hide
Free keywords:
biomarkers, genome-wide association study, meta-analysis, methylation, smoking
Abstract:
Background DNA methylation leaves a long-term signature of smoking
exposure and is one potential mechanism by which tobacco exposure
predisposes to adverse health outcomes, such as cancers, osteoporosis,
lung, and cardiovascular disorders.
Methods and Results To comprehensively determine the association between
cigarette smoking and DNA methylation, we conducted a meta-analysis of
genome-wide DNA methylation assessed using the Illumina BeadChip 450K
array on 15907 blood-derived DNA samples from participants in 16 cohorts
(including 2433 current, 6518 former, and 6956 never smokers). Comparing
current versus never smokers, 2623 cytosine-phosphate-guanine sites
(CpGs), annotated to 1405 genes, were statistically significantly
differentially methylated at Bonferroni threshold of P<1x10(-7) (18760
CpGs at false discovery rate <0.05). Genes annotated to these CpGs were
enriched for associations with several smoking-related traits in
genome-wide studies including pulmonary function, cancers, inflammatory
diseases, and heart disease. Comparing former versus never smokers, 185
of the CpGs that differed between current and never smokers were
significant P<1x10(-7) (2623 CpGs at false discovery rate <0.05),
indicating a pattern of persistent altered methylation, with
attenuation, after smoking cessation. Transcriptomic integration
identified effects on gene expression at many differentially methylated
CpGs.
Conclusions Cigarette smoking has a broad impact on genome-wide
methylation that, at many loci, persists many years after smoking
cessation. Many of the differentially methylated genes were novel genes
with respect to biological effects of smoking and might represent
therapeutic targets for prevention or treatment of tobacco-related
diseases. Methylation at these sites could also serve as sensitive and
stable biomarkers of lifetime exposure to tobacco smoke.
