affymetrix GeneChip Human Transcriptome Array 2.0, was correlated with DM. Biological networks of DM genes were assigned using Ingenuity Pathway Analysis. Fifty-seven CpG sites were DM in association with eight SNPs in FTHFD, MTHFD1, MTHFR, MTR, MTRR, and TYMS (P <5.0 x 10-5); 56% of the DM CpGs were associated with FTHFD SNPs, including DM within FTHFD. Gene expression was negatively correlated with FTHFD methylation (r=-0.25, P=0.017). Four DM CpGs identified by SNPs in MTRR, MTHFR, and FTHFD were significantly associated with alcohol consumption and/or breast folate. The top biological network of DM CpGs was associated with Energy Production, Molecular Transportation, and Nucleic Acid Metabolism. This is the first comprehensive study of the association between SNPs in one-carbon metabolism genes and genome-wide DNA methylation in normal breast tissues. These SNPs, especially FTHFD, as well as alcohol intake and folate exposure, appear to affect DM in breast tissues of healthy women. The finding that SNPs in FTHFD and MTR are associated with their own methylation is novel and highlights a role for these SNPs as cis-methylation quantitative trait loci.
authors.affiliation: Comprehensive Cancer Center, The Ohio State University and James Cancer Hospital, Columbus, Ohio.
authors.forename: Min-Ae
authors.initials: MA
authors.lastname: Song
authors.affiliation: Comprehensive Cancer Center, The Ohio State University and James Cancer Hospital, Columbus, Ohio.
authors.forename: Theodore M
authors.initials: TM
authors.lastname: Brasky
authors.affiliation: Comprehensive Cancer Center, The Ohio State University and James Cancer Hospital, Columbus, Ohio Biochemistry and Pharmacology Department, Victor Babes University of Medicine and Pharmacy, 300041 Timisoara, Romania.
authors.forename: Catalin
authors.initials: C
authors.lastname: Marian
authors.affiliation: Comprehensive Cancer Center, The Ohio State University and James Cancer Hospital, Columbus, Ohio.
authors.forename: Daniel Y
authors.initials: DY
authors.lastname: Weng
authors.affiliation: Comprehensive Cancer Center, The Ohio State University and James Cancer Hospital, Columbus, Ohio.
authors.forename: Cenny
authors.initials: C
authors.lastname: Taslim
authors.affiliation: Department of Epidemiology, Rutgers School of Public Health and Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08903, USA.
authors.forename: Adana A
authors.initials: AA
authors.lastname: Llanos
authors.affiliation: Distilled Spirits Council of the United States, Washington, DC, USA.
authors.forename: Ramona G
authors.initials: RG
authors.lastname: Dumitrescu
authors.affiliation: Department of Nutrition; School of Public Health and Health Sciences; University of Massachusetts; Amherst, MA USA.
authors.forename: Zhenua
authors.initials: Z
authors.lastname: Liu
authors.affiliation: U.S.D.A. Human Nutrition Research Center; Tufts University; Boston, MA USA.
authors.forename: Joel B
authors.initials: JB
authors.lastname: Mason
authors.affiliation: Department of Plastic Surgery; Georgetown University; Washington, DC USA.
authors.forename: Scott L
authors.initials: SL
authors.lastname: Spear
authors.affiliation: Department of Pathology; Georgetown University; Washington, DC USA.
authors.forename: Bhaskar V S
authors.initials: BV
authors.lastname: Kallakury
authors.affiliation: Department of Epidemiology and Environmental Health; School of Public Health and Health Professions; University at Buffalo; Buffalo, NY USA.
authors.forename: Jo L
authors.initials: JL
authors.lastname: Freudenheim
authors.affiliation: Comprehensive Cancer Center, The Ohio State University and James Cancer Hospital, Columbus, Ohio Peter.Shields@osumc.edu.
authors.forename: Peter G
authors.initials: PG
authors.lastname: Shields
keywords: Genome-wide DNA methylation; breast; gene expression; one-carbon metabolism genes; single nucleotide polymorphism