title: Erythrocyte folate concentrations, CpG methylation at genomically imprinted domains, and birth weight in a multiethnic newborn cohort.
abstract: Epigenetic mechanisms are proposed to link maternal concentrations of methyl group donor nutrients with the risk of low birth weight. However, empirical data are lacking. We have examined the association between maternal folate and birth weight and assessed the mediating role of DNA methylation at nine differentially methylated regions (DMRs) of genomically imprinted genes in these associations. Compared with newborns of women with folate levels in the lowest quartile, birth weight was higher in newborns of mothers in the second (β = 143.2, se = 63.2, P = 0.02), third (β = 117.3, se = 64.0, P = 0.07), and fourth (β = 133.9, se = 65.2, P = 0.04) quartiles, consistent with a threshold effect. This pattern of association did not vary by race/ethnicity but was more apparent in newborns of non-obese women. DNA methylation at the PLAGL1, SGCE, DLK1/MEG3 and IGF2/H19 DMRs was associated with maternal folate levels and also birth weight, suggestive of threshold effects. MEG3 DMR methylation mediated the association between maternal folate levels and birth weight (P =0.06). While the small sample size and partial scope of examined DMRs limit our conclusions, our data suggest that, with respect to birth weight, no additional benefits may be derived from increased maternal folate concentrations, especially in non-obese women. These data also support epigenetic plasticity as a key mechanistic response to folate availability during early fetal development.
authors.affiliation: Department of Biological Sciences; North Carolina State University; Raleigh, NC USA; Department of Obstetrics and Gynecology; Division of Clinical Epidemiology; School of Medicine; Duke University; Durham, NC USA.
authors.forename: Cathrine
authors.initials: C
authors.lastname: Hoyo
authors.affiliation: Department of Global Public Health and Primary Care; University of Bergen; Bergen, Norway.
authors.forename: Anne Kjersti
authors.initials: AK
authors.lastname: Daltveit
authors.affiliation: Department of Statistics; Duke University; Durham, NC USA.
authors.forename: Edwin
authors.initials: E
authors.lastname: Iversen
authors.affiliation: Department of Community and Family Medicine; Duke University School of Medicine and Duke Global Health Institute; Durham, NC USA.
authors.forename: Sara E
authors.initials: SE
authors.lastname: Benjamin-Neelon
authors.affiliation: Department of Community and Family Medicine; Duke University; Durham, NC USA.
authors.forename: Bernard
authors.initials: B
authors.lastname: Fuemmeler
authors.affiliation: Department of Community and Family Medicine; Duke Cancer Institute; Duke University; Durham, NC USA.
authors.forename: Joellen
authors.initials: J
authors.lastname: Schildkraut
authors.affiliation: Department of Obstetrics and Gynecology; Division of Maternal-Fetal Medicine; School of Medicine; Duke University; Durham, NC USA.
authors.forename: Amy P
authors.initials: AP
authors.lastname: Murtha
authors.affiliation: Department of Obstetrics and Gynecology; Division of Clinical Epidemiology; School of Medicine; Duke University; Durham, NC USA.
authors.forename: Francine
authors.initials: F
authors.lastname: Overcash
authors.affiliation: Department of Obstetrics and Gynecology; Division of Clinical Epidemiology; School of Medicine; Duke University; Durham, NC USA.
authors.forename: Adriana C
authors.initials: AC
authors.lastname: Vidal
authors.affiliation: Department of Community and Family Medicine; Duke Cancer Institute; Duke University; Durham, NC USA.
authors.forename: Frances
authors.initials: F
authors.lastname: Wang
authors.affiliation: Department of Obstetrics and Gynecology; Division of Gynecologic Oncology; School of Medicine; Duke University; Durham, NC USA.
authors.forename: Zhiqing
authors.initials: Z
authors.lastname: Huang
authors.affiliation: Duke University Department of Pediatrics; Duke Cancer Institute; School of Medicine; Duke University; Durham, NC USA.
authors.forename: Joanne
authors.initials: J
authors.lastname: Kurtzberg
authors.affiliation: Department of Medicine; Division of Oncology; School of Medicine; Duke University; Durham, NC USA.
authors.forename: Victoria
authors.initials: V
authors.lastname: Seewaldt
authors.affiliation: Department of Nutritional Sciences; University of Texas; Austin, TX USA.
authors.forename: Michele
authors.initials: M
authors.lastname: Forman
authors.affiliation: Department of Oncology; McArdle Laboratory for Cancer Research; University of Wisconsin-Madison; Madison, WI USA.
authors.forename: Randy L
authors.initials: RL
authors.lastname: Jirtle
authors.affiliation: Department of Obstetrics and Gynecology; Division of Gynecologic Oncology; School of Medicine; Duke University; Durham, NC USA.
authors.forename: Susan K
authors.initials: SK
authors.lastname: Murphy
mesh_terms: D000293:Adolescent; D000328:Adult; D001724:Birth Weight / Q000235:genetics*; D015331:Cohort Studies; D018899:CpG Islands; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D004912:Erythrocytes / Q000378:metabolism*; D005006:Ethnicity; D005260:Female; D005492:Folic Acid / Q000097:blood*; D018392:Genomic Imprinting; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D011247:Pregnancy; D044469:Racial Groups; D055815:Young Adult
chemical_list: D005492:Folic Acid
keywords: DNA methylation; birth weight; epidemiology; epigenetics; folate; imprinted genes