Prenatal parental tobacco smoking, gene specific DNA methylation, and newborns size: the Generation R study

Background: Deleterious effects of prenatal tobacco smoking on fetal growth and newborn weight are well-established. One of the proposed mechanisms underlying this relationship is alterations in epigenetic programming. We selected 506 newborns from a population-based prospective birth cohort in the Netherlands. Prenatal parental tobacco smoking was assessed using self-reporting questionnaires. Information on birth outcomes was obtained from medical records. The deoxyribonucleic acid (DNA) methylation of the growth genes IGF2DMR and H19 was measured in newborn umbilical cord white blood cells. Associations were assessed between parental tobacco smoking and DNA methylation using linear mixed models and adjusted for potential confounders. Results: The DNA methylation levels of IGF2DMR and H19 in the non-smoking group were median (90 % range), 54.0 % (44.6–62.0), and 30.0 % (25.5–34.0), in the first trimester only smoking group 52.2 % (44.5–61.1) and 30.8 % (27.1–34.1), and in the continued smoking group 51.6 % (43.9–61.3) and 30.2 % (23.7–34.8), respectively. Continued prenatal maternal smoking was inversely associated with IGF2DMR methylation (β = −1.03, 95 % CI −1.76; −0.30) in a dose-dependent manner (P-trend = 0.030). This association seemed to be slightly more profound among newborn girls (β = −1.38, 95 % CI −2.63; −0.14) than boys (β = −0.72, 95 % CI −1.68; 0.24). H19 methylation was also inversely associated continued smoking <5 cigarettes/day (β = −0.96, 95 % CI −1.78; −0.14). Moreover, the association between maternal smoking and newborns small for gestational age seems to be partially explained by IGF2DMR methylation (β = −0.095, 95 % CI −0.249; −0.018). Among non-smoking mothers, paternal tobacco smoking was not associated with IGF2DMR or H19 methylation. Conclusions: Maternal smoking is inversely associated with IGF2DMR methylation in newborns, which can be one of the underlying mechanisms through which smoking affects fetal growth

Scales, Implicatures, and in fact, if not, and let alone Constructions.

太田朗先生傘寿記念論文

Maternal soluble fms-like tyrosine kinase-1, placental growth factor, plasminogen activator inhibitor-2, and folate concentrations and early fetal size:the Generation R study

<p>OBJECTIVE: Fetal growth is dependent on adequate development of the placenta. Impaired angiogenesis and vasculogenesis in early pregnancy compromises placental and embryonic development. The proteins soluble fms-like tyrosine kinase (sFlt)-1, placental growth factor (PlGF), and plasminogen activator inhibitor (PAI)-2, and the B vitamin folate are determinants of placental development. This study aims to identify associations between these maternal biomarkers and early fetal size.</p><p>STUDY DESIGN: From a prospective birth cohort study in The Netherlands, 1491 pregnant women were selected for this study. At a mean gestational age (GA) of 12.4 weeks (SD 0.8) maternal venous blood samples were obtained to determine the concentrations of sFlt-1, PlGF, PAI-2, and folate. Early fetal size was assessed with measurement of the crown-to-rump length (CRL) at a mean of 12.4 weeks' GA (SD 0.8). Analyses were performed using multivariable linear regression analyses with the biomarkers (continuous, quintiles) as regressors and CRL as main outcome measure.</p><p>RESULTS: Linear trend analysis showed positive associations between maternal sFlt-1 (P <.001), PlGF (P = .042), PAI-2 (P <.001), and folate (P = .039) and CRL. These associations were independent of GA, maternal age, height, body mass index, ethnicity, fetal sex, parity, educational level, smoking, and folic acid supplement use (folate not adjusted).</p><p>CONCLUSION: sFlt-1, PlGF, PAI-2, and folate are positively associated with first-trimester fetal size.</p>

Baseline characteristics for the two study groups.

<p>Data is presented of the Dutch study group (n = 110) and the Texan study group (n = 119). Values are presented as * mean (SD) or ^† median (IQR). Chi-square, t- and Mann-Whitney U tests were used to test differences between NTD and control children.</p

Epigenetic Profiles in Children with a Neural Tube Defect; A Case-Control Study in Two Populations

<div><p>Folate deficiency is implicated in the causation of neural tube defects (NTDs). The preventive effect of periconceptional folic acid supplement use is partially explained by the treatment of a deranged folate-dependent one carbon metabolism, which provides methyl groups for DNA-methylation as an epigenetic mechanism. Here, we hypothesize that variations in DNA-methylation of genes implicated in the development of NTDs and embryonic growth are part of the underlying mechanism. In 48 children with a neural tube defect and 62 controls from a Dutch case-control study and 34 children with a neural tube defect and 78 controls from a Texan case-control study, we measured the DNA-methylation levels of imprinted candidate genes (<i>IGF2</i>-DMR, <i>H19, KCNQ1OT1)</i> and non-imprinted genes (the <i>LEKR/CCNL</i> gene region associated with birth weight, and <i>MTHFR</i> and <i>VANGL1</i> associated with NTD). We used the MassARRAY EpiTYPER assay from Sequenom for the assessment of DNA-methylation. Linear mixed model analysis was used to estimate associations between DNA-methylation levels of the genes and a neural tube defect. In the Dutch study group, but not in the Texan study group we found a significant association between the risk of having an NTD and DNA methylation levels of <i>MTHFR</i> (absolute decrease in methylation of −0.33% in cases, P-value = 0.001), and <i>LEKR/CCNL</i> (absolute increase in methylation: 1.36% in cases, P-value = 0.048), and a borderline significant association for <i>VANGL</i> (absolute increase in methylation: 0.17% in cases, P-value = 0.063). Only the association between <i>MTHFR</i> and NTD-risk remained significant after multiple testing correction. The associations in the Dutch study were not replicated in the Texan study. We conclude that the associations between NTDs and the methylation of the <i>MTHFR</i> gene, and maybe <i>VANGL</i> and <i>LEKKR/CNNL</i>, are in line with previous studies showing polymorphisms in the same genes in association with NTDs and embryonic development, respectively.</p></div

Methylation levels per locus stratified by study and case-control status.

<p>Box and whisker plots of methylation values (y-axis) of all individuals are shown for each CpG unit (x-axis) for NTD case and control children separately.</p

Maternal and infant characteristics.

<p>Values are presented as</p>*<p>mean (standard deviation) and</p><p>†median (90% range).</p>1<p>Student's T-test, Mann Whitney U and chi-square tests are used to test differences between the control group and the SGA group.</p

Associations between fetal and infant growth parameters and DNA methylation.

<p>Results from linear mixed model analyses with DNA methylation as dependent variable and the fetal growth parameters as independent variables. Results are presented for the whole study population and stratified for SGA/AGA. Analyses were performed with square-root transformed methylation data and values are presented as regression coefficients (95% confidence interval).</p>1<p>Crude values are adjusted for the correlations between CpG sites, bisulphite batch, and gestational age.</p>2<p>Adjusted values were additionally adjusted for maternal characteristics (age, educational level, parity, BMI, folic acid supplement use, smoking and the occurrence of preeclampsia) and fetal gender.</p