title: Association of cigarette smoking and CRP levels with DNA methylation in α-1 antitrypsin deficiency.
abstract: Alpha-1 antitrypsin (AAT) deficiency and tobacco smoking are confirmed risk factors for Chronic Obstructive Pulmonary Disease. We hypothesized that variable DNA methylation would be associated with smoking and inflammation, as reflected by the level of C-Reactive Protein (CRP) in AAT-deficient subjects. Methylation levels of 1,411 autosomal CpG sites from the Illumina GoldenGate Methylation Cancer Panel I were analyzed in 316 subjects. Associations of five smoking behaviors and CRP levels with individual CpG sites and average methylation levels were assessed using non-parametric testing, linear regression and linear mixed effect models, with and without adjustment for age and gender. Univariate linear regression analysis revealed that methylation levels of 16 CpG sites significantly associated with ever-smoking status. A CpG site in the TGFBI gene was the only site associated with ever-smoking after adjustment for age and gender. No highly significant associations existed between age at smoking initiation, pack-years smoked, duration of smoking, and time since quitting smoking as predictors of individual CpG site methylation levels. However, ever-smoking and younger age at smoking initiation associated with lower methylation level averaged across all sites. DNA methylation at CpG sites in the RUNX3, JAK3 and KRT1 genes associated with CRP levels. The most significantly associated CpG sites with gender and age mapped to the CASP6 and FZD9 genes, respectively. In summary, this study identified multiple potential candidate CpG sites associated with ever-smoking and CRP level in AAT-deficient subjects. Phenotypic variability in Mendelian diseases may be due to epigenetic factors.
authors.affiliation: Channing Laboratory, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
authors.forename: Mateusz
authors.initials: M
authors.lastname: Siedlinski
authors.forename: Barbara
authors.initials: B
authors.lastname: Klanderman
authors.forename: Robert A
authors.initials: RA
authors.lastname: Sandhaus
authors.forename: Alan F
authors.initials: AF
authors.lastname: Barker
authors.forename: Mark L
authors.initials: ML
authors.lastname: Brantly
authors.forename: Edward
authors.initials: E
authors.lastname: Eden
authors.forename: N Gerard
authors.initials: NG
authors.lastname: McElvaney
authors.forename: Stephen I
authors.initials: SI
authors.lastname: Rennard
authors.forename: James M
authors.initials: JM
authors.lastname: Stocks
authors.forename: James K
authors.initials: JK
authors.lastname: Stoller
authors.forename: Charlie
authors.initials: C
authors.lastname: Strange
authors.forename: Gerard M
authors.initials: GM
authors.lastname: Turino
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Campbell
authors.forename: Dawn L
authors.initials: DL
authors.lastname: Demeo
mesh_terms: D000328:Adult; D002097:C-Reactive Protein / Q000032:analysis*; D053178:Caspase 6 / Q000235:genetics; D018899:CpG Islands; D019175:DNA Methylation; D005260:Female; D051157:Frizzled Receptors / Q000235:genetics; D056426:Genetic Loci; D006720:Homozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D029424:Pulmonary Disease, Chronic Obstructive / Q000209:etiology; D012907:Smoking / Q000009:adverse effects*; D019896:alpha 1-Antitrypsin Deficiency / Q000097:blood / Q000235:genetics*
chemical_list: C549560:FZD9 protein, human; D051157:Frizzled Receptors; D002097:C-Reactive Protein; C505514:CASP6 protein, human; D053178:Caspase 6