Reversion of AHRR Demethylation Is a Quantitative Biomarker of Smoking Cessation
TL;DR: It is concluded that AHRR methylation status is a quantifiable biomarker for progress in smoking cessation that could have substantial impact on both smoking cessation treatment and research.
Abstract: Smoking is the largest preventable cause of morbidity and mortality in the world. Although there are effective pharmacologic and behavioral treatments for smoking cessation, our inability to objectively quantify smokers’ progress in decreasing smoking has been a barrier to both clinical and research efforts. In prior work, we and others have shown that DNA methylation at cg05575921, a CpG residue in the aryl hydrocarbon receptor repressor (AHRR), can be used to determine smoking status and infer cigarette consumption history. In this study, we serially assessed self-report and existing objective markers of cigarette consumption in 35 subjects undergoing smoking cessation therapy, then quantified DNA methylation at cg05575921 at study entry and three subsequent time points. Five subjects who reported serum cotinine and exhaled carbon monoxide verified smoking abstinence for the three months prior to study exit averaged a 5.9% increase in DNA methylation at cg05575921 (p<0.004) over the six month study. Although the other 30 subjects did not achieve smoking cessation at the six-month time point, their self-reported reduction of cigarette consumption (mean = 6 cigarettes per day) was associated with a 2.8% increase DNA methylation at cg05575921 (p<0.05). Finally, a survey of subjects as they exited the study demonstrated strong support for the clinical use of epigenetic biomarkers. We conclude that AHRR methylation status is a quantifiable biomarker for progress in smoking cessation that could have substantial impact on both smoking cessation treatment and research.
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TL;DR: AHRR (cg05575921) hypomethylation, a marker of smoking behaviour, provides potentially clinical relevant predictions of future smoking-related morbidity and mortality.
Abstract: Rationale and objectives Self-reported smoking underestimates disease risk. Smoking affects DNA methylation, in particular the cg05575921 site in the aryl hydrocarbon receptor repressor (AHRR ) gene. We tested the hypothesis that AHRR cg05575921 hypomethylation is associated with risk of smoking-related morbidity and mortality. Methods From the Copenhagen City Heart Study representing the Danish general population, we studied 9234 individuals. Using bisulphite treated leucocyte DNA, AHRR (cg05575921) methylation was measured. Rs1051730 ( CHRN3A ) genotype was used to evaluate smoking heaviness. Participants were followed for up to 22 years for exacerbations of COPD, event of lung cancer and all-cause mortality. Six-year lung cancer risk was calculated according to the Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO M2012 ). Measurements and main results AHRR (cg05575921) hypomethylation was associated with former and current smoking status, high daily and cumulative smoking, short time since smoking cessation (all p values –31 ), and the smoking-related CHRN3A genotype (−0.48% per T-allele, p=0.002). The multifactorially adjusted HRs for the lowest versus highest methylation quintiles were 4.58 (95% CI 2.83 to 7.42) for COPD exacerbations, 4.87 (2.31 to 10.3) for lung cancer and 1.67 (1.48 to 1.88) for all-cause mortality. Finally, among 2576 high-risk smokers eligible for lung cancer screening by CT, observed cumulative incidences of lung cancer after 6 years for individuals in the lowest and highest methylation quintiles were 3.7% and 0.0% (p=2×10 –7 ), whereas predicted PLCO M2012 6-year risks were similar (4.3% and 4.4%, p=0.77). Conclusion AHRR (cg05575921) hypomethylation, a marker of smoking behaviour, provides potentially clinical relevant predictions of future smoking-related morbidity and mortality.
120 citations
TL;DR: 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.
Abstract: 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. 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. 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.
72 citations
Cites background from "Reversion of AHRR Demethylation Is ..."
...[16] that there can be overcorrection of methylation after cessation of smoking....
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...To our knowledge, there have been only three reports investigating smoking and methylation with repeated measures: two candidate locus studies, one focusing on a small group of young women [15] and another on a small group of individuals attempting to quit smoking [16]; and a family-based study focused on maternal smoking [17]....
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TL;DR: The findings suggest that smoking–associated DNA methylation changes are a result of prolonged exposure to cigarette smoke, and can be reversed following cessation, and may provide an additional criterion on which to stratify risk.
62 citations
TL;DR: This systematic review lists the epigenetic events/alterations known to occur in response to cigarette smoke exposure and identifies the major genes and miRNAs that are potential targets for translational research in associated pathologies.
Abstract: The aim of this study is to provide a systematic review of the known epigenetic alterations caused by cigarette smoke; establish an evidence-based perspective of their clinical value for screening, diagnosis, and treatment of smoke-related disorders; and discuss the challenges and ethical concerns associated with epigenetic studies. A well-defined, reproducible search strategy was employed to identify relevant literature (clinical, cellular, and animal-based) between 2000 and 2019 based on AMSTAR guidelines. A total of 80 studies were identified that reported alterations in DNA methylation, histone modifications, and miRNA expression following exposure to cigarette smoke. Changes in DNA methylation were most extensively documented for genes including AHRR, F2RL3, DAPK, and p16 after exposure to cigarette smoke. Likewise, miR16, miR21, miR146, and miR222 were identified to be differentially expressed in smokers and exhibit potential as biomarkers for determining susceptibility to COPD. We also identified 22 studies highlighting the transgenerational effects of maternal and paternal smoking on offspring. This systematic review lists the epigenetic events/alterations known to occur in response to cigarette smoke exposure and identifies the major genes and miRNAs that are potential targets for translational research in associated pathologies. Importantly, the limitations and ethical concerns related to epigenetic studies are also highlighted, as are the effects on the ability to address specific questions associated with exposure to tobacco/cigarette smoke. In the future, improved interpretation of epigenetic signatures will lead to their increased use as biomarkers and/or in drug development.
59 citations
TL;DR: The construction of a polyepigenetic DNA methylation score is described that indexes smoking behavior and that can be utilized for multiple purposes in population health research and introduced as a tool both for discovery and theory-guided research in epigenetic epidemiology.
Abstract: Large-scale epigenome-wide association meta-analyses have identified multiple ‘signatures’’ of smoking. Drawing on these findings, we describe the construction of a polyepigenetic DNA methylation score that indexes smoking behavior and that can be utilized for multiple purposes in population health research. To validate the score, we use data from two birth cohort studies: The Dunedin Longitudinal Study, followed to age-38 years, and the Environmental Risk Study, followed to age-18 years. Longitudinal data show that changes in DNA methylation accumulate with increased exposure to tobacco smoking and attenuate with quitting. Data from twins discordant for smoking behavior show that smoking influences DNA methylation independently of genetic and environmental risk factors. Physiological data show that changes in DNA methylation track smoking-related changes in lung function and gum health over time. Moreover, DNA methylation changes predict corresponding changes in gene expression in pathways related to inflammation, immune response, and cellular trafficking. Finally, we present prospective data about the link between adverse childhood experiences (ACEs) and epigenetic modifications; these findings document the importance of controlling for smoking-related DNA methylation changes when studying biological embedding of stress in life-course research. We introduce the polyepigenetic DNA methylation score as a tool both for discovery and theory-guided research in epigenetic epidemiology.
51 citations
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12,729 citations
TL;DR: A revision of the FTQ: the Fagerström Test for Nicotine Dependence (FTND), which found that a revised scoring of time to the first cigarette of the day (TTF) and number of cigarettes smoked per day (CPD) improved the scale.
Abstract: We examine and refine the Fagerstrom Tolerance Questionnaire (FTQ: Fagerstrom, 1978). The relation between each FTQ item and biochemical measures of heaviness of smoking was examined in 254 smokers. We found that the nicotine rating item and the inhalation item were unrelated to any of our biochemical measures and these two items were primary contributors to psychometric deficiencies in the FTQ. We also found that a revised scoring of time to the first cigarette of the day (TTF) and number of cigarettes smoked per day (CPD) improved the scale. We present a revision of the FTQ: the Fagerstrom Test for Nicotine Dependence (FTND).
9,766 citations
Additional excerpts
...Notably, the Fagerstrom Test for Nicotine Dependence (FTND) (23) is embedded within the interview....
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...To better understand how this consumption is linked to other factors, such as nicotine craving and key genetic variables, we conducted a series of regression analyses with methylation as the independent variable, and total history of smoking (pack years), current smoking, FTND, and rs16969968 genotype....
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...R2 = 0.38, p 0.001) with significant effects of FTND score (p 0.0002) and a trend (p 0.06) for an interaction between FTND and rs16969968 genotype but no main effect of rs16969968 genotype....
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...4 Hispanic 1 Other 3 Consumption at intake Lifetime 16.3 Past month 11.3 cigarettes/day rs16969968 genotype GG 24 AG 15 AA 5 FTND score 3.7 ± 2.5 3 Philibert et al. AHRR Provides Smoking Cessation Biomarker Frontiers in Psychiatry | www.frontiersin.org April 2016 | Volume 7 | Article 55 using cold protein precipitation, quantified with a NanoDrop photometer (ThermoFisher, Holtsville, NY, USA) and stored at −20°C until use (24)....
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...In addition, a regression model that included FTND score and rs16969968 fitted to cg05575921 methylation was highly significant (Adj....
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Journal Article•
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TL;DR: A randomized controlled experiment is designed to test whether access to affordable day care (in the form of subsidies, for example) would incentivize Saudi mothers to search actively for employment and to remain employed once they are hired.
Abstract: This pilot aims to better understand the market for childcare in Saudi Arabia – both the supply and demand sides – and to design a randomized controlled experiment to test whether access to affordable day care (in the form of subsidies, for example) would incentivize Saudi mothers to search actively for employment and to remain employed once they are hired. In addition, the study seeks to understand the degree to which employment early on in one’s life impacts employment in later stages. The pilot will provide information on the groups of women the experiment should target, appropriate levels for the childcare subsidy, and the quality and current geographic locations of daycare sites. Expected Impact Determine the effects of facilitating childcare access on Saudi women’s employment. PRINCIPAL INVESTIGATORS Boston University Patricia Cortes Harvard University Claudia Goldin Swarthmore College Jennifer Peck
9,609 citations
"Reversion of AHRR Demethylation Is ..." refers background in this paper
...In previous work, Hetherington and colleagues showed that the use of CO monitoring feedback was not only accepted by patients but also increased the odds of smoking cessation by fourfold (33)....
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01 May 2008
TL;DR: The Panel recognized that variations in study inclusion criteria sometimes were warranted and made recommendations based on evidence, which occurred with topics such as tobacco dependence treatment in specific populations, tailoring interventions, and cost-effectiveness of Tobacco dependence treatment.
Abstract: s obtained Abstracts reviewed for inclusion/exclusion criteria by literature reviewerss reviewed for inclusion/exclusion criteria by literature reviewers Update topics chosen by Panel Full copy of each accepted article read and independently coded by at least 3 literature reviewers Evidence tables created by literature reviewers Initial meta-analyses conducted Panel reviewed relevant literature and meta-analytic results Panel formed tentative conclusions, identified need for further analyses Additional literature reviews and meta-analyses conducted Panel reviewed updated evidence and made recommendations based on evidence Manuscript drafted and reviewed by Panel Additional manuscript drafts reviewed by Panel Manuscript draft reviewed by peer reviewers and the public Manuscript revised and reviewed by Panel Manuscript submitted to PHS Overview and Methods 21 comparative effectiveness. Most of these randomized trials, however, were conducted with individuals who proactively sought treatment and who volunteered to fulfill various research requirements. It is possible that these individuals were more highly motivated to quit smoking than the typical smoker encountered in a clinical practice setting. Thus, the percentage abstinent estimates supplied with the meta-analyses may overestimate the actual level of abstinence produced by some of the treatments in real-world settings. Analyses conducted for the previous Guideline editions, though, suggest that the treatment effect sizes (odds ratios or ORs) are relatively stable across individuals seeking treatment (“treatment seekers”) and those recruited via inclusive recruitment strategies (“all-comers”). Randomized controlled trials were exclusively used in meta-analyses. However, the Panel recognized that variations in study inclusion criteria sometimes were warranted. For instance, research on tobacco interventions in adolescents frequently assigns interventions on the basis of larger units, such as schools. These units, rather than individuals, were allowed to serve as units of analysis when analyzing interventions for adolescents. In such cases, studies were combined for inclusion in meta-analyses if the study satisfied other review criteria. A similar strategy was followed in the review of health systems research. In certain areas, research other than randomized clinical trials was evaluated and considered to inform Panel opinion and judgment, though not submitted to meta-analysis. This occurred with topics such as tobacco dependence treatment in specific populations, tailoring interventions, and cost-effectiveness of tobacco dependence treatment. Literature Review and Inclusion Criteria Approximately 8,700 articles were screened to identify evaluable literature. This figure includes approximately 2,700 articles added to the literature since publication of the 2000 Guideline. These articles were obtained through searches of 11 electronic databases and reviews of published abstracts and bibliographies. An article was deemed appropriate for meta-analysis if it met the criteria for inclusion established a priori by the Panel. These criteria were that the article: (a) reported the results of a randomized, placebo/comparison controlled trial of a tobacco use treatment intervention randomized on the patient level (except as noted above); (b) provided followup results at least 5 months after the quit date (except in the case of studies evaluating tobacco dependence treatments Treating Tobacco Use and Dependence: 2008 Update 22 for pregnant smokers); (c) was published in a peer-reviewed journal; (d) was published between January 1975 and June 2007; (e) was published in English; and (f) was one of the 11 topics chosen to be included in the 2008 update (see Table 1.1). It is important to note that the article-screening criteria were updated for the 2008 Guideline update. Additionally, articles were screened for relevance to safety, economic, or health systems issues. As a result of the original and update literature reviews, more than 300 articles were identified for possible inclusion in a meta-analysis, and more than 600 additional articles were examined in detail by the Panel. These latter articles were used in the formulation of Panel recommendations that were not supported by meta-analyses. The literature search for the update project was validated by comparing the results against a search conducted by the CDC and through review by the expert Panel. When individual authors published multiple articles meeting the metaanalytic inclusion criteria, the articles were screened to determine whether they contained unique data. When two articles reported data from the same group of subjects, both articles were reviewed to ensure that complete data were obtained. The data were treated as arising from a single study in meta-analyses. Preparation of Evidence Tables Two Guideline staff reviewers independently read and coded each article that met inclusion criteria. The reviewers coded the treatment characteristics that were used in data analyses (see Tables 6.1 and 6.2 in Chapter 6). The same general coding procedure employed during the 2000 Guideline process was employed during the update. When adjustments to the coding process were made, articles coded with the original process were re-coded to reflect the changed coding (e.g., more refined coding criteria were used for the coding of treatment intensity). A third reviewer then examined the coding of both reviewers and adjudicated any differences. Discrepancies that could not be resolved through this process were adjudicated by the project manager, Panel chair, and/or the Panel’s senior scientist. Finally, each article accepted for a meta-analysis had key fields reviewed by the project manager as a final quality check. The data then were compiled and used in relevant analyses and/or Panel deliberations. Analyses done for the 2000 Guideline revealed that intervention coding categories could be used reliably by independent raters.94 Overview and Methods
3,175 citations
TL;DR: Kilpatrick et al. as mentioned in this paper discussed the limitations of the A1C assay for populations in which it is not available or is currently too expensive, as well as for individuals in whom the assay may be misleading.
Abstract: We appreciate the comment by Kilpatrick et al (1) regarding the International Expert Committee report on the diagnosis of diabetes with the A1C assay (2) The Committee considered all of the limitations of the A1C assay for populations in which it is not available or is currently too expensive, as well as for individuals in whom the assay may be misleading On the basis of these recognized limitations, the Committee emphasized the use of the currently recommended glucose tests and criteria in such populations or individuals We did not “breeze over” any of the relative advantages or disadvantages of the A1C assay as a means of diagnosis; rather, the …
2,601 citations