Tobacco exposure-related alterations in DNA methylation and gene expression in human monocytes: the Multi-Ethnic Study of Atherosclerosis (MESA)

Abstract

Alterations in DNA methylation and gene expression in blood leukocytes are potential biomarkers of harm and mediators of the deleterious effects of tobacco exposure. However, methodological issues, including the use of self-reported smoking status and mixed cell types have made previously identified alterations in DNA methylation and gene expression difficult to interpret. In this study, we examined associations of tobacco exposure with DNA methylation and gene expression, utilizing a biomarker of tobacco exposure (urine cotinine) and CD14+ purified monocyte samples from 934 participants of the community-based Multi-Ethnic Study of Atherosclerosis (MESA). Urine cotinine levels were measured using an immunoassay. DNA methylation and gene expression were measured with microarrays. Multivariate linear regression was used to test for associations adjusting for age, sex, race/ethnicity, education, and study site. Urine cotinine levels were associated with methylation of 176 CpGs [false discovery rate (FDR)<0.01]. Four CpGs not previously identified by studies of non-purified blood samples nominally replicated (P value<0.05) with plasma cotinine-associated methylation in 128 independent monocyte samples. Urine cotinine levels associated with expression of 12 genes (FDR<0.01), including increased expression of P2RY6 (Beta ± standard error = 0.078 ± 0.008, P = 1.99 × 10−22), a gene previously identified to be involved in the release of pro-inflammatory cytokines. No cotinine-associated (FDR<0.01) methylation profiles significantly (FDR<0.01) correlated with cotinine-associated (FDR<0.01) gene expression profiles. In conclusion, our findings i) identify potential monocyte-specific smoking-associated methylation patterns and ii) suggest that alterations in methylation may not be a main mechanism regulating gene expression in monocytes in response to cigarette smoking.

High-dimensional mediation analysis in survival models

“…As a motivating example, smoking has side effects on human health, especially for lung cancer which is the leading cause of cancer mortality worldwide and creates an enormous public health burden [30]. When individual level phenotype and genotype data are available, numerous researches have indicated that mutation in CpG sites are related to tobacco smoking [31][32][33][34][35]. It is of great scientific interest to identify which methylation markers are acting as mediators between smoking and lung cancer patient's survival, as this is essential for finding the disease diagnosis markers and the treatment target in precision medicine.…”

A cell-type deconvolution meta-analysis of whole blood EWAS reveals lineage-specific smoking-associated DNA methylation changes

“…This is a critically important question given the fundamental role the immune response and inflammation plays in the development of cancer 18,41,42 and cardiovascular disease 43,44 . Some EWAS performed in purified blood cell populations have begun to address this important question, but were limited to one or two cell-types 45 , or limited in terms of sample size 46,47 . Thus, preliminary findings from these studies await confirmation from large EWAS performed in purified blood cell subtypes, ideally encompassing all major cell subtypes.…”

Smoking history: relationships with inflammatory markers, metabolic markers, body composition, muscle strength, and cardiopulmonary capacity in current smokers

“…Reynolds et al 25 found that exposure to smoking causes changes in monocyte gene expression. When monocytes enter the subendothelial spaces of blood vessels, they can predispose the organism to the development of atherosclerosis.…”