Postnatal stability, tissue, and time specific effects of<i>AHRR</i>methylation change in response to maternal smoking in pregnancy

Novakovic, Boris; Ryan, Joanne; Pereira, Natalie; Boughton, Berin A.; Craig, Jeffrey M; Saffery, Richard

doi:10.4161/epi.27248

Cited by 118 publications

(127 citation statements)

References 33 publications

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“…Several subsequent studies have now linked exposure to smoking with lower methylation in the AHRR gene (encoding the aryl hydrocarbon receptor repressor). Such changes appear to be stable in the early postnatal period and to be tissue specific [23]. Similar replication of other exposure data is urgently required, as are adequately powered findings that fail to replicate previous associations.…”

Section: Genetic and Environmental Influences On The Early-life Epigementioning

confidence: 85%

Epigenetic Change as the Major Mediator of Fetal Programming in Humans: Are We There Yet?

Saffery

2014

Ann Nutr Metab

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The developmental origins of health and disease (DOHaD) hypothesis predicts that environmental exposures experienced early in life have the potential to modify the risk associated with later-onset disease. The DOHaD hypothesis is supported by a large number of direct animal studies and a smaller number of compelling observational studies in humans, but the mechanism(s) underlying the ‘programming' effects of DOHaD remain largely unclear. Given the inherent property of environmental sensitivity, the demonstrated role in gene regulation, and the capacity for stable maintenance over time once established, epigenetic variation has rapidly emerged as a candidate mediator of such effects. However, little direct evidence exists in humans, primarily due to the inherent problems associated with unraveling the relative contributions of genetic and environmental influences to phenotypic outcomes. Robust evidence is required in several domains to establish epigenetic variation in the causal pathway to DoHAD-associated disease. Firstly, interindividual epigenetic variability in response to specific early-life environmental exposures needs to be demonstrated. Further, compelling data linking specific epigenetic variants to specific disease(s) is needed. Epigenetic variation should be apparent in a tissue relevant to the disease of interest prior to phenotypic onset in order to avoid confounding and the potential for reverse causation. Finally, the functional relevance of specific epigenetic change must be demonstrated. Compelling evidence is mounting in each of these domains but remains somewhat fragmented, providing small pieces of the overall complex puzzle. It is likely that only large longitudinal life course studies commencing prior to birth, with extensive environmental exposure data and biospecimens, can provide direct evidence in support of a role of epigenetic processes as drivers of the DOHaD in humans.

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Section: Genetic and Environmental Influences On The Early-life Epigementioning

confidence: 85%

Epigenetic Change as the Major Mediator of Fetal Programming in Humans: Are We There Yet?

Saffery

2014

Ann Nutr Metab

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“…All regions corresponding to the CpG sites significant in this analysis, and all CpG sites themselves, have previously been identified as being associated with smoking [8,12,[33][34][35][36], and discussed with regard to their biological implications in a number of publications, in particular 2q37.1 [8,13,37], AHRR [7,38,39], GFI1 [40], MYO1G [41] and F2RL3 [7,42]. Further, most of these loci have been identified as associated with conditions or diseases also related to smoking.…”

Section: Biological Relevancementioning

confidence: 99%

The dynamics of smoking-related disturbed methylation: a two time-point study of methylation change in smokers, non-smokers and former smokers

et al. 2017

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Background: The evidence for epigenome-wide associations between smoking and DNA methylation continues to grow through cross-sectional studies. However, few large-scale investigations have explored the associations using observations for individuals at multiple time-points. Here, through the use of the Illumina 450K BeadChip and data collected at two time-points separated by approximately 7 years, we investigate changes in methylation over time associated with quitting smoking or remaining a former smoker, and those associated with continued smoking. Results: Our results indicate that after quitting smoking the most rapid reversion of altered methylation occurs within the first two decades, with reversion rates related to the initial differences in methylation. For 52 CpG sites, the change in methylation from baseline to follow-up is significantly different for former smokers relative to the change for never smokers (lowest p-value 3.61 x 10 -39 for cg26703534, gene AHRR). Most of these sites' respective regions have been previously implicated in smoking-associated diseases. Despite the early rapid change, dynamism of methylation appears greater in former smokers vs never smokers even four decades after cessation. Furthermore, our study reveals the heterogeneous effect of continued smoking: the methylation levels of some loci further diverge between smokers and non-smokers, while others re-approach. Though intensity of smoking habit appears more significant than duration, results remain inconclusive. Conclusions: This study improves the understanding of the dynamic link between cigarette smoking and methylation, revealing the continued fluctuation of methylation levels decades after smoking cessation and demonstrating that continuing smoking can have an array of effects. The results can facilitate insights into the molecular mechanisms behind smoking-induced disturbed methylation, improving the possibility for development of biomarkers of past smoking behavior and increasing the understanding of the molecular path from exposure to disease.

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“…A recent study, using a low-density DNAm array showed detectible prenatal smoking associations in childhood, but could not assess the reported birth sample associations now confirmed by several groups, given the incompatible array content (Breton et al, 2014). A candidate gene-based study (Novakovic et al, 2014) of 11 individuals showed that comparable differences in DNAm at AHRR , a tobacco-related gene, were detectable at birth as well as at 18 months. Finally, a recent longitudinal investigation revealed some smoking-related DNAm alterations, initially detected in their sample at birth, persist within the same individuals over time (Richmond et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Presence of an epigenetic signature of prenatal cigarette smoke exposure in childhood

Ladd‐Acosta

Shu

Lee

et al. 2016

Environmental Research

102

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Prenatal exposure to tobacco smoke has lifelong health consequences. Epigenetic signatures such as differences in DNA methylation (DNAm) may be a biomarker of exposure and, further, might have functional significance for how in utero tobacco exposure may influence disease risk. Differences in infant DNAm associated with maternal smoking during pregnancy have been identified. Here we assessed whether these infant DNAm patterns are detectible in early childhood, whether they are specific to smoking, and whether childhood DNAm can classify prenatal smoke exposure status. Using the Infinium 450 K array, we measured methylation at 26 CpG loci that were previously associated with prenatal smoking in infant cord blood from 572 children, aged 3–5, with differing prenatal exposure to cigarette smoke in the Study to Explore Early Development (SEED). Striking concordance was found between the pattern of prenatal smoking associated DNAm among preschool aged children in SEED and those observed at birth in other studies. These DNAm changes appear to be tobacco-specific. Support vector machine classification models and 10-fold cross-validation were applied to show classification accuracy for childhood DNAm at these 26 sites as a biomarker of prenatal smoking exposure. Classification models showed prenatal exposure to smoking can be assigned with 81% accuracy using childhood DNAm patterns at these 26 loci. These findings support the potential for blood-derived DNAm measurements to serve as biomarkers for prenatal exposure.

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Postnatal stability, tissue, and time specific effects ofAHRRmethylation change in response to maternal smoking in pregnancy

Cited by 118 publications

References 33 publications

Epigenetic Change as the Major Mediator of Fetal Programming in Humans: Are We There Yet?

Epigenetic Change as the Major Mediator of Fetal Programming in Humans: Are We There Yet?

The dynamics of smoking-related disturbed methylation: a two time-point study of methylation change in smokers, non-smokers and former smokers

Presence of an epigenetic signature of prenatal cigarette smoke exposure in childhood

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