BackgroundChildren exposed to gestational diabetes mellitus (GDM) are at a higher risk of developing obesity and type 2 diabetes. This susceptibility might involve brown adipose tissue (BAT), which is suspected to protect against obesity. The objective of this study is to assess whether fetal exposure to maternal hyperglycemia is associated with DNA methylation variations in genes involved in BAT genesis and activation.MethodsDNA methylation levels at the PRDM16, BMP7, CTBP2, and PPARGC1α gene loci were measured in placenta samples using bisulfite pyrosequencing in E-21 (n = 133; 33 cases of GDM) and the HumanMethylation450 array in Gen3G (n = 172, all from non-diabetic women) birth cohorts. Glucose tolerance was assessed in all women using an oral glucose tolerance test at the second trimester of pregnancy. Participating women were extensively phenotyped throughout pregnancy, and placenta and cord blood samples were collected at birth.ResultsWe report that maternal glycemia at the second and third trimester of pregnancy are correlated with variations in DNA methylation levels at PRDM16, BMP7, and PPARGC1α and with cord blood leptin levels. Variations in PRDM16 and PPARGC1α DNA methylation levels were also correlated with cord blood leptin levels. Mediation analyses support that DNA methylation variations at the PPARGC1α gene locus explain 0.8 % of the cord blood leptin levels variance independently of maternal fasting glucose levels (p = 0.05).ConclusionsThese results suggest that maternal glucose in pregnancy could produce variations in DNA methylation in BAT-related genes and that some of these DNA methylation marks seem to mediate the impact of maternal glycemia on cord blood leptin levels, an adipokine regulating body weight.Electronic supplementary materialThe online version of this article (doi:10.1186/s13148-016-0239-9) contains supplementary material, which is available to authorized users.

Maternal hyperglycemia during pregnancy is associated with excess fetal growth and adverse perinatal and developmental outcomes. Placental epigenetic maladaptation may underlie these associations. We performed an epigenome-wide association study (>850,000 CpG sites) of term placentas and prenatal maternal glycemic response 2-h post oral glucose challenge at 24-30 weeks of gestation among 448 mother-infant pairs. Maternal 2-h glycemia postload was strongly associated with lower DNA methylation of four CpG sites (false discovery rate [FDR] <0.05) within the phosphodiesterase 4B gene (). Additionally, three other individual CpG sites were differentially methylated relative to maternal glucose response within the ,, and genes (FDR <0.05). DNA methylation correlated with expression of its respective genes in placental tissue at three out of four independent identified loci: ( = 0.31, < 0.01), ( = -0.24, = 0.013), and ( = 0.32, < 0.001). In an independent replication cohort ( = 65-108 samples), results were consistent in direction but not significantly replicated among tested CpG sites in and Our study provides evidence that maternal glycemic response during pregnancy is associated with placental DNA methylation of key inflammatory genes whose expression levels are partially under epigenetic control.

Gestational diabetes mellitus (GDM) is associated with obesity in childhood. This suggests that consequences of in utero exposure to maternal hyperglycemia extend beyond the fetal development, possibly through epigenetic programming. The aims of this study were to assess whether placental DNA methylation (DNAm) marks were associated with maternal GDM status and to offspring body composition at 5 years old in a prospective birth cohort. DNAm levels were measured in the fetal side of the placenta in 66 samples (24 from GDM mothers) using bisDNA-pyrosequencing. Anthropometric and body composition (bioimpedance) were measured in children at 5 years of age. Mann-Whitney and Spearman tests were used to assess associations between GDM, placental DNAm levels at the lipoprotein lipase (LPL) locus and children's weight, height, body mass index (BMI), body fat, and lean masses at 5 years of age. Weight, height, and BMI z-scores were computed according to the World Health Organization growth chart. Analyses were adjusted for gestational age at birth, child sex, maternal age, and pre-pregnancy BMI. LPL DNAm levels were positively correlated with birth weight z-scores (r D 0.252, P D 0.04), and with midchildhood weight z-scores (r D 0.314, P D 0.01) and fat mass (r D 0.275, P D 0.04), and negatively correlated with lean mass (r D ¡0.306, P D 0.02). We found a negative correlation between LPL DNAm and mRNA levels in placenta (r D ¡0.459; P < 0.001), which highlights the regulation of transcriptional activity by these epivariations. We demonstrated that alterations in fetal placental DNAm levels at the LPL gene locus are associated with the anthropometric profile in children at 5 years of age. These findings support the concept of fetal metabolic programming through epigenetic changes.

The local genotype influences methylation levels at SLC22A5 and ZPBP2 promoters independently of the asthma status. Further studies are necessary to confirm the relationship between GSDMA-ZPBP2 and SLC22A5 methylation and asthma in females and males separately.

Changes in fetal DNA methylation (DNAm) of the leptin (LEP) gene have been associated with exposure to maternal hyperglycemia, but their links with childhood obesity risk are still unclear. We investigated the association between maternal hyperglycemia, placental LEP DNAm (25 5′-C-phosphate-G-3′ (CpG) sites), neonatal leptinemia, and adiposity (i.e., BMI and skinfold thickness (ST) (subscapular (SS) + triceps (TR) skinfold measures, and the ratio of SS:TR) at 3-years-old, in 259 mother–child dyads, from Gen3G birth cohort. We conducted multivariate linear analyses adjusted for gestational age at birth, sex of the child, age at follow-up, and cellular heterogeneity. We assessed the causal role of DNAm in the association between maternal glycemia and childhood outcomes, using mediation analysis. We found three CpGs associated with neonatal leptinemia (p ≤ 0.002). Of these, cg05136031 and cg15758240 were also associated with BMI (β = −2.69, p = 0.05) and fat distribution (β = −0.581, p = 0.05) at 3-years-old, respectively. Maternal glycemia was associated with DNAm at cg15758240 (β = −0.01, p = 0.04) and neonatal leptinemia (β = 0.19, p = 0.004). DNAm levels at cg15758240 mediates 0.8% of the association between maternal glycemia and neonatal leptinemia (p < 0.001). Our results support that DNAm regulation of the leptin pathway in response to maternal glycemia might be involved in programming adiposity in childhood.

DNA methylation of a MIR-based enhancer downregulates the expression of PLPP3 and promotes the mineralization of the AV.

A previous genome-wide linkage scan of bronchial hyperresponsiveness (BHR) in the French Epidemiological study on the Genetics and Environment of Asthma (EGEA) families, performed in the presence of a gene×early-life environmental tobacco smoke (ETS) exposure interaction, showed the strongest interaction in the 17p11 region where linkage was detected only among unexposed siblings. Our goal was to conduct fine-scale mapping of 17p11 to identify single nucleotide polymorphisms (SNPs) interacting with ETS that influence BHR.Analyses were performed in 388 French EGEA asthmatic families, using a two-step strategy: 1) selection of SNPs displaying family-based association test (FBAT) association signals (p≤0.01) with BHR in unexposed siblings, and 2) a FBAT homogeneity test between exposed and unexposed siblings plus a robust log-linear interaction test.A single SNP reached the threshold (p≤3×10−3) for significant interaction with ETS using both interaction tests, after accounting for multiple testing. Results were replicated in 253 French-Canadian families, but not in 341 UK families, probably due in part to differences in phenotypic features between datasets.The SNP showing significant interaction with ETS belongs to DNAH9 (dynein, axonemal, heavy chain 9), a promising candidate gene involved in respiratory cilia mobility and associated with primary ciliary dyskinesia, a disease associated with abnormalities of pulmonary function.

Interleukin 1 and its receptors are associated with allergic diseases such as asthma. In the present study, we measured DNA methylation at the IL1R1 and IL1R2 gene loci and assessed for associations with asthma-related phenotypes and gene expressions. We found that asthmatic and atopic individuals have higher IL1R2 promoter DNA methylation than control subjects. Additionally, we observed a negative correlation between DNA methylation at the IL1R2 promoter and IL1R2 mRNA expression. These results suggest for the first time that IL1R2 promoter DNA methylation is associated with its gene repression in allergic diseases such as asthma.Electronic supplementary materialThe online version of this article (doi:10.1186/s13148-015-0114-0) contains supplementary material, which is available to authorized users.