Epigenome-wide studies have identified five loci where there is decreased blood DNA methylation associated with adult smoking. We examined smoking history in relation to DNA methylation in women from our 27K CpG methylation study and in women from our 450K CpG study of DES. We confirm smoking associations for four previously identified smoking-related CpGs in F2RL3, GPR15, AHRR and an intergenic region of chromosome 2. In addition we provide the first report of an association between a CpG in the coproporphyrinogen oxidase (CPOX) gene. CPOX codes for an enzyme involved in heme biosynthesis that is localized to the intermembrane space of the mitochondria, and mutations in CPOX are a cause of hereditary coproporphyria. In order to validate this locus we designed a pyrosequencing assay for the CpG shore site in the first intron of CPOX, and replicated our smoking result in an independent set of 476 women from the Sister Study. We found that relative to the levels in never smokers, there was lower methylation in former smokers (p < 2x10-6) and even lower methylation levels among current smokers (p < 2x10-18). These results suggest that the oxidative stress or the increased heme biosynthesis associated with smoking might lead to persistent decreased methylation in the first intron of CPOX. In addition we have completed a study epigenetic changes in blood of babies born to mothers who smoke. Maternal smoking during pregnancy is associated with significant infant morbidity and mortality, and may influence later disease risk. One mechanism by which smoking (and other environmental factors) might have long-lasting effects is through epigenetic modifications such as DNA methylation. We analyzed blood collected from 889 infants shortly after delivery and examined the DNA using the Illumina 450K methylation chip. We identified 185 CpGs with altered methylation in infants of smokers at genome-wide significance. These correspond to 110 gene regions, of which 7 have been previously reported and 10 are newly confirmed using publically-available results. Among these 10 the most noteworthy are FRMD4A, ATP9A, GALNT2, and MEG3, implicated in processes related to nicotine dependence, smoking cessation, and placental and embryonic development. The methylation changes identified in newborns may mediate the association between in utero maternal smoking exposure and later health outcomes. Exposure to diethylstilbesterol during the in utero period is associated with increased risk of fertility problems and increased cancer risk. Animal studies have linked prenatal DES exposure to epigenetic changes including changes in DNA methylation. We examined blood DNA methylation in 100 adult women with and 100 without prenatal exposure to DES using 450K methylation arrays. Although 4 methylation sites had p<10-5, none reached genome-wide significance, suggesting that there is little evidence for large persistent effects of DES exposure in blood. Body mass index is an important risk factor for postmenopausal breast cancer and may act by multiple pathways. We examined whether BMI was associated with epigenetic changes in normal breast tissue by examining normal breast tissue DNA using 450K methylation arrays in 81 women. After adjusting for multiple comp 2573 methylation sites were significantly associated with BMI and pathway analysis showed that these sites were enriched for genes involved in inflammation, insulin receptor signaling and leptin signaling. This work suggests that BMI is associated with methylation changes in normal-appearing breast tissue and may influence genes in inflammatory and other carcinogenic processes.
| O'Brien, Katie M; Sandler, Dale P; Xu, Zongli et al. (2018) Vitamin D, DNA methylation, and breast cancer. Breast Cancer Res 20:70 |
| Herceg, Zdenko; Ghantous, Akram; Wild, Christopher P et al. (2018) Roadmap for investigating epigenome deregulation and environmental origins of cancer. Int J Cancer 142:874-882 |
| Wu, Lang; Shi, Wei; Long, Jirong et al. (2018) A transcriptome-wide association study of 229,000 women identifies new candidate susceptibility genes for breast cancer. Nat Genet 50:968-978 |
| Felix, Janine F; Joubert, Bonnie R; Baccarelli, Andrea A et al. (2018) Cohort Profile: Pregnancy And Childhood Epigenetics (PACE) Consortium. Int J Epidemiol 47:22-23u |
| O'Brien, Katie M; Sandler, Dale P; Shi, Min et al. (2018) Genome-Wide Association Study of Serum 25-Hydroxyvitamin D in US Women. Front Genet 9:67 |
| O'Brien, Katie M; Sandler, Dale P; Kinyamu, H Karimi et al. (2017) Single-Nucleotide Polymorphisms in Vitamin D-Related Genes May Modify Vitamin D-Breast Cancer Associations. Cancer Epidemiol Biomarkers Prev 26:1761-1771 |
| Wilson, L E; Harlid, S; Xu, Z et al. (2017) An epigenome-wide study of body mass index and DNA methylation in blood using participants from the Sister Study cohort. Int J Obes (Lond) 41:194-199 |
| Harlid, Sophia; Adgent, Margaret; Jefferson, Wendy N et al. (2017) Soy Formula and Epigenetic Modifications: Analysis of Vaginal Epithelial Cells from Infant Girls in the IFED Study. Environ Health Perspect 125:447-452 |
| Michailidou, Kyriaki (see original citation for additional authors) (2017) Association analysis identifies 65 new breast cancer risk loci. Nature 551:92-94 |
| Sandler, Dale P; Hodgson, M Elizabeth; Deming-Halverson, Sandra L et al. (2017) The Sister Study Cohort: Baseline Methods and Participant Characteristics. Environ Health Perspect 125:127003 |
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