title: Genetic and non-genetic influences during pregnancy on infant global and site specific DNA methylation: role for folate gene variants and vitamin B12.
abstract: Inter-individual variation in patterns of DNA methylation at birth can be explained by the influence of environmental, genetic and stochastic factors. This study investigates the genetic and non-genetic determinants of variation in DNA methylation in human infants. Given its central role in provision of methyl groups for DNA methylation, this study focuses on aspects of folate metabolism. Global (LUMA) and gene specific (IGF2, ZNT5, IGFBP3) DNA methylation were quantified in 430 infants by Pyrosequencing®. Seven polymorphisms in 6 genes (MTHFR, MTRR, FOLH1, CβS, RFC1, SHMT) involved in folate absorption and metabolism were analysed in DNA from both infants and mothers. Red blood cell folate and serum vitamin B(12) concentrations were measured as indices of vitamin status. Relationships between DNA methylation patterns and several covariates viz. sex, gestation length, maternal and infant red cell folate, maternal and infant serum vitamin B(12), maternal age, smoking and genotype were tested. Length of gestation correlated positively with IGF2 methylation (rho = 0.11, p = 0.032) and inversely with ZNT5 methylation (rho = -0.13, p = 0.017). Methylation of the IGFBP3 locus correlated inversely with infant vitamin B(12) concentration (rho = -0.16, p = 0.007), whilst global DNA methylation correlated inversely with maternal vitamin B(12) concentrations (rho = 0.18, p = 0.044). Analysis of common genetic variants in folate pathway genes highlighted several associations including infant MTRR 66G>A genotype with DNA methylation (χ(2) = 8.82, p = 0.003) and maternal MTHFR 677C>T genotype with IGF2 methylation (χ(2) = 2.77, p = 0.006). These data support the hypothesis that both environmental and genetic factors involved in one-carbon metabolism influence DNA methylation in infants. Specifically, the findings highlight the importance of vitamin B(12) status, infant MTRR genotype and maternal MTHFR genotype, all of which may influence the supply of methyl groups for DNA methylation. In addition, gestational length appears to be an important determinant of infant DNA methylation patterns.
authors.affiliation: Institute for Ageing and Health, Human Nutrition Research Centre, Newcastle University, Newcastle upon Tyne, Tyne and Wear, United Kingdom. jill.mckay@ncl.ac.uk
authors.forename: Jill A
authors.initials: JA
authors.lastname: McKay
authors.forename: Alexandra
authors.initials: A
authors.lastname: Groom
authors.forename: Catherine
authors.initials: C
authors.lastname: Potter
authors.forename: Lisa J
authors.initials: LJ
authors.lastname: Coneyworth
authors.forename: Dianne
authors.initials: D
authors.lastname: Ford
authors.forename: John C
authors.initials: JC
authors.lastname: Mathers
authors.forename: Caroline L
authors.initials: CL
authors.lastname: Relton
mesh_terms: D000328:Adult; D027682:Cation Transport Proteins / Q000235:genetics; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation; D005260:Female; D005287:Ferredoxin-NADP Reductase / Q000235:genetics / Q000378:metabolism; D005492:Folic Acid / Q000097:blood* / Q000378:metabolism; D005787:Gene Frequency; D005838:Genotype; D005865:Gestational Age; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000235:genetics; D007335:Insulin-Like Growth Factor II / Q000235:genetics; D016014:Linear Models; D008297:Male; D008423:Maternal Age; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics / Q000378:metabolism; D015999:Multivariate Analysis; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D011247:Pregnancy; D014805:Vitamin B 12 / Q000097:blood* / Q000378:metabolism; D055815:Young Adult
chemical_list: D027682:Cation Transport Proteins; C035170:IGF2 protein, human; C515497:IGFBP3 protein, human; D018972:Insulin-Like Growth Factor Binding Protein 3; C457225:SLC30A5 protein, human; D007335:Insulin-Like Growth Factor II; D005492:Folic Acid; C111241:methionine synthase reductase; D005287:Ferredoxin-NADP Reductase; C573423:MTHFR protein, human; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D014805:Vitamin B 12