Abstract
Numerous studies have shown that cg05575921 methylation decreases in response to smoking. However, secondary to methodological issues, the magnitude and dose dependency of that response is as of yet unclear. This lack of certainty is a barrier to the use of DNA methylation clinically to assess and monitor smoking status. To better define this relationship, we conducted a joint analysis of methylation sensitive PCR digital (MSdPCR) assessments of cg05575921 methylation in whole blood and/or saliva DNA to smoking using samples from 421 smokers and 423 biochemically confirmed non-smokers from 4 previously published studies. We found that cg05575921 methylation manifested a curvilinear dose dependent decrease in response to increasing cigarette consumption. In whole blood DNA, the Receiver Operating Characteristic (ROC) Area Under the Curve (AUC) of cg05575921 methylation for predicting daily smoking status was 0.98. In saliva DNA, the gross AUC was 0.91 with correction for cellular heterogeneity improving the AUC to 0.94. Methylation status was significantly associated with the Fagerstrom Test for Nicotine Dependence score, but with significant sampling heterogeneity. We conclude that MSdPCR assessments of cg05575921 methylation are a potentially powerful, clinically implementable tool for the assessment and management of smoking.
Highlights
Numerous studies have shown that cg05575921 methylation decreases in response to smoking
All procedures were performed in accordance with the Declaration of Helsinki with the individual institutional approvals noted separately for each cohort being noted in the supplementary methods section with each subject providing written informed consent
We examined the relationship of whole blood (WB) cg05575921 methylation to serum cotinine (COT) and exhaled carbon monoxide (CO) levels
Summary
Numerous studies have shown that cg05575921 methylation decreases in response to smoking. Secondary to methodological issues, the magnitude and dose dependency of that response is as of yet unclear This lack of certainty is a barrier to the use of DNA methylation clinically to assess and monitor smoking status. These studies have shown that smoking is associated with broad changes across the epigenome with the majority of these changes at least partially reverting in response to smoking c essation[7,8,9] Using this methylation information, several groups have attempted to construct methylation indices for the prediction of s moking[5,10,11]. These indices rely on array hybridization techniques, which are costly, relatively imprecise, time consuming and reference dependent that do not produce reliable beta values for clinical interpretation[15,16,17]
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