title: Combined influence of gene-specific cord blood methylation and maternal smoking habit on birth weight.
abstract: OBJECTIVE
  Evidence suggests that folic acid intake affects birth weight and that these effects may be mediated via the fetal epigenome. Our previous array data indicate that methylation in human cord blood at gene-specific CpGs is associated with birth weight percentile (BWP). Our aims were to investigate associations with BWP in specific CpGs identified by the array analysis in a significantly larger cohort and investigate the effects of other relevant factors on this association.
  
  
  METHODS
  Methylation status was examined in candidate CpGs in 129 cord blood samples using Pyrosequencing™. The effects of other potentially important factors; maternal smoking, folate-related metabolite levels and genetic variation in the MTHFR gene, were examined. Linear and logistic regression analyses were used to identify relationships between BWP and methylation levels in the context of other key factors.
  
  
  RESULTS
  Increased cord methylation at CpGs in GSTM5 and MAP2K3 was associated with a reduced risk of having a birth weight below the 50th percentile (p = 0.010; odds ratio [OR]: 0.33 and p = 0.024; OR: 0.24, respectively) while higher methylation levels in APOB were associated with an increased risk (p = 0.023; OR: 2.56). Smoking during pregnancy modified the effect of methylation on BWP. Thus, compared with nonsmokers with a GSTM5 methylation level of >25% (median BWP: 54.7%), those who had smoked during pregnancy and whose GSTM5 methylation was <25% had the lowest median BWP (12.0%; p = 0.001). Furthermore, this latter group had the highest proportion of cases with BWPs below 50% (92.9 compared with 47.8% in nonsmokers with a GSTM5 methylation level of >25%; p = 0.013; OR: 14.2). Similar results were identified for MAP2K3, while the link with APOB reflected the inverse relationship between methylation at this locus and BWP.
  
  
  CONCLUSIONS
  Our data suggest that gene-specific methylation of cord DNA is associated with BWP and this methylation provides an additional effect on BWP to that of smoking during pregnancy.
authors: Institute of Science & Technology in Medicine, Keele University School of Medicine, Stoke-on-Trent, Staffordshire, UK.
authors: Kim E
authors: KE
authors: Haworth
authors: William E
authors: WE
authors: Farrell
authors: Richard D
authors: RD
authors: Emes
authors: Khaled M K
authors: KM
authors: Ismail
authors: William D
authors: WD
authors: Carroll
authors: Hazel-Ann D
authors: HA
authors: Borthwick
authors: Alexandra M
authors: AM
authors: Yates
authors: Emma
authors: E
authors: Hubball
authors: Angela
authors: A
authors: Rooney
authors: Mazeda
authors: M
authors: Khanam
authors: Neyha
authors: N
authors: Aggarwal
authors: Peter W
authors: PW
authors: Jones
authors: Anthony A
authors: AA
authors: Fryer
mesh_terms: D001724:Birth Weight / Q000235:genetics*; D019175:DNA Methylation / Q000235:genetics*; D005260:Female; D005312:Fetal Blood; D056726:Genetic Association Studies; D005982:Glutathione Transferase / Q000235:genetics; D006801:Humans; D007231:Infant, Newborn; D048371:MAP Kinase Kinase 3 / Q000235:genetics; D008297:Male; D011247:Pregnancy; D012907:Smoking / Q000009:adverse effects*
chemical_list: C524366:GSTM5 protein, human; D005982:Glutathione Transferase; D048371:MAP Kinase Kinase 3; C482530:MAP2K3 protein, human