DNA methylation and body mass index from birth to adolescence : meta-analyses of epigenome-wide association studies

Background DNA methylation has been shown to be associated with adiposity in adulthood. However, whether similar DNA methylation patterns are associated with childhood and adolescent body mass index (BMI) is largely unknown. More insight into this relationship at younger ages may have implications for future prevention of obesity and its related traits. Methods We examined whether DNA methylation in cord blood and whole blood in childhood and adolescence was associated with BMI in the age range from 2 to 18 years using both cross-sectional and longitudinal models. We performed meta-analyses of epigenome-wide association studies including up to 4133 children from 23 studies. We examined the overlap of findings reported in previous studies in children and adults with those in our analyses and calculated enrichment. Results DNA methylation at three CpGs (cg05937453, cg25212453, and cg10040131), each in a different age range, was associated with BMI at Bonferroni significance, P <1.06 x 10(-7), with a 0.96 standard deviation score (SDS) (standard error (SE) 0.17), 0.32 SDS (SE 0.06), and 0.32 BMI SDS (SE 0.06) higher BMI per 10% increase in methylation, respectively. DNA methylation at nine additional CpGs in the cross-sectional childhood model was associated with BMI at false discovery rate significance. The strength of the associations of DNA methylation at the 187 CpGs previously identified to be associated with adult BMI, increased with advancing age across childhood and adolescence in our analyses. In addition, correlation coefficients between effect estimates for those CpGs in adults and in children and adolescents also increased. Among the top findings for each age range, we observed increasing enrichment for the CpGs that were previously identified in adults (birth P-enrichment = 1; childhood P-enrichment = 2.00 x 10(-4); adolescence P-enrichment = 2.10 x 10(-7)). Conclusions There were only minimal associations of DNA methylation with childhood and adolescent BMI. With the advancing age of the participants across childhood and adolescence, we observed increasing overlap with altered DNA methylation loci reported in association with adult BMI. These findings may be compatible with the hypothesis that DNA methylation differences are mostly a consequence rather than a cause of obesity.Peer reviewe

Epigenome-wide meta-analysis of blood DNA methylation in newborns and children identifies numerous loci related to gestational age

Background Preterm birth and shorter duration of pregnancy are associated with increased morbidity in neonatal and later life. As the epigenome is known to have an important role during fetal development, we investigated associations between gestational age and blood DNA methylation in children. Methods We performed meta-analysis of Illumina's HumanMethylation450-array associations between gestational age and cord blood DNA methylation in 3648 newborns from 17 cohorts without common pregnancy complications, induced delivery or caesarean section. We also explored associations of gestational age with DNA methylation measured at 4-18 years in additional pediatric cohorts. Follow-up analyses of DNA methylation and gene expression correlations were performed in cord blood. DNA methylation profiles were also explored in tissues relevant for gestational age health effects: fetal brain and lung. Results We identified 8899 CpGs in cord blood that were associated with gestational age (range 27-42 weeks), at Bonferroni significance, P <1.06 x 10(- 7), of which 3343 were novel. These were annotated to 4966 genes. After restricting findings to at least three significant adjacent CpGs, we identified 1276 CpGs annotated to 325 genes. Results were generally consistent when analyses were restricted to term births. Cord blood findings tended not to persist into childhood and adolescence. Pathway analyses identified enrichment for biological processes critical to embryonic development. Follow-up of identified genes showed correlations between gestational age and DNA methylation levels in fetal brain and lung tissue, as well as correlation with expression levels. Conclusions We identified numerous CpGs differentially methylated in relation to gestational age at birth that appear to reflect fetal developmental processes across tissues. These findings may contribute to understanding mechanisms linking gestational age to health effects.Peer reviewe

Supplementary Material for: Antenatal Magnesium Sulfate and Preeclampsia Differentially Affect Neonatal Cerebral Oxygenation

Introduction: Magnesium sulfate (MgSO4) is frequently administered for maternal and fetal neuroprotection in preeclampsia (PE) and imminent preterm birth, respectively. Objective: To assess whether MgSO4 affects neonatal cerebral oxygenation, blood flow, and cerebral autoregulation (CAR) during the first postnatal days independently from PE. Methods: 148 neonates &lt;32 weeks gestational age were included. Cerebral fractional tissue oxygen extraction (cFTOE) was extracted from a daily 2-h period, during which peak systolic blood flow velocity (PSV) and resistance index (RI) of the pericallosal artery were obtained. The percent time of impaired CAR (correlation coefficient between mean arterial blood pressure and cerebral oxygen saturation &gt;0.5) was determined. Linear mixed models were applied. Results: MgSO4 exposure was recorded in 77 neonates. Twenty-nine neonates were born following PE. MgSO4 independently lowered cFTOE (B: –0.026, 95% CI: –0.050 to 0.002, p &lt; 0.05) but did not affect PSV and RI. PE was associated with a lower cFTOE (B: –0.041, 95% CI: –0.067 to –0.015, p &lt; 0.05) and a tendency towards both lower PSV (B: –4.285, 95% CI: –9.067 to 0.497, p &lt; 0.1) and more impaired CAR (B: 4.042, 95% CI: –0.028 to 8.112, p &lt; 0.1), which seemed to be strongly mediated by fetal brain sparing. MgSO4 did not alter CAR. Conclusions: In contrast to fetal brain sparing in PE, MgSO4 seems to lower cFTOE by lowering cerebral oxygen demands in preterm neonates without affecting the cerebrovasculature

Supplementary Material for: Course of Stress during the Neonatal Intensive Care Unit Stay in Preterm Infants

Introduction: Understanding the course of stress during the neonatal intensive care unit stay may provide targets for interventions. Our aim was to describe the course of stress in preterm infants during the first 28 days of life, the influence of gestational age, and associations with clinical characteristics. Methods: In a single centre prospective cohort study, we included infants with a gestational age &lt;30 weeks and/or birth weight &lt;1,000 g. We measured stress over the first 28 days using the Neonatal Infant Stressor Scale (NISS). We plotted daily NISS total and subcategory scores by gestational age. The subcategories were (1) nursing, (2) skin-breaking, (3) monitoring and imaging, and (4) medical morbidity-related scores. We assessed associations of cumulative NISS scores over the first 7, 14, and 28 days with clinical characteristics using regression analyses. Results: We included 45 infants, with a median gestational age of 27 weeks. The mean daily NISS score was 66.5 (SD 8.7), with highest scores in the first 7 days of life. Scores decreased the slowest for the lowest gestational ages, in particular for nursing scores, rather than skin-breaking, monitoring and imaging, and medical morbidity-related scores. Adjusted for gestational age, infants with lower Apgar scores, sepsis, intraventricular haemorrhages, and on mechanical ventilation had significantly higher cumulative NISS scores at 7, 14, and 28 days. Conclusion: NISS scores varied greatly within infants and over time, with the highest mean scores in the first week after birth. The course of declining NISS scores in the first 28 days depended on gestational age at birth

Supplementary Material for: Course of Stress during the Neonatal Intensive Care Unit Stay in Preterm Infants

Introduction: Understanding the course of stress during the neonatal intensive care unit stay may provide targets for interventions. Our aim was to describe the course of stress in preterm infants during the first 28 days of life, the influence of gestational age, and associations with clinical characteristics. Methods: In a single centre prospective cohort study, we included infants with a gestational ag

Supplementary Material for: Cerebral and Renal Oxygen Saturation Are Not Compromised in the Presence of Retrograde Blood Flow in either the Ascending or Descending Aorta in Term or Near-Term Infants with Left-Sided Obstructive Lesions

Background: In infants with left-sided obstructive lesions (LSOL), the presence of retrograde blood flow in either the ascending or descending aorta may lead to diminished cerebral and renal blood flow, respectively. Objectives: Our aim was to compare cerebral and renal tissue oxygen saturation (rSO2) between infants with LSOL with antegrade and retrograde blood flow in the ascending aorta and with and without diastolic backflow in the descending aorta. Methods: Based on 2 echocardiograms, the study group was categorized according to the direction of blood flow in the ascending and descending aorta. We measured cerebral and renal rSO2 using near-infrared spectroscopy and calculated fractional tissue oxygen extraction (FTOE). Results: Nineteen infants with LSOL, admitted to the NICU between 0 and 28 days after birth, were included. Infants with antegrade blood flow (n = 12) and infants with retrograde blood flow in the ascending aorta (n = 7) had similar cerebral rSO2 and FTOE during both echocardiograms. Only during the first echocardiogram, infants with retrograde blood flow in the ascending aorta had lower renal FTOE (0.14 vs. 0.32, p = 0.04) and tended to have higher renal rSO2 (80 vs. 65%, p = 0.09). The presence of diastolic backflow in the descending aorta was not associated with cerebral or renal rSO2 and FTOE during the first (n = 8) as well as the second echocardiogram (n = 10). Conclusions: Retrograde blood flow in the ascending aorta was not associated with cerebral oxygenation, while diastolic backflow in the descending aorta was not associated with renal oxygenation in infants with LSOL

Additional file 1: of Current phototherapy practice on Java, Indonesia

Intensity data of all phototherapy devices from participating hospitals. (XLSX 86 kb