Differential DNA methylation profiles of infants exposed to maternal asthma during pregnancy

Gunawardhana, Lakshitha; Baines, Katherine J.; Mattes, Joërg; Murphy, Vanessa E.; Simpson, Jodie L.; Gibson, Peter G.

doi:10.1002/ppul.22930

Cited by 61 publications

(54 citation statements)

References 41 publications

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“…In humans, methylation of PM20D1 in cord blood is associated with birthweight centile [43]. Methylation of PM20D1 has also been associated with several adverse health events during early life, indicating that PM20D1 may be a target gene for in utero epigenetic programming in multiple organs [44,45]. Differential methylation of PM20D1 in obese and non-obese individuals at older ages suggests that in utero programming of PM20D1 has sustainable effects much later in life [46].…”

Section: −5mentioning

confidence: 99%

Differential methylation of genes in individuals exposed to maternal diabetes in utero

et al. 2017

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Aims/hypothesis Individuals exposed to maternal diabetes in utero are more likely to develop metabolic and cardiovascular diseases later in life. This may be partially attributable to epigenetic regulation of gene expression. We performed an epigenome-wide association study to examine whether differential DNA methylation, a major source of epigenetic regulation, can be observed in offspring of mothers with type 2 diabetes during the pregnancy (OMD) compared with offspring of mothers with no diabetes during the pregnancy (OMND). Methods DNA methylation was measured in peripheral blood using the Illumina HumanMethylation450K BeadChip. A total of 423,311 CpG sites were analysed in 388 Pima Indian individuals, mean age at examination was 13.0 years, 187 of whom were OMD and 201 were OMND. Differences in methylation between OMD and OMND were assessed. Results Forty-eight differentially methylated CpG sites (with an empirical false discovery rate ≤0.05), mapping to 29 genes and ten intergenic regions, were identified. The gene with the strongest evidence was LHX3, in which six CpG sites were hypermethylated in OMD compared with OMND (p ≤ 1.1 × 10 −5 ). Similarly, a CpG near PRDM16 was hypermethylated in OMD (1.1% higher, p = 5.6 × 10), where hypermethylation also predicted future diabetes risk (HR 2.12 per SD methylation increase, p = 9.7 × 10 −5). Hypermethylation near AK3 and hypomethylation at PCDHGA4 and STC1 were associated with exposure to diabetes in utero (AK3: 2.5% higher, p = 7.8 × 10 ) and decreased insulin secretory function among offspring with normal glucose tolerance (AK3: 0.088 SD lower per SD of methylation increase, p = 0.02; PCDHGA4: 0.08 lower SD per SD of methylation decrease, p = 0.03; STC1: 0.072 SD lower per SD of methylation decrease, p = 0.05). Seventeen CpG sites were also associated with BMI (p ≤ 0.05). Pathway analysis of the genes with at least one differentially methylated CpG (p < 0.005) showed enrichment for three relevant biological pathways. Conclusions/interpretation Intrauterine exposure to diabetes can affect methylation at multiple genomic sites. Methylation status at some of these sites can impair insulin secretion, increase body weight and increase risk of type 2 diabetes.

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Section: −5mentioning

confidence: 99%

Differential methylation of genes in individuals exposed to maternal diabetes in utero

et al. 2017

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“…Infants exposed in utero to the biological milieu associated with maternal asthma, the strongest and most replicated predictor of asthma during childhood [24], had distinct DNA methylation profiles in their peripheral blood cells at 12 months of age [33]. Of the 70 loci identified as being differentially methylated depending on maternal asthma status, 12 showed differences >10%, with increased methylation at FAM181A, MRI1, PIWIL1, CHFR, DEFA1, MRPL28, AURKA, and decreased methylation at NALP1L5, MAP8KIP3, ACAT2, and PM20D1, in children with maternal asthma.…”

Section: Impact Of Prenatal Exposures On the Epigenetic Trajectory Tomentioning

confidence: 99%

The Neonatal Methylome as a Gatekeeper in the Trajectory to Childhood Asthma

DeVries

Vercelli

2017

Epigenomics

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Asthma is a heterogeneous group of conditions that typically begin in early life and result in recurrent, reversible bronchial obstruction. The role played by epigenetic mechanisms in the pathogenesis of childhood asthma is understood only in part. Here we discuss asthma epigenetics within a developmental perspective based on our recent demonstration that the epigenetic trajectory to childhood asthma begins at birth. We next discuss how this trajectory may be affected by prenatal environmental exposures. Finally, we examine in vitro studies that model the impact of asthma-associated exposures on the epigenome. All of these studies specifically surveyed human DNA methylation and involved a genome-wide component. In combination, their results broaden our understanding of asthma pathogenesis and the role the methylome plays in this process.

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“…In the same study, low Th1:Th2 and Treg:Th2 cell ratios in cord blood predicted increased risk of eczema development in the infants by two years of age (Fu et al 2013). DNA in peripheral blood is also differentially methylated in peripheral blood of 1 year-old infants born to mothers with asthma, compared to infants of nonasthmatic mothers, and some of the changes in DNA methylation correlate with characteristics of asthma and allergy severity in the mother or with infant circulating immune cell abundance (Gunawardhana et al 2014). Whether these methylation changes at birth predict subsequent allergic outcomes in children is yet to be determined.…”

Section: Evidence For Maternal Asthma and Allergy During Pregnancy Asmentioning

confidence: 96%

Pre-birth origins of allergy and asthma

Gatford¹,

Wooldridge

Kind

et al. 2017

Journal of Reproductive Immunology

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Highlights Key points (3-5 dot points, max 85 characters including spaces)  Prenatal exposures alter later disease risk, including for allergy  Epidemiological and experimental evidence suggests IUGR protects against allergy  Elevated methyl donor abundance in late pregnancy may predispose progeny to allergy  Maternal asthma and allergy during pregnancy predispose progeny to allergy Abstract: Allergy is a chronic disease that can develop as early as infancy, suggesting that early life factors are important in its aetiology. Variable associations between size at birth, a crude marker of the fetal environment, and allergy have been reported in humans and require comprehensive review. Associations between birth weight and allergy are however confounded in humans, and we and others have therefore begun exploring the effects of early life events on allergy in experimental models. In particular, we are using ovine models to investigate whether and how a restricted environment before birth protects against allergy, whether methyl donor availability contributes to allergic protection in IUGR, and why maternal asthma during pregnancy is associated with increased risks of allergic disease in children. We found that experimental intrauterine growth restriction (IUGR) in sheep reduced cutaneous responses to antigens in progeny, despite normal or elevated IgE responses. Furthermore, maternal methyl donor supplementation in late pregnancy partially reversed effects of experimental IUGR, consistent with the proposal that epigenetic pathways underlie some but not all effects of IUGR on allergic susceptibility. Ovine experimental allergic asthma with exacerbations reduces relative fetal size in late gestation, with some changes in immune populations in fetal thymus suggestive of increased activation. Maternal allergic asthma in mice also predisposes progeny to allergy development. In conclusion, these findings in experimental models provide direct evidence that a perturbed environment before birth alters immune system development and postnatal function, and provide opportunities to investigate underlying mechanisms and develop and evaluate interventions.

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Differential DNA methylation profiles of infants exposed to maternal asthma during pregnancy

Abstract: In an Australian study population, exposure to maternal asthma during pregnancy is associated with differential methylation profiles of infants' peripheral blood DNA, which may act as risk factors for future asthma development.

Cited by 61 publications

References 41 publications

Differential methylation of genes in individuals exposed to maternal diabetes in utero

Differential methylation of genes in individuals exposed to maternal diabetes in utero

The Neonatal Methylome as a Gatekeeper in the Trajectory to Childhood Asthma

Pre-birth origins of allergy and asthma

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