Associations of maternal early-pregnancy blood glucose and insulin concentrations with DNA methylation in newborns

BACKGROUND: Intrauterine exposure to a disturbed maternal glucose metabolism is associated with adverse offspring outcomes. DNA methylation is a potential mechanism underlying these associations. We examined whether maternal early-pregnancy glucose and insulin concentrations are associated with newborn DNA methylation. In a population-based prospective cohort study among 935 pregnant women, maternal plasma concentrations of non-fasting glucose and insulin were measured at a median of 13.1 weeks of gestation (95% range 9.4-17.4). DNA methylation was measured using the Infinium HumanMethylation450 BeadChip (Ilumina). We analyzed associations of maternal early-pregnancy glucose and insulin concentrations with single-CpG DNA methylation using robust linear regression models. Differentially methylated regions were analyzed using the dmrff package in R. We stratified the analyses on normal weight versus overweight or obese women. We also performed a look-up of CpGs and differently methylated regions from previous studies to be associated with maternal gestational diabetes, hyperglycemia or hyperinsulinemia, or with type 2 diabetes in adults. RESULTS: Maternal early-pregnancy glucose and insulin concentrations were not associated with DNA methylation at single CpGs nor with differentially methylated regions in the total group. In analyses stratified on maternal BMI, maternal early-pregnancy glucose concentrations were associated with DNA methylation at one CpG (cg03617420, XKR6) among normal weight women and at another (cg12081946, IL17D) among overweight or obese women. No stratum-specific associations were found for maternal early-pregnancy insulin concentrations. The two CpGs were not associated with birth weight or childhood glycemic measures (p values > 0.1). Maternal early-pregnancy insulin concentrations were associated with one CpG known to be related to adult type 2 diabetes. Enrichment among nominally significant findings in our maternal early-pregnancy glucose concentrations was found for CpGs identified in a previous study on adult type 2 diabetes. CONCLUSIONS: Maternal early-pregnancy glucose concentrations, but not insulin concentrations, were associated with DNA methylation at one CpG each in the subgroups of normal weight and of overweight or obese women. No associations were present in the full group. The role of these CpGs in mechanisms underlying offspring health outcomes needs further study. Future studies should replicate our results in larger samples with early-pregnancy information on maternal fasting glucose metabolism

Invloed van DNA-methylatie op gezondheid en ziekte van kinderen

De ontwikkeling in de eerste fase van het leven is van groot belang voor de gezondheid van kinderen en volwassenen. Ongunstige invloeden in specifieke kritieke perioden tijdens de vroege ontwikkeling hebben nadelige effecten op de gezondheid op latere leeftijd. Er zijn steeds meer aanwijzingen dat vroege en permanente epigenetische veranderingen een belangrijke rol spelen in de onderliggende mechanismen. In dit artikel bespreken wij de rol van DNA-methylatie, het bekendste epigenetische mechanisme, op gezondheid en ziekte van kinderen. Wij gaan in op de achtergrond van DNA-methylatie, op factoren die hierop van invloed zijn en op gevolgen van DNA-methylatie. Onderzoek gericht op het identificeren van factoren tijdens en kort na de zwangerschap die via epigenetische mechanismen bijdragen aan de kans op ziekten, moet uiteindelijk leiden tot preventieprogramma’s gericht op de vroegste fase van het leven

Associations of genetic risk scores based on adult adiposity pathways with childhood growth and adiposity measures

Background: Results from genome-wide association studies (GWAS) identified many loci and biological pathways that influence adult body mass index (BMI). We aimed to identify if biological pathways related to adult BMI also affect infant growth and childhood adiposity measures. Methods: We used data from a population-based prospective cohort study among 3,975 children with a mean age of 6 years. Genetic risk scores were constructed based on the 97 SNPs associated with adult BMI previously identified with GWAS and on 28 BMI related biological pathways based on subsets of these 97 SNPs. Outcomes were infant peak weight velocity, BMI at adiposity peak and age at adiposity peak, and childhood BMI, total fat mass percentage, android/gynoid fat ratio, and preperitoneal fat area. Analyses were performed using linear regression models. Results: A higher overall adult BMI risk score was associated with infant BMI at adiposity peak and childhood BMI, total fat mass, android/gynoid fat ratio, and preperitoneal fat area (all p-values < 0.05). Analyses focused on specific biological pathways showed that the membrane proteins genetic risk score was associated with infant peak weight velocity, and the genetic risk scores related to neuronal developmental processes, hypothalamic processes, cyclicAMP, WNT-signaling, membrane proteins, monogenic obesity and/or energy homeostasis, glucose homeostasis, cell cycle, and muscle biology pathways were associated with childhood adiposity measures (all p-values <0.05). None of the pathways were associated with childhood preperitoneal fat area. Conclusions: A genetic risk score based on 97 SNPs related to adult BMI was associated with peak weight velocity during infancy and general and abdominal fat measurements at the age of 6 years. Risk scores based on genetic variants linked to specific biological pathways, including central nervous system and hypothalamic processes, influence body fat development from early life onwards

Newborn and childhood differential DNA methylation and liver fat in school-age children

Background: Non-alcoholic fatty liver disease is the most common chronic liver disease in children in western countries. Adverse early-life exposures are associated with higher liver fat percentages in children. Differential DNA methylation may underlie these associations. We aimed to identify differential DNA methylation in newborns and children associated with liver fat accumulation in childhood. We also examined whether DNA methylation at 22 cytosine-phosphate-guanine sites (CpGs) associated with adult non-alcoholic fatty liver disease is associated with liver fat in children. Within a population-based prospective cohort study, we analyzed epigenome-wide DNA methylation data of 785 newborns and 344 10-year-old children in relation to liver fat fraction at 10 years. DNA methylation was measured using the Infinium HumanMethylation450 BeadChip (Illumina). We measured liver fat fraction by Magnetic Resonance Imaging. Associations of single CpG DNA methylation at the two-time points with liver fat accumulation were analyzed using robust linear regression models. We also analyzed differentially methylation regions using the dmrff package. We looked-up associations of 22 known adult CpGs at both ages with liver fat at 10 years. Results: The median liver fat fraction was 2.0% (95% range 1.3, 5.1). No single CpGs and no differentially methylated regions were associated with liver fat accumulation. None of the 22 known adult CpGs were associated with liver fat in children. Conclusions: DNA methylation at birth and in childhood was not associated with liver fat accumulation in 10-year-old children in this study. This may be due to modest sample sizes or DNA methylation changes being a consequence rather than a determinant of liver fat

Liver Fat and Cardiometabolic Risk Factors Among School-Age Children

BACKGROUND AND AIMS: Nonalcoholic fatty liver disease is a major risk factor for cardiometabolic disease in adults. The burden of liver fat and associated cardiometabolic risk factors in healthy children is unknown. In a

Sugar-containing beverage intake at the age of 1 year and cardiometabolic health at the age of 6 years: The Generation R Study

Background: Consumption of sugar-containing beverages (SCBs) in adults has been associated with an increased risk of metabolic syndrome. Although the effect of SCB on body weight in children is well established, little is known about the cardiometabolic effects in young children. We studied the associations of SCB intake at the age of 1 year with cardiometabolic health at age 6 years. Methods: This study was performed among 2,045 Dutch children from a population based prospective birth cohort. SCB intake was assessed with a semi-quantitative food frequency questionnaire at the age of 13 months and sex-specific tertiles were created. Children visited the research center at the age of 6 years. We created a continuous cardiometabolic risk factor score including: body fat percentage, blood pressure, insulin, HDL-cholesterol and triglycerides. Age-and sex-specific standard deviation (SD) scores were created for all outcomes. Multivariable linear regression was performed with adjustment for socio-demographic and lifestyle variables of mother and child. Results: In the total population, we observed an association between higher SCB intake at 13 months of age and a higher cardiometabolic risk factor score at the age of 6 years (0.13SD (95 % CI 0.01; 0.25), highest vs. lowest tertile) After stratification by sex, we found that boys in the highest tertile of SCB intake had a higher cardiometabolic risk factor score (0.18 SD (95 % CI 0.01; 0.34)), as compared to boys in the lowest tertile of SCB intake. There was no significant association in girls. We did not find associations of SCB intake with the individual cardiometabolic risk factors in the total population, or in the stratified analyses. Conclusion: Higher SCB intake at 1 year of age was associated with a higher cardiometabolic risk factor score at age 6 years in boys, but not in girls. Further research on sex-specific effects of SCBs is needed

Psychological Distress and Weight Gain in Pregnancy: a Population-Based Study.

Background Psychological distress and inappropriate or excessive weight gain are common in pregnancy and are associated with adverse maternal and offspring outcomes. Psychological well-being and weight status of women during pregnancy might be interrelated. We aimed to examine whether psychological distress during pregnancy is associated with gestational weight gain. Method In a population-based cohort of 3393 pregnant women, information about psychological distress, depressive and anxiety symptoms was assessed at 20 weeks of gestation using the Brief Symptom Inventory questionnaire. Weight was repeatedly measured during pregnancy and obtained by questionnaire before and after pregnancy. Linear regression and multinomial logistic regression models were used. Weight gain in the second half of pregnancy, total weight gain, and the risks of inadequate and excessive total weight gain were the main outcome measures. Results In total, 7.0% of all women experienced psychological distress. Overall psychological distress and anxiety were associated with lower weight gain in the second half of pregnancy (differences − 1.00 kg (95% confidence interval (CI) − 1.62, − 0.37) and − 0.68 kg (95% CI - 1.24, -0.11), respectively). These associations fully attenuated into non-significance after taking account for socio-demographic variables. Similar results were observed for total weight gain. Only women with anxiety symptoms had, independently of potential confounders, a lower risk of excessive weight gain (odds ratio (OR) 0.61 (95% CI 0.48, 0.91)). Conclusions In this large prospective cohort study, the observed associations of psychological distress with weight gain during pregnancy seem to be largely explained by common socio-demographic factors

Risk Factors for Chronic Lung Disease and Mortality in Newborns with Congenital Diaphragmatic Hernia

Background: Congenital diaphragmatic hernia (CDH) is associated with a mortality rate of 10-35% in live-born infants. Moreover, CDH survivors have a substantial risk of developing long-term pulmonary sequelae, such as bronchopulmonary dysplasia (BPD). Objectives: This study aims to evaluate risk factors associated with BPD and mortality in neonates with CDH, with particular focus on the initial ventilation mode. Methods: Eligible for inclusion were live-born infants with CDH born from 2001 through 2006 at the centers participating in the CDH Study Group. BPD (defined as oxygen dependency at day 30) and/or mortality by day 30 served as the primary endpoint. Results: A total of 2,078 neonates were included in the analysis. At day 30, 56% of the patients had either died or met the criteria for BPD. In infants who survived until day 30, the prevalence of BPD was 41%. The overall mortality rate was 31%. High-frequency oscillatory ventilation as initial ventilation mode, a right-sided defect, a prenatal diagnosis, a lower Apgar score at 5 min, a cardiac anomaly, a chromosomal anomaly and a lower gestational age were all associated with BPD and/or mortality by day 30. Conclusions: Despite improvements in neonatal care, the rates of BPD and early mortality in newborns with CDH are still considerable. Several important risk factors for a worse outcome are reported in this nonrandomized prospe

Timing- and Dose-Specific Associations of Prenatal Smoke Exposure With Newborn DNA Methylation

Introduction: Fetal changes in DNA methylation may underlie associations of maternal smoking during pregnancy with adverse outcomes in children. We examined critical periods and doses of maternal smoking during pregnancy in relation to newborn DNA methylation, and associations of paternal smoking with newborn DNA methylation. Aims and Methods: This study was embedded in the Generation R Study, a population-based prospective cohort study from early pregnancy onwards. We assessed parental smoking during pregnancy using questionnaires. We analyzed associations of prenatal smoke exposure with newborn DNA methylation at 5915 known maternal smoking-related cytosine-phosphate-guanine sites (CpGs) in 1261 newborns using linear regression. Associations with false discovery rate-corrected p-values < .05 were taken forward. Results: Sustained maternal smoking was associated with newborn DNA methylation at 1391 CpGs, compared with never smoking. Neither quitting smoking early in pregnancy nor former smoking was associated with DNA methylation, compared with never smoking. Among sustained smokers, smoking ≥5, compared with <5, cigarettes/d was associated with DNA methylation at seven CpGs. Paternal smoking was not associated with DNA methylation, independent of maternal smoking status. Conclusions: Our results suggest that CpGs associated with sustained maternal smoking are not associated with maternal smoking earlier in pregnancy or with paternal smoking. Some of these CpGs show dose–response relationships with sustained maternal smoking. The third trimester may comprise a critical period for associations of smoking with newborn DNA methylation, or sustained smoking may reflect higher cumulative doses. Alternatively, maternal smoking limited to early pregnancy and paternal smoking may be associated with DNA methylation at specific other CpGs not studied here. Implications: Our results suggest that quitting maternal smoking before the third trimester of pregnancy, and possibly lowering smoking dose, may prevent differential DNA methylation in the newborns at CpGs associated with sustained smoking. If the relevance of DNA methylation for clinical outcomes is established, these results may help in counseling parents-to-be about quitting smoking