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Associations Between Genome-wide Gene Expression and Ambient Nitrogen Oxides

Mostafavi, Nahid; Vlaanderen, Jelle; Portengen, Lutzen; Chadeau-Hyam, Marc; Modig, Lars; Palli, Domenico; Bergdahl, Ingvar A.; Brunekreef, Bert; Vineis, Paolo; Hebels, Dennie G. A. J.; Kleinjans, Jos C. S.; Krogh, Vittorio; Hoek, Gerard; Georgiadis, Panagiotis; Kyrtopoulos, Soterios .; Vermeulen, Roel

doi: 10.1097/EDE.0000000000000628
Air Pollution

Background: We hypothesize that biological perturbations due to exposure to ambient air pollution are reflected in gene expression levels in peripheral blood mononuclear cells.

Methods: We assessed the association between exposure to ambient air pollution and genome-wide gene expression levels in peripheral blood mononuclear cells collected from 550 healthy subjects participating in cohorts from Italy and Sweden. Annual air pollution estimates of nitrogen oxides (NOx) at time of blood collection (1990–2006) were available from the ESCAPE study. In addition to univariate analysis and two variable selection methods to investigate the association between expression and exposure to NOx, we applied gene set enrichment analysis to assess overlap between our most perturbed genes and gene sets hypothesized to be related to air pollution and cigarette smoking. Finally, we assessed associations between NOx and CpG island methylation at the identified genes.

Results: Annual average NOx exposure in the Italian and Swedish cohorts was 94.2 and 6.7 µg/m3, respectively. Long-term exposure to NOx was associated with seven probes in the Italian cohort and one probe in the Swedish (and combined) cohorts. For genes AHCYL2 and MTMR2, changes were also seen in the methylome. Genes hypothesized to be downregulated due to cigarette smoking were enriched among the most strongly downregulated genes from our study.

Conclusion: This study provides evidence of subtle changes in gene expression related to exposure to long-term NOx. On a global level, the observed changes in the transcriptome may indicate similarities between air pollution and tobacco induced changes in the transcriptome.

Supplemental Digital Content is available in the text.

From the aDivision of Environmental Epidemiology, Institute for Risk Assessment Sciences, Utrecht University, Utrecht, The Netherlands; bMedical Research Council-Health Protection Agency Centre for Environment and Health, Department of Epidemiology and Biostatistics, Imperial College London, London, United Kingdom; cDepartment of Public Health and Clinical Medicine, Occupational and Environmental Medicine, Umeå University, Umeå, Sweden; dDepartment of Biobank Research, Umeå University, Umeå, Sweden; eMolecular and Nutritional Epidemiology Unit, Cancer Prevention and Research Institute (ISPO), Florence, Italy; fJulius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands; gHuGeF Foundation, Turin, Italy; hDepartment of Toxicogenomics, Maastricht University, Maastricht, The Netherlands; iEpidemiology Unit, Instituto Tumori, Milan, Italy; and jNational Hellenic Research Foundation, Institute of Biology, Pharmaceutical Chemistry and Biotechnology, Athens, Greece.

Submitted 8 December 2015; accepted 19 January 2017.

The research leading to these results has received funding from the European Community’s Seventh Framework Program (FP7/2007e2011) under Grant Agreement Number: 211250 (the European Study of Cohorts for Air Pollution Effects), 226756 (Envirogenomarkers), and 308610 (Exposomics). Data of EnviroGenoMarkers will not be made available online, because the use of these samples for anything other than we have ethical permission for is prohibited. The results of this study are available for re-evaluation whenever needed.

The authors report no conflicts of interest.

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Correspondence: Roel Vermeulen, Division Environmental Epidemiology, Institute for Risk Assessment Sciences, Yalelaan 2, Room 353, 3584 CM, Utrecht, The Netherlands. E-mail:

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