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This study aims to investigate the involvement of oxidative stress and inflammation in the causal chain, and to identify intermediate biomarkers that are associated retrospectively with the exposure and prospectively with the disease. We designed a case\u2010control study on CCVD nested in a cohort of 18,982 individuals from the EPIC\u2010Italy study. We measured air pollution, inflammatory biomarkers, and whole\u2010genome DNA methylation in blood collected up to 17 years before the diagnosis. The study sample includes all the incident CCVD cases among former\u2010 and never\u2010smokers, with available stored blood sample, that arose in the cohort during the follow\u2010up. We identified enrichment of altered DNA methylation in \u201cROS\/Glutathione\/Cytotoxic granules\u201d and \u201cCytokine signaling\u201d pathways related genes, associated with both air pollution (multiple comparisons adjusted p for enrichment ranging from 0.01 to 0.03 depending on pollutant) and with CCVD risk (<jats:italic>P<\/jats:italic>\u2009=\u20090.04 and <jats:italic>P<\/jats:italic>\u2009=\u20090.03, respectively). Also, Interleukin\u201017 was associated with higher exposure to NO<jats:sub>2<\/jats:sub> (<jats:italic>P<\/jats:italic>\u2009=\u20090.0004), NO<jats:sub><jats:italic>x<\/jats:italic><\/jats:sub> (<jats:italic>P<\/jats:italic>\u2009=\u20090.0005), and CCVD risk (OR\u2009=\u20091.79; CI 1.04\u20133.11; <jats:italic>P<\/jats:italic>\u2009=\u20090.04 comparing extreme tertiles). Our findings indicate that chronic exposure to air pollution can lead to oxidative stress, which in turn activates a cascade of inflammatory responses mainly involving the \u201cCytokine signaling\u201d pathway, leading to increased risk of CCVD. Inflammatory proteins and DNA methylation alterations can be detected several years before CCVD diagnosis in blood samples, being promising preclinical biomarkers. Environ. Mol. Mutagen. 59:234\u2013246, 2018. \u00a9 2017 Wiley Periodicals, Inc.<\/jats:p>","DOI":"10.1002\/em.22153","type":"journal-article","created":{"date-parts":[[2017,11,8]],"date-time":"2017-11-08T08:47:16Z","timestamp":1510130836000},"page":"234-246","source":"Crossref","is-referenced-by-count":101,"title":["Oxidative stress and inflammation mediate the effect of air pollution on cardio\u2010 and cerebrovascular disease: A prospective study in nonsmokers"],"prefix":"10.1002","volume":"59","author":[{"given":"Giovanni","family":"Fiorito","sequence":"first","affiliation":[{"name":"Italian Institute for Genomic Medicine (IIGM) Turin Italy"},{"name":"Department of Medical Sciences University of Turin  Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jelle","family":"Vlaanderen","sequence":"additional","affiliation":[{"name":"Utrecht University, Institute for Risk Assessment Sciences, Environmental Epidemiology Division Utrecht 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