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Causal effect of smoking on DNA methylation in peripheral blood: a twin and family study.

ABSTRACT: Background:Smoking has been reported to be associated with peripheral blood DNA methylation, but the causal aspects of the association have rarely been investigated. We aimed to investigate the association and underlying causation between smoking and blood methylation. Methods:The methylation profile of DNA from the peripheral blood, collected as dried blood spots stored on Guthrie cards, was measured for 479 Australian women including 66 monozygotic twin pairs, 66 dizygotic twin pairs, and 215 sisters of twins from 130 twin families using the Infinium HumanMethylation450K BeadChip array. Linear regression was used to estimate associations between methylation at ~?410,000 cytosine-guanine dinucleotides (CpGs) and smoking status. A regression-based methodology for twins, Inference about Causation through Examination of Familial Confounding (ICE FALCON), was used to assess putative causation. Results:At a 5% false discovery rate, 39 CpGs located at 27 loci, including previously reported AHRR, F2RL3, 2q37.1 and 6p21.33, were found to be differentially methylated across never, former and current smokers. For all 39 CpG sites, current smokers had the lowest methylation level. Our study provides the first replication for two previously reported CpG sites, cg06226150 (SLC2A4RG) and cg21733098 (12q24.32). From the ICE FALCON analysis with smoking status as the predictor and methylation score as the outcome, a woman's methylation score was associated with her co-twin's smoking status, and the association attenuated towards the null conditioning on her own smoking status, consistent with smoking status causing changes in methylation. To the contrary, using methylation score as the predictor and smoking status as the outcome, a woman's smoking status was not associated with her co-twin's methylation score, consistent with changes in methylation not causing smoking status. Conclusions:For middle-aged women, peripheral blood DNA methylation at several genomic locations is associated with smoking. Our study suggests that smoking has a causal effect on peripheral blood DNA methylation, but not vice versa.

SUBMITTER: Li S

PROVIDER: S-EPMC5810186 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Causal effect of smoking on DNA methylation in peripheral blood: a twin and family study.

Li Shuai S Wong Ee Ming EM Bui Minh M Nguyen Tuong L TL Joo Ji-Hoon Eric JE Stone Jennifer J Dite Gillian S GS Giles Graham G GG Saffery Richard R Southey Melissa C MC Hopper John L JL

Clinical epigenetics 20180209

<h4>Background</h4>Smoking has been reported to be associated with peripheral blood DNA methylation, but the causal aspects of the association have rarely been investigated. We aimed to investigate the association and underlying causation between smoking and blood methylation.<h4>Methods</h4>The methylation profile of DNA from the peripheral blood, collected as dried blood spots stored on Guthrie cards, was measured for 479 Australian women including 66 monozygotic twin pairs, 66 dizygotic twin ...[more]

PMID: 29456763

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Project description:BACKGROUND:Alzheimer's disease results from a neurodegenerative process that starts well before the diagnosis can be made. New prognostic or diagnostic markers enabling early intervention into the disease process would be highly valuable. Environmental and lifestyle factors largely modulate the disease risk and may influence the pathogenesis through epigenetic mechanisms, such as DNA methylation. As environmental and lifestyle factors may affect multiple tissues of the body, we hypothesized that the disease-associated DNA methylation signatures are detectable in the peripheral blood of discordant twin pairs. RESULTS:Comparison of 23 disease discordant Finnish twin pairs with reduced representation bisulfite sequencing revealed peripheral blood DNA methylation differences in 11 genomic regions with at least 15.0% median methylation difference and FDR adjusted p value ??0.05. Several of the affected genes are primarily associated with neuronal functions and pathologies and do not display disease-associated differences in gene expression in blood. The DNA methylation mark in ADARB2 gene was found to be differentially methylated also in the anterior hippocampus, including entorhinal cortex, of non-twin cases and controls. Targeted bisulfite pyrosequencing of the DNA methylation mark in ADARB2 gene in 62 Finnish and Swedish twin pairs revealed that, in addition to the disease status, DNA methylation of this region is influenced by gender, age, zygosity, APOE genotype, and smoking. Further analysis of 120 Swedish twin pairs indicated that this specific DNA methylation mark is not predictive for Alzheimer's disease and becomes differentially methylated after disease onset. CONCLUSIONS:DNA methylation differences can be detected in the peripheral blood of twin pairs discordant for Alzheimer's disease. These DNA methylation signatures may have value as disease markers and provide insights into the molecular mechanisms of pathogenesis. We found no evidence that the DNA methylation marks would be associated with gene expression in blood. Further studies are needed to elucidate the potential importance of the associated genes in neuronal functions and to validate the prognostic or diagnostic value of the individual marks or marker panels.

Project description:BackgroundHigh surrounding greenness has many health benefits and might contribute to slower biological aging. However, very few studies have evaluated this from the perspective of epigenetics.ObjectivesWe aimed to evaluate the association between surrounding greenness and biological aging based on DNA methylation.MethodsWe derived Horvath's DNA methylation age (DNAmAge), Hannum's DNAmAge, PhenoAge, and GrimAge based on DNA methylation measured in peripheral blood samples from 479 Australian women in 130 families. Measures of DNAmAge acceleration (DNAmAgeAC) were derived from the residuals after regressing each DNAmAge metric on chronological age. Greenness was represented by satellite-derived Normalized Difference Vegetation Index (NDVI) and Enhanced Vegetation Index (EVI) metrics within 300-, 500-, 1,000-, and 2,000-m buffers surrounding participant addresses. Greenness-DNAmAgeAC associations were estimated using a within-sibship design fitted by linear mixed effect models, adjusting for familial clustering and important covariates.ResultsGreenness metrics were associated with significantly lower DNAmAgeAC based on GrimAge acceleration, suggesting slower biological aging with higher greenness based on both NDVI and EVI in 300-2,000m buffer areas. For example, each interquartile range increase in NDVI within 1,000m was associated with a 0.59 (95% CI: 0.18, 1.01)-year decrease in GrimAge acceleration. Greenness was also inversely associated with three of the eight components of GrimAge, specifically, DNA methylation-based surrogates of serum cystatin-C, serum growth differentiation factor 15, and smoking pack years. Associations between greenness and biological aging measured by Horvath's and Hannum's DNAmAgeAC were less consistent, and depended on neighborhood socioeconomic status. No significant associations were estimated for PhenoAge acceleration.DiscussionHigher surrounding greenness was associated with slower biological aging, as indicated by GrimAge age acceleration, in Australian women. Associations were also evident for three individual components of GrimAge, but were inconsistent for other measures of biological aging. Additional studies are needed to confirm our results. https://doi.org/10.1289/EHP8793.

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Dataset Information

Causal effect of smoking on DNA methylation in peripheral blood: a twin and family study.

Publications

Causal effect of smoking on DNA methylation in peripheral blood: a twin and family study.

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