Cigarette smoking reduces DNA methylation levels at multiple genomic loci but the effect is partially reversible upon cessation

Tsaprouni, Loukia; Yang, Tsun-Po; Bell, Jordana T.; Dick, Katherine; Kanoni, Stavroula; Nisbet, James; Viñuela, Ana; Grundberg, Elin; Nelson, Christopher P.; Meduri, Eshwar; Buil, Alfonso; Cambien, François; Hengstenberg, Christian; Erdmann, Jeanette; Schunkert, Heribert; Goodall, Alison H.; Ouwehand, Willem H.; Dermitzakis, Emmanouil T.; Spector, Tim D.; Samani, Nilesh J.; Deloukas, Panos

doi:10.4161/15592294.2014.969637

Cited by 287 publications

(310 citation statements)

References 45 publications

(68 reference statements)

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“…The observed decreasing trend of the FI after smoking cessation was also in line with the previous findings that the methylation levels of smoking-related CpG sites might "recover" after quitting smoking. 21,29 Prior to the present study, epigenetic changes of several promoter CpG islands and global DNA methylation were proposed to explain the development of frailty syndrome. 30,31 To the best of our knowledge, this is the first study identifying specific CpG sites that were not only associated with frailty but also are well established as smoking-related loci.…”

Section: Discussionmentioning

confidence: 99%

Tobacco smoking and smoking-related DNA methylation are associated with the development of frailty among older adults

et al. 2017

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Tobacco smoking is a preventable environmental factor that contributes to a wide spectrum of age-related health outcomes; however, its association with the development of frailty is not yet well established. We examined the associations of self-reported smoking indicators, serum cotinine levels and smoking-related DNA methylation biomarkers with a quantitative frailty index (FI) in 2 independent subsets of older adults (age 50-75) recruited in Saarland, Germany in 2000 -2002 (discovery set: n D 978, validation set: n D 531). We obtained DNA methylation profiles in whole blood samples by Illumina HumanMethylation450 BeadChip and calculated the FI according to the method of Mitnitski and Rockwood. Mixed linear regression models were implemented to assess the associations between smoking indicators and the FI. After controlling for potential covariates, current smoking, cumulative smoking exposure (pack-years), and time after smoking cessation (years) were significantly associated with the FI (P-value < 0.05). In the discovery panel, 17 out of 151 previously identified smoking-related CpG sites were associated with the FI after correction for multiple testing (FDR < 0.05). Nine of them survived in the validation phase and were designated as frailty-associated loci. A smoking index (SI) based on the 9 loci manifested a monotonic association with the FI. In conclusion, this study suggested that epigenetic alterations could play a role in smoking-associated development of frailty. The identified CpG sites have the potential to be prognostic biomarkers of frailty and frailty-related health outcomes. Our findings and the underlying mechanisms should be followed up in further, preferably longitudinal studies.

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Section: Discussionmentioning

confidence: 99%

Tobacco smoking and smoking-related DNA methylation are associated with the development of frailty among older adults

et al. 2017

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“…Methylation levels were detected using the Infinium 450K and the intensity images captured by GenomeStudio (2010.3) Methylation module (1.8.5) software. Details of the method are described elsewhere for a subset of our sample (Tsaprouni et al, 2014). The beta mixture quantile dilation (BMIQ) method was performed to correct for the technical issues caused by the two Illumina probe types (Teschendorff et al, TWIN RESEARCH AND HUMAN GENETICS 2013).…”

Section: Dna Methylationmentioning

confidence: 99%

DNA Methylation Changes in theIGF1RGene in Birth Weight Discordant Adult Monozygotic Twins

et al. 2015

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Low birth weight (LBW) can have an impact on health outcomes in later life, especially in relation to predisposition to metabolic disease. Several studies suggest that LBW resulting from restricted intrauterine growth leaves a footprint on DNA methylation in utero, and this influence likely persists into adulthood. To investigate this further, we performed epigenome-wide association analyses of blood DNA methylation using Infinium HumanMethylation450 BeadChip profiles in 71 adult monozygotic (MZ) twin pairs who were extremely discordant for birth weight. A signal mapping to the IGF1R gene (cg12562232, p = 2.62 × 10 −8 ), was significantly associated with birth weight discordance at a genome-wide false-discovery rate (FDR) of 0.05. We pursued replication in three additional independent datasets of birth weight discordant MZ pairs and observed the same direction of association, but the results were not significant. However, a meta-analysis across the four independent samples, in total 216 birth-weight discordant MZ twin pairs, showed a significant positive association between birth weight and DNA methylation differences at IGF1R (random-effects meta-analysis p = .04), and the effect was particularly pronounced in older twins (randomeffects meta-analysis p = .008, 98 older birth-weight discordant MZ twin pairs). The results suggest that severe intra-uterine growth differences (birth weight discordance >20%) are associated with methylation changes in the IGF1R gene in adulthood, independent of genetic effects.

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“…Previous evaluations of the effect of time since smoking cessation have revealed CpG sites that could be classified as reversible and sites that could be classified as persistently differentially methylated [8,[18][19][20]. Reversible sites are those that are differentially methylated between smokers and non-smokers but with the difference disappearing some time after cessation of smoking.…”

Section: Introductionmentioning

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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Cigarette smoking reduces DNA methylation levels at multiple genomic loci but the effect is partially reversible upon cessation

Cited by 287 publications

References 45 publications

Tobacco smoking and smoking-related DNA methylation are associated with the development of frailty among older adults

Tobacco smoking and smoking-related DNA methylation are associated with the development of frailty among older adults

DNA Methylation Changes in theIGF1RGene in Birth Weight Discordant Adult Monozygotic Twins

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

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