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Differential methylation in glucoregulatory genes of offspring born before vs. after maternal gastrointestinal bypass surgery.

ABSTRACT: Obesity and overnutrition during pregnancy affect fetal programming of adult disease. Children born after maternal bariatric gastrointestinal bypass surgery (AMS) are less obese and exhibit improved cardiometabolic risk profiles carried into adulthood compared with siblings born before maternal surgery (BMS). This study was designed to analyze the impact of maternal weight loss surgery on methylation levels of genes involved in cardiometabolic pathways in BMS and AMS offspring. Differential methylation analysis between a sibling cohort of 25 BMS and 25 AMS (2-25 y-old) offspring from 20 mothers was conducted to identify biological functions and pathways potentially involved in the improved cardiometabolic profile found in AMS compared with BMS offspring. Links between gene methylation and expression levels were assessed by correlating genomic findings with plasma markers of insulin resistance (fasting insulin and homeostatic model of insulin resistance). A total of 5,698 genes were differentially methylated between BMS and AMS siblings, exhibiting a preponderance of glucoregulatory, inflammatory, and vascular disease genes. Statistically significant correlations between gene methylation levels and gene expression and plasma markers of insulin resistance were consistent with metabolic improvements in AMS offspring, reflected in genes involved in diabetes-related cardiometabolic pathways. This unique clinical study demonstrates that effective treatment of a maternal phenotype is durably detectable in the methylome and transcriptome of subsequent offspring.

SUBMITTER: Guenard F

PROVIDER: S-EPMC3710842 | biostudies-literature | 2013 Jul

REPOSITORIES: biostudies-literature

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Differential methylation in glucoregulatory genes of offspring born before vs. after maternal gastrointestinal bypass surgery.

Guénard Frédéric F Deshaies Yves Y Cianflone Katherine K Kral John G JG Marceau Picard P Vohl Marie-Claude MC

Proceedings of the National Academy of Sciences of the United States of America 20130528 28

Obesity and overnutrition during pregnancy affect fetal programming of adult disease. Children born after maternal bariatric gastrointestinal bypass surgery (AMS) are less obese and exhibit improved cardiometabolic risk profiles carried into adulthood compared with siblings born before maternal surgery (BMS). This study was designed to analyze the impact of maternal weight loss surgery on methylation levels of genes involved in cardiometabolic pathways in BMS and AMS offspring. Differential meth ...[more]

PMID: 23716672

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Project description:This study aims to evaluate the association of maternal DNA methylation (DNAm) during pregnancy and offspring birthweight. One hundred twenty-two newborn-mother dyads from the Isle of Wight (IOW) cohort were studied to identify differentially methylated cytosine-phosphate-guanine sites (CpGs) in maternal blood associated with offspring birthweight. Peripheral blood samples were drawn from mothers at 22-38 weeks of pregnancy for epigenome-wide DNAm assessment using the Illumina Infinium HumanMethylation450K array. Candidate CpGs were identified using a course of 100 repetitions of a training and testing process with robust regressions. CpGs were considered informative if they showed statistical significance in at least 80% of training and testing samples. Linear mixed models adjusting for covariates were applied to further assess the selected CpGs. The Swedish Born Into Life cohort was used to replicate our findings (n = 33). Eight candidate CpGs corresponding to the genes LMF1, KIF9, KLHL18, DAB1, VAX2, CD207, SCT, SCYL2, DEPDC4, NECAP1, and SFRS3 in mothers were identified as statistically significantly associated with their children's birthweight in the IOW cohort and confirmed by linear mixed models after adjusting for covariates. Of these, in the replication cohort, three CpGs (cg01816814, cg23153661, and cg17722033 with p values = 0.06, 0.175, and 0.166, respectively) associated with four genes (LMF1, VAX2, CD207, and NECAP1) were marginally significant. Biological pathway analyses of three of the genes revealed cellular processes such as endocytosis (possibly sustaining an adequate maternal-fetal interface) and metabolic processes such as regulation of lipoprotein lipase activity (involved in providing substrates for the developing fetus). Our results contribute to an epigenetic understanding of maternal involvement in offspring birthweight. Measuring DNAm levels of maternal CpGs may in the future serve as a diagnostic tool recognizing mothers at risk for pregnancies ending with altered birthweights.

Project description:BackgroundRecent studies suggest an intergenerational influence of stress such that maternal exposure even before pregnancy could impact offspring health outcomes later in life. In humans, investigations on the impact of maternal stressors on offspring health outcomes, including stress-sensitive biomarkers, have largely been limited to extreme stressors. Prior studies have not addressed more moderate maternal stressors, such as rotating night shift work, on offspring stress markers in young adulthood.MethodsWe investigated the association between maternal rotating night shift work before conception and offspring salivary cortisol and alpha amylase (sAA) patterns in young adulthood among mothers enrolled in the Nurses' Health Study II (NHSII) and their offspring participating in the Growing Up Today Study 2 (GUTS2). Our sample included over 300 mother-child pairs where, between 2011 and 2014, the children provided 5 saliva samples over the course of one day. We used piecewise linear mixed models to compare awakening responses, overall slopes as well as several other diurnal patterns of cortisol and sAA between offspring born to shift working versus non-shift working mothers.ResultsOffspring born to shift working mothers had a flattened late decline in cortisol (percent differences in slope (%D): 2.1%; 95%CI: 0.3, 3.8) and their sAA awakening response was steeper (%D -37.4%; 95%CI: -59.0, -4.4), whereas sAA increase before bedtime appeared less pronounced (%D -35.9%; 95%CI: -55.3, -8.3), compared to offspring born to mothers without shift work. For cortisol, we observed a significant difference in the Area Under the Curve (AUC) (%D 1.5%; 95%CI: 0.3, 2.7) with higher AUC for offspring of mothers who worked rotating night shifts. In offspring-sex-stratified analyses we found differences primarily among males.ConclusionOur results provide some - albeit modest - evidence that maternal rotating night shift work-a moderate stressor-influences offspring stress markers. Future studies with larger samples sizes, more detailed exposure assessment (particularly during maternal pregnancy), and multiple offspring biomarker assessments at different developmental stages are needed to further investigate these associations.

Dataset Information

Differential methylation in glucoregulatory genes of offspring born before vs. after maternal gastrointestinal bypass surgery.

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Differential methylation in glucoregulatory genes of offspring born before vs. after maternal gastrointestinal bypass surgery.

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