title: Identification of a new locus and validation of previously reported loci showing differential methylation associated with smoking. The REGICOR study.
abstract: Smoking increases the risk of many diseases and could act through changes in DNA methylation patterns. The aims of this study were to determine the association between smoking and DNA methylation throughout the genome at cytosine-phosphate-guanine (CpG) site level and genomic regions. A discovery cross-sectional epigenome-wide association study nested in the follow-up of the REGICOR cohort was designed and included 645 individuals. Blood DNA methylation was assessed using the Illumina HumanMethylation450 BeadChip. Smoking status was self-reported using a standardized questionnaire. We identified 66 differentially methylated CpG sites associated with smoking, located in 38 genes. In most of these CpG sites, we observed a trend among those quitting smoking to recover methylation levels typical of never smokers. A CpG site located in a novel smoking-associated gene (cg06394460 in LNX2) was hypomethylated in current smokers. Moreover, we validated two previously reported CpG sites (cg05886626 in THBS1, and cg24838345 in MTSS1) for their potential relation to atherosclerosis and cancer diseases, using several different approaches: CpG site methylation, gene expression, and plasma protein level determinations. Smoking was also associated with higher THBS1 gene expression but with lower levels of thrombospondin-1 in plasma. Finally, we identified differential methylation regions in 13 genes and in four non-coding RNAs. In summary, this study replicated previous findings and identified and validated a new CpG site located in LNX2 associated with smoking.
authors.affiliation: a Cardiovascular Epidemiology and Genetics Research Group; IMIM (Hospital del Mar Medical Research Institute); 08003 Barcelona , Catalonia , Spain.|b Universitat Pompeu Fabra (UPF); 08003 Barcelona , Catalonia , Spain.
authors.forename: Sergi
authors.initials: S
authors.lastname: Sayols-Baixeras
authors.affiliation: a Cardiovascular Epidemiology and Genetics Research Group; IMIM (Hospital del Mar Medical Research Institute); 08003 Barcelona , Catalonia , Spain.
authors.forename: Carla
authors.initials: C
authors.lastname: Lluís-Ganella
authors.affiliation: a Cardiovascular Epidemiology and Genetics Research Group; IMIM (Hospital del Mar Medical Research Institute); 08003 Barcelona , Catalonia , Spain.|c CIBER Epidemiology and Public Health; 08003 Barcelona , Catalonia , Spain.
authors.forename: Isaac
authors.initials: I
authors.lastname: Subirana
authors.affiliation: b Universitat Pompeu Fabra (UPF); 08003 Barcelona , Catalonia , Spain.|c CIBER Epidemiology and Public Health; 08003 Barcelona , Catalonia , Spain.|d Centre for Research in Environmental Epidemiology (CREAL); 08003 Barcelona , Catalonia , Spain.
authors.forename: Lucas A
authors.initials: LA
authors.lastname: Salas
authors.affiliation: d Centre for Research in Environmental Epidemiology (CREAL); 08003 Barcelona , Catalonia , Spain.
authors.forename: Nadia
authors.initials: N
authors.lastname: Vilahur
authors.affiliation: e Preventive Medicine Department; Genetic and Molecular Epidemiology Unit; University of Valencia; 46010 Valencia , Spain.|f CIBER Obesity and Nutrition; 15706 Santiago de Compostela , Galicia , Spain.
authors.forename: Dolores
authors.initials: D
authors.lastname: Corella
authors.affiliation: g Cardiovascular Risk and Nutrition Research Group; IMIM (Hospital del Mar Medical Research Institute); 08003 Barcelona , Catalonia , Spain.
authors.forename: Dani
authors.initials: D
authors.lastname: Muñoz
authors.affiliation: h Health Sciences Institute; 45600 Talavera de la Reina , Toledo , Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Segura
authors.affiliation: i Department of Neurology; Neurovascular Research Group; IMIM-Hospital del Mar (Hospital del Mar Medical Research Institute); 08003 Barcelona , Catalonia , Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Jimenez-Conde
authors.affiliation: j Cancer Epigenetics and Biology Program (PEBC); Bellvitge Biomedical Research Institute (IDIBELL); 08908 Barcelona , Catalonia , Spain.
authors.forename: Sebastián
authors.initials: S
authors.lastname: Moran
authors.affiliation: i Department of Neurology; Neurovascular Research Group; IMIM-Hospital del Mar (Hospital del Mar Medical Research Institute); 08003 Barcelona , Catalonia , Spain.
authors.forename: Carolina
authors.initials: C
authors.lastname: Soriano-Tárraga
authors.affiliation: i Department of Neurology; Neurovascular Research Group; IMIM-Hospital del Mar (Hospital del Mar Medical Research Institute); 08003 Barcelona , Catalonia , Spain.
authors.forename: Jaume
authors.initials: J
authors.lastname: Roquer
authors.affiliation: k School of Medicine; Universidad Complutense de Madrid , Madrid , Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Lopez-Farré
authors.affiliation: a Cardiovascular Epidemiology and Genetics Research Group; IMIM (Hospital del Mar Medical Research Institute); 08003 Barcelona , Catalonia , Spain.
authors.forename: Jaume
authors.initials: J
authors.lastname: Marrugat
authors.affiliation: f CIBER Obesity and Nutrition; 15706 Santiago de Compostela , Galicia , Spain.|g Cardiovascular Risk and Nutrition Research Group; IMIM (Hospital del Mar Medical Research Institute); 08003 Barcelona , Catalonia , Spain.
authors.forename: Montse
authors.initials: M
authors.lastname: Fitó
authors.affiliation: a Cardiovascular Epidemiology and Genetics Research Group; IMIM (Hospital del Mar Medical Research Institute); 08003 Barcelona , Catalonia , Spain.
authors.forename: Roberto
authors.initials: R
authors.lastname: Elosua
mesh_terms: D000368:Aged; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D015331:Cohort Studies; D018899:CpG Islands; D003430:Cross-Sectional Studies; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008875:Middle Aged; D012907:Smoking / Q000009:adverse effects*; D019700:Thrombospondin 1 / Q000235:genetics / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D019700:Thrombospondin 1; C570847:LNX2 protein, human; C000611726:thrombospondin-1, human
keywords: 450K; DNA methylation; EWAS; LNX2; MTSS1; THBS1; epigenetics; smoking
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