title: The impact of genetic variation and cigarette smoke on DNA methylation in current and former smokers from the COPDGene study.
abstract: DNA methylation can be affected by systemic exposures, such as cigarette smoking and genetic sequence variation; however, the relative impact of each on the epigenome is unknown. We aimed to assess if cigarette smoking and genetic variation are associated with overlapping or distinct sets of DNA methylation marks and pathways. We selected 85 Caucasian current and former smokers with genome-wide single nucleotide polymorphism (SNP) genotyping available from the COPDGene study. Genome-wide methylation was obtained on DNA from whole blood using the Illumina HumanMethylation27 platform. To determine the impact of local sequence variation on DNA methylation (mQTL), we examined the association between methylation and SNPs within 50 kb of each CpG site. To examine the impact of cigarette smoking on DNA methylation, we examined the differences in methylation by current cigarette smoking status. We detected 770 CpG sites annotated to 708 genes associated at an FDR < 0.05 in the cis-mQTL analysis and 1,287 CpG sites annotated to 1,242 genes, which were nominally associated in the smoking-CpG association analysis (P(unadjusted) < 0.05). Forty-three CpG sites annotated to 40 genes were associated with both SNP variation and current smoking; this overlap was not greater than that expected by chance. Our results suggest that cigarette smoking and genetic variants impact distinct sets of DNA methylation marks, the further elucidation of which may partially explain the variable susceptibility to the health effects of cigarette smoking. Ascertaining how genetic variation and systemic exposures differentially impact the human epigenome has relevance for both biomarker identification and therapeutic target development for smoking-related diseases.
authors.affiliation: a Channing Division of Network Medicine; Brigham and Women's Hospital/Harvard Medical School ; Boston , MA USA.
authors.forename: Weiliang
authors.initials: W
authors.lastname: Qiu
authors.affiliation: a Channing Division of Network Medicine; Brigham and Women's Hospital/Harvard Medical School ; Boston , MA USA.|b Division of Pulmonary/Critical Care; Brigham and Women's Hospital/Harvard Medical School ; Boston , MA USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Wan
authors.affiliation: a Channing Division of Network Medicine; Brigham and Women's Hospital/Harvard Medical School ; Boston , MA USA.
authors.forename: Jarrett
authors.initials: J
authors.lastname: Morrow
authors.affiliation: a Channing Division of Network Medicine; Brigham and Women's Hospital/Harvard Medical School ; Boston , MA USA.|b Division of Pulmonary/Critical Care; Brigham and Women's Hospital/Harvard Medical School ; Boston , MA USA.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Cho
authors.affiliation: c National Jewish Health ; Denver , CO USA.
authors.forename: James D
authors.initials: JD
authors.lastname: Crapo
authors.affiliation: a Channing Division of Network Medicine; Brigham and Women's Hospital/Harvard Medical School ; Boston , MA USA.|b Division of Pulmonary/Critical Care; Brigham and Women's Hospital/Harvard Medical School ; Boston , MA USA.
authors.forename: Edwin K
authors.initials: EK
authors.lastname: Silverman
authors.affiliation: a Channing Division of Network Medicine; Brigham and Women's Hospital/Harvard Medical School ; Boston , MA USA.|b Division of Pulmonary/Critical Care; Brigham and Women's Hospital/Harvard Medical School ; Boston , MA USA.
authors.forename: Dawn L
authors.initials: DL
authors.lastname: DeMeo
mesh_terms: D000368:Aged; D002874:Chromosome Mapping; D018899:CpG Islands; D019175:DNA Methylation / Q000187:drug effects*; D005260:Female; D056726:Genetic Association Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D012907:Smoking / Q000009:adverse effects* / Q000235:genetics; D044465:White People / Q000235:genetics*
keywords: CpG site; cis-mQTL; environmental factor; epigenetics; genetic variant