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Quantitative, high-resolution epigenetic profiling of CpG loci identifies associations with cord blood plasma homocysteine and birth weight in humans.

ABSTRACT: Supplementation with folic acid during pregnancy is known to reduce the risk of neural tube defects and low birth weight. It is thought that folate and other one-carbon intermediates might secure these clinical effects via DNA methylation. We examined the effects of folate on the human methylome using quantitative interrogation of 27,578 CpG loci associated with 14,496 genes at single-nucleotide resolution across 12 fetal cord blood samples. Consistent with previous studies, the majority of CpG dinucleotides located within CpG islands exhibited hypo-methylation while those outside CpG islands showed mid-high methylation. However, for the first time in human samples, unbiased analysis of methylation across samples revealed a significant correlation of methylation patterns with plasma homocysteine, LINE-1 methylation and birth weight centile. Additionally, CpG methylation significantly correlated with either birth weight or LINE-1 methylation were predominantly located in CpG islands. These data indicate that levels of folate-associated intermediates in cord blood reflect their influence and consequences for the fetal epigenome and potentially on pregnancy outcome. In these cases, their influence might be exerted during late gestation or reflect those present during the peri-conceptual period.

SUBMITTER: Fryer AA

PROVIDER: S-EPMC3052917 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature

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Quantitative, high-resolution epigenetic profiling of CpG loci identifies associations with cord blood plasma homocysteine and birth weight in humans.

Fryer Anthony A AA Emes Richard D RD Ismail Khaled M K KM Haworth Kim E KE Mein Charles C Carroll William D WD Farrell William E WE

Epigenetics 20110101 1

Supplementation with folic acid during pregnancy is known to reduce the risk of neural tube defects and low birth weight. It is thought that folate and other one-carbon intermediates might secure these clinical effects via DNA methylation. We examined the effects of folate on the human methylome using quantitative interrogation of 27,578 CpG loci associated with 14,496 genes at single-nucleotide resolution across 12 fetal cord blood samples. Consistent with previous studies, the majority of CpG ...[more]

PMID: 20864804

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Project description:BackgroundCirculating folate, vitamin B12 and homocysteine concentrations during fetal development have been associated with health outcomes in childhood. Changes in fetal DNA methylation may be an underlying mechanism. This may be reflected in altered epigenetic aging of the fetus, as compared to chronological aging. The difference between gestational age derived in clinical practice and gestational age predicted from neonatal DNA methylation data is referred to as gestational age acceleration. Differences in circulating folate, vitamin B12 and homocysteine concentrations during fetal development may be associated with gestational age acceleration.ResultsUp to 1346 newborns participating in the Generation R Study, a population-based prospective cohort study, had both cord blood DNA methylation data available and information on plasma folate, serum total and active B12 and plasma homocysteine concentrations, measured in early pregnancy and/or in cord blood. A subgroup of 380 newborns had mothers with optimal pregnancy dating based on a regular menstrual cycle and a known date of last menstrual period. For comparison, gestational age acceleration was calculated based the method of both Bohlin and Knight. In the total study population, which was more similar to Bohlin's training population, one standard deviation score (SDS) higher maternal plasma homocysteine concentrations was nominally associated with positive gestational age acceleration [0.07 weeks, 95% confidence interval (CI) 0.02, 0.13] by Bohlin's method. In the subgroup with pregnancy dating based on last menstrual period, the method that was also used in Knight's training population, one SDS higher cord serum total and active B12 concentrations were nominally associated with negative gestational age acceleration [(- 0.16 weeks, 95% CI - 0.30, - 0.02) and (- 0.15 weeks, 95% CI - 0.29, - 0.01), respectively] by Knight's method.ConclusionsWe found some evidence to support associations of higher maternal plasma homocysteine concentrations with positive gestational age acceleration, suggesting faster epigenetic than clinical gestational aging. Cord serum vitamin B12 concentrations may be associated with negative gestational age acceleration, indicating slower epigenetic than clinical gestational aging. Future studies could examine whether altered fetal epigenetic aging underlies the associations of circulating homocysteine and vitamin B12 blood concentrations during fetal development with long-term health outcomes.

Project description:Selection for larger litter size has increased the number of low individual birth weight (BWi) pigs and produced sows with a repeatable low average litter birth weight phenotype (BWP). Using an average of 3.6 litters records per sow, BWP was established in 644 nucleus-multiplication sows producing replacement gilts in a large commercial operation and classified as low (L-BWP, <1.18 kg, n = 85), medium (M-BWP, ≥1.18 to ≤1.35 kg, n = 250), or high (H-BWP, >1.35 kg, n = 309) on the basis of a BWi of 1.18 kg below which there was a high risk of early mortality and the average BWi (1.35 kg) for the population. In subsequent litters, potential replacement gilts born to these sows (n = 7,341) received a unique identification tag that allowed the impact of BWi, BWP, and their interactions on the efficiency of replacement gilt production to be evaluated. Negative effects of BWi on mortality until day 4 after birth were confirmed (P < 0.05) and cumulative losses to weaning, to day 70 of age, and to final pre-selection at 165 d of age were affected (P ≤ 0.05) by the interaction between BWP and BWi. Among the 2,035 gilts for which records for selection efficiency and production to fourth parity were available, a lower BWi decreased the probability of gilts reaching pubertal estrus (P < 0.05) after 21 and 28 d of boar stimulation starting at 180 d of age, with no effect of BWP. Overall, neither BWi, BWP, nor their interaction affected age at puberty. After breeding, only the main effect of BWP affected productivity and retention in the sow herd. In parities 1 and 2, percent stillborn was higher in litters born to gilts from H-BWP compared with L-BWP dams (P < 0.05), and in parity 2, total born and born alive were lower in sows derived from H-BWP compared with other BWPs. There were no differences in retention based on BWP classes until parity 2, after which retention tended (P ≤ 0.09) to be lower in sows derived from H-BWP compared with L-BWP dams. These results provide evidence that sow BWP is an important factor in the overall efficiency of replacement gilt management. This study also confirms that effective gilt selection and pre-breeding management protocols support excellent sow lifetime productivity and mitigate the risk of a high BWP in the litter of origin affecting retention in the breeding herd.

Dataset Information

Quantitative, high-resolution epigenetic profiling of CpG loci identifies associations with cord blood plasma homocysteine and birth weight in humans.

Publications

Quantitative, high-resolution epigenetic profiling of CpG loci identifies associations with cord blood plasma homocysteine and birth weight in humans.

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