title: Nightshift work and genome-wide DNA methylation.
abstract: The negative health effects of shift work, including carcinogenesis, may be mediated by changes in DNA methylation, particularly in the circadian genes. Using the Infinium HumanMethylation450 Bead Array (Illumina, San Diego, CA), we compared genome-wide methylation between 65 actively working dayshift workers and 59 actively working nightshift workers in the healthcare industry. A total of 473 800 loci, including 391 loci across the 12 core circadian genes, were analyzed to identify methylation markers associated with shift work status using linear regression models adjusted for gender, age, body mass index, race, smoking status and leukocyte cell profile as measured by flow cytometry. Analyses at the level of gene, CpG island and gene region were also conducted. To account for multiple comparisons, we controlled the false discovery rate (FDR ≤0.05). Significant differences between nightshift and dayshift workers were found at 16 135 of 473 800 loci, across 3769 of 20 164 genes, across 7173 of 22 721 CpG islands and across 5508 of 51 843 gene regions. For each significant loci, gene, CpG island or gene region, average methylation was consistently found to be decreased among nightshift workers compared to dayshift workers. Twenty-one loci located in the circadian genes were also found to be significantly hypomethylated among nightshift workers. The largest differences were observed for three loci located in the gene body of PER3. A total of nine significant loci were found in the CSNK1E gene, most of which were located in a CpG island and near the transcription start site of the gene. Methylation changes in these circadian genes may lead to altered expression of these genes which has been associated with cancer in previous studies. Gene ontology enrichment analysis revealed that among the significantly hypomethylated genes, processes related to host defense and immunity were represented. Our results indicate that the health effects of shift work may be mediated by hypomethylation of a wide variety of genes, including those related to circadian rhythms. While these findings need to be followed-up among a considerably expanded group of shift workers, the data generated by this study supports the need for future targeted research into the potential impacts of shift work on specific carcinogenic mechanisms.
authors.affiliation: Program in Epidemiology .
authors.forename: Parveen
authors.initials: P
authors.lastname: Bhatti
authors.forename: Yuzheng
authors.initials: Y
authors.lastname: Zhang
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Song
authors.forename: Karen W
authors.initials: KW
authors.lastname: Makar
authors.forename: Cassandra L
authors.initials: CL
authors.lastname: Sather
authors.forename: Karl T
authors.initials: KT
authors.lastname: Kelsey
authors.forename: E Andres
authors.initials: EA
authors.lastname: Houseman
authors.forename: Pei
authors.initials: P
authors.lastname: Wang
mesh_terms: D000328:Adult; D002940:Circadian Rhythm / Q000235:genetics*; D056925:Circadian Rhythm Signaling Peptides and Proteins / Q000235:genetics*; D018899:CpG Islands; D019175:DNA Methylation; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D056426:Genetic Loci; D015894:Genome, Human; D055106:Genome-Wide Association Study; D019981:Health Care Sector; D006801:Humans; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D010561:Personnel Staffing and Scheduling; D020178:Sleep Disorders, Circadian Rhythm / Q000175:diagnosis / Q000235:genetics*; D013997:Time Factors; D016526:Workload; D055815:Young Adult
chemical_list: D056925:Circadian Rhythm Signaling Peptides and Proteins
keywords: Circadian genes; DNA methylation; shift work