Age is one of the strongest predictors of cancer, chronic disease and mortality, but biological responses to aging differ among people. Epigenetic DNA modifications have been used to estimate biological age, which may be a useful predictor of disease risk. We test this hypothesis for breast cancer. Using a case-cohort approach, we measured baseline blood DNA methylation of 2,764 women enrolled in the Sister Study, 1,566 of whom subsequently developed breast cancer after an average of six years. Using three previously established methylation-based clocks (Hannum, Horvath, and Levine) we defined biological age acceleration for each woman by comparing her estimated biological age with her chronological age. Hazard ratios (HRs) and 95% confidence intervals (CIs) for breast cancer risk were estimated using Cox regression models. All statistical tests were two-sided. Each of the three clocks showed that biological age acceleration was statistically significantly associated with increased risk of developing breast cancer (5 year age acceleration, Hannum's clock: HR=1.10, 95% CI: 1.00, 1.21, P= 0.04; Horvath's clock: HR=1.08, 95% CI: 1.00, 1.17, P= 0.04; Levine's clock: HR: 1.15, 95% CI: 1.07, 1.23, P<0.001 ). For Levine's clock, each five-year acceleration in biological age corresponded with a 15% increase in breast cancer risk. Although biological age may accelerate with menopausal transition, age acceleration in premenopausal women independently predicted breast cancer. Case-only analysis suggested that, among women who develop breast cancer, increased age acceleration is associated with invasive cancer (OR for invasive=1.09, 95% CI: 0.98, 1.22, P=0.10). DNA methylation-based measures of biological age may be important predictors of breast cancer risk. Hormone therapy (HT) is associated with increased risk of breast cancer, strongly dependent on type, duration, and recency of use. HT use could affect cancer risk by changing breast tissue transcriptional programs. We hypothesize that these changes are preceded by changes in DNA methylation. To explore this hypothesis we used histologically normal-appearing breast tissue from the Normal Breast Study (NBS). DNA methylation -values were obtained using the Illumina HumanMethylation 450 BeadChips for 90 samples including all NBS-participants who used HT within 5 y before surgery. Data were analyzed using the reference-free cell mixture method. Cancer Genome Atlas (TCGA) mRNA-Seq data were used to assess correlation between DNA methylation and gene expression. We identified 527 CpG sites in 403 genes that were associated with ever using HT at genome wide significance (FDR q < 0.05), of these, 68 sites were also significantly associated with duration of use or recency of use. Twelve sites reached significance in all analyses one of which was cg01382688 in ARHGEF4 (p < 1.2x10-7). Mutations in ARHGEF4 have been reported in breast tumors, but this is the first report of possible breast cancer-related DNA methylation changes. In addition, 22 genes included more than one significant CpG site and a majority of these sites were significantly correlated with gene expression. Although based on small numbers, these findings support the hypothesis that HT is associated with epigenetic alterations in breast tissue, and identifies genes with altered DNA methylation states which could be linked to breast cancer development. Women of advanced maternal age account for an increasing proportion of live births in many developed countries across the globe. Offspring of older mothers are at an increased risk for a variety of subsequent health outcomes, including outcomes that do not manifest until childhood or adulthood. The molecular underpinnings of the association between maternal aging and offspring morbidity remain elusive. However, one possible mechanism is that maternal aging produces specific alterations in the offspring's epigenome in utero, and these epigenetic alterations persist into adulthood. We conducted an epigenome-wide association study (EWAS) of the effect of a mother's age on blood DNA methylation in 2,740 adult daughters using the Illumina Infinium HumanMethylation450 array. A false discovery rate (FDR) q-value threshold of 0.05 was used to identify differentially methylated CpG sites (dmCpGs). We identified 87 dmCpGs associated with increased maternal age. The majority (84%) of the dmCpGs had lower methylation in daughters of older mothers, with an average methylation difference of 0.6% per 5-year increase in mother's age. Thirteen genomic regions contained multiple dmCpGs. Most notably, nine dmCpGs were found in the promoter region of the gene LIM homeobox 8 (LHX8), which plays a pivotal role in female fertility. Other dmCpGs were found in genes associated with metabolically active brown fat, carcinogenesis, and neurodevelopmental disorders. We conclude that maternal age is associated with persistent epigenetic changes in daughters at genes that have intriguing links to health. Shift work has been associated with increased risk of age-related morbidity and mortality. Biological age, estimated using DNA methylation (DNAm), may quantify the biological consequences of shift work on the risk of age-related disease. We examined whether prior employment in shift-working occupations was associated with epigenetic age acceleration. In a sample of non-Hispanic White women aged 35-74 (n=2574), we measured DNAm using the Illumina Infinium Human450 BeadChip and calculated DNAm age using three established epigenetic clocks. Age-acceleration metrics were derived by regressing DNAm age on chronological age and predicting the residuals. Using linear regression, we estimated associations between shift work history and age acceleration. We also conducted an epigenome-wide association study using robust linear-regression models corrected with false discovery rate (FDR) q-values. Approximately 7% of women reported any shift work. Higher age acceleration was observed for a 1-year increase in overall =0.11, 95% confidence interval (CI): 0.02-0.21 and night-specific shift work (=0.12, 95% CI: 0.03-0.21). The association was strongest for 10years of night shift work (=3.16, 95% CI: 1.17-5.15). From the epigenome-wide association study, years of overall and night shift work were associated with DNAm at 66 and 85 CpG sites (FDR<0.05), respectively. Years of night shift work was associated with lower methylation of a CpG in the gene body of ZFHX3 (cg04994202, q=0.04), a gene related to circadian rhythm. Shift work was associated with differential CpG site methylation and with differential DNAm patterns, measured by epigenetic age acceleration, consistent with long-term negative health effects.
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