Methylation of the FGFR2 gene is associated with high birth weight centile in humans.

AIMS: This study examined links between DNA methylation and birth weight centile (BWC), and explored the impact of genetic variation. MATERIALS & METHODS: Using HumanMethylation450 arrays, we examined candidate gene-associated CpGs in cord blood from newborns with low (<15th centile), medium (40-60th centile) and high (>85th centile) BWC (n = 12). Candidates were examined in an investigation cohort (n = 110) using pyrosequencing and genotyping for putative methylation-associated polymorphisms performed using standard PCR. RESULTS: Array analysis identified 314 candidate genes associated with BWC extremes, four of which showed ≥ 4 BWC-linked CpGs. Of these, PM20D1 and MI886 suggested genetically determined methylation levels. However, methylation at three CpGs in FGFR2 remained significantly associated with high BWC (p = 0.004-0.027). CONCLUSION: We identified a novel biologically plausible candidate (FGFR2) for with BWC that merits further study.

Combined influence of gene-specific cord blood methylation and maternal smoking habit on birth weight.

AIM: 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. MATERIALS & 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. CONCLUSION: 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.