Genetically contextual effects of smoking on genome wide DNA methylation

Abstract

Smoking is the leading cause of death in the United States. It exerts its effects by increasing susceptibility to a variety of complex disorders among those who smoke, and if pregnant, to their unborn children. In prior efforts to understand the epigenetic mechanisms through which this increased vulnerability is conveyed, a number of investigators have conducted genome wide methylation analyses. Unfortunately, secondary to methodological limitations, these studies were unable to examine methylation in gene regions with significant amounts of genetic variation. Using genome wide genetic and epigenetic data from the Framingham Heart Study, we re-examined the relationship of smoking status to genome wide methylation status. When only methylation status is considered, smoking was significantly associated with differential methylation in 310 genes that map to a variety of biological process and cellular differentiation pathways. However, when SNP effects on the magnitude of smoking associated methylation changes are also considered, cis and trans-interaction effects were noted at a total of 266 and 4353 genes with no marked enrichment for any biological pathways. Furthermore, the SNP variation participating in the significant interaction effects is enriched for loci previously associated with complex medical illnesses. The enlarged scope of the methylome shown to be affected by smoking may better explicate the mediational pathways linking smoking with a myriad of smoking related complex syndromes. Additionally, these results strongly suggest that combined epigenetic and genetic data analyses may be critical for a more complete understanding of the relationship between environmental variables, such as smoking, and pathophysiological outcomes.

Genome‐wide and digital polymerase chain reaction epigenetic assessments of alcohol consumption

“…Please see Supporting Information Table 1 for a complete listing of the significant markers for each analysis. In addition, to better understand whether the changes at a given locus were related to alcohol or tobacco consumption, the ranking of a given probe with respect to smoking status in the Framingham Heart Study ( n = 1,599) is also provided (Dogan et al, ).…”

“…Although, smoking and drinking are well known to cosegregate (Bierut et al, ) the extent of the comorbidity surprised us with nearly 90% of the first 100 subjects recruited through our current project (R44AA022041) being daily smokers. Given the profound effects of smoking on genome‐wide methylation, (Dogan et al, , ; Zeilinger et al, ) this comorbidity has significant implications on strategies for identifying loci capable of measuring alcohol intake in all potential subjects. In that regard, we note that none of our candidate markers associated with smoking status in any of five genome‐wide methylation datasets in our possession (Dogan et al, , ; Monick et al, ; Philibert, Beach, & Brody, , ).…”

“…However, chronic heavy alcohol consumption is invariably associated with increased risk for undesirable outcomes (Dogan, Beach, & Philibert, ). Heavy drinking increases risk for hypertension, stroke, liver disease, as well as various forms of cancers (International Agency for Research on Cancer, ; Rehm et al, ; World Health Organization, ).…”

Placental DNA methylation signatures of maternal smoking during pregnancy and potential impacts on fetal growth

“…Future research is needed to characterize this convergence of genetic effects on growth and placental epigenetic responsiveness to MSDP within similar genomic proximities. It is possible that MSDP, genetic variation, and placental DNAm in these regions yield additive or interactive effects on birth outcomes; prior studies have addressed this question in blood 52,53 . Additionally, while our MSDP-associated CpGs are in similar genomic regions (1 Mb windows) with birth outcome SNPs, very few of our CpGs (9 of 1224) and very few of the birth outcome SNPs (3 of 324) are known placental mQTLs 32,33 .…”

The dynamics of smoking-related disturbed methylation: a two time-point study of methylation change in smokers, non-smokers and former smokers

“…A further possibility for the seemingly conflicting results is interaction with other molecular factors. Recent studies [55,56] have indicated that single-nucleotide polymorphisms influence the smoking-associated CpG sites. These studies further highlight the complexity of molecular networks, and underline the need for functional analysis.…”