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 15,907 blood derived DNA samples from participants in 16 cohorts (including 2,433 current, 6,518 former, and 6,956 never smokers). Comparing current versus never smokers, 2,623 CpG sites (CpGs), annotated to 1,405 genes, were statistically significantly differentially methylated at Bonferroni threshold of p<1×10−7 (18,760 CpGs at False Discovery Rate (FDR)<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<1×10−7 (2,623 CpGs at FDR<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 biologic 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.

Background-Clinic-based observational studies in men have reported that obstructive sleep apnea is associated with an increased incidence of coronary heart disease. The objective of this study was to assess the relation of obstructive sleep apnea to incident coronary heart disease and heart failure in a general community sample of adult men and women. Methods and Results-A total of 1927 men and 2495 women Ն40 years of age and free of coronary heart disease and heart failure at the time of baseline polysomnography were followed up for a median of 8.7 years in this prospective longitudinal epidemiological study. After adjustment for multiple risk factors, obstructive sleep apnea was a significant predictor of incident coronary heart disease (myocardial infarction, revascularization procedure, or coronary heart disease death) only in men Յ70 years of age (adjusted hazard ratio 1.10 [95% confidence interval 1.00 to 1.21] per 10-unit increase in apnea-hypopnea index [AHI]) but not in older men or in women of any age. Among men 40 to 70 years old, those with AHI Ն30 were 68% more likely to develop coronary heart disease than those with AHI Ͻ5.Obstructive sleep apnea predicted incident heart failure in men but not in women (adjusted hazard ratio 1.13 [95% confidence interval 1.02 to 1.26] per 10-unit increase in AHI). Men with AHI Ն30 were 58% more likely to develop heart failure than those with AHI Ͻ5. Conclusions-Obstructive sleep apnea is associated with an increased risk of incident heart failure in communitydwelling middle-aged and older men; its association with incident coronary heart disease in this sample is equivocal. (Circulation. 2010;122:352-360.)Key Words: epidemiology Ⅲ sleep apnea Ⅲ coronary disease Ⅲ heart failure O bstructive sleep apnea (OSA), characterized by recurrent partial or complete collapse of the upper airway during sleep, is a common chronic condition that affects an estimated 9% of adult women and 24% of adult men. 1 A number of cross-sectional studies have reported an association of OSA with coronary heart disease (CHD), 2-6 although most were small hospital or clinic-based case-control studies that often lacked adjustment for important cardiovascular risk factors. Recent longitudinal studies have found an association of untreated OSA with incident or recurrent cardiovascular disease events. [7][8][9][10] Because untreated OSA generally reflected refusal or voluntary discontinuance of continuous positive airway pressure (CPAP) therapy, a healthy-user effect might be an important source of confounding bias in these studies. Moreover, women were absent from or underrepresented in these studies. Clinical Perspective on p 360Several cross-sectional studies indicate a high prevalence of OSA of 11% to 37% in patients with heart failure. [11][12][13] One study found echocardiographic evidence of left ventricular diastolic dysfunction in 56% of newly diagnosed OSA patients but in only 20% of control subjects; diastolic dysfunction improved with CPAP therapy. 14 Small clinical trials Continuing me...