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 conducted an epigenome-wide association study (EWAS) investigating alterations in DNA methylation in infants exposed in utero to maternal tobacco smoke, using the Norway Facial Clefts Study.
The Illumina HumanMethylation450 BeadChip was used to assess DNA methylation in whole blood from 889 infants shortly after delivery. Of 889 mothers, 287 reported smoking-twice as many smokers as in any previous EWAS of maternal smoking. CpG sites related to maternal smoking during the first trimester were identified using robust linear regression.
We identified 185 CpGs with altered methylation in infants of smokers at genome-wide significance (q-value < 0.05; mean Δβ = ± 2%). These correspond to 110 gene regions, of which 7 have been previously reported and 10 are newly confirmed using publicly 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.
Our study identified 10 genes with newly established links to maternal smoking. Further, we note differences between smoking-related methylation changes in newborns and adults, suggesting possible distinct effects of direct versus indirect tobacco smoke exposure as well as potential differences due to age. Further work would be needed to determine whether these small changes in DNA methylation are biologically or clinically relevant. The methylation changes identified in newborns may mediate the association between in utero maternal smoking exposure and later health outcomes.
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CEKLJ, DOBA, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
Epigenetic age, as defined by DNA methylation, may be influenced by air pollution exposure.
To evaluate the relationship between NO2, particulate matter (PM), PM components and accelerated epigenetic ...age.
In a sample of non-Hispanic white women living in the contiguous U.S. (n = 2747), we estimated residential exposure to PM2.5, PM10 and NO2 using a model incorporating land-use regression and kriging. Predictive k-means was used to assign participants to clusters representing different PM2.5 component profiles. We measured DNA methylation (DNAm) in blood using the Illumina's Infinium HumanMethylation450 BeadChip and calculated DNAm age using the Hannum, Horvath and Levine epigenetic clocks. Age acceleration was defined based on residuals after regressing DNAm age on chronological age. We estimated associations between interquartile range (IQR) increases in pollutants and age acceleration using linear regression. For PM2.5, we stratified by cluster membership. We examined epigenome-wide associations using robust linear regression models corrected with false discovery rate q-values.
NO2 was inversely associated with age acceleration using the Hannum clock (β = −0.24, 95% CI: −0.47, −0.02). No associations were observed for PM10. For PM2.5, the association with age acceleration varied by PM2.5 component cluster. For example, with the Levine clock, an IQR increase in PM2.5 was associated with an over 6-year age acceleration in a cluster that has relatively high fractions of crustal elements relative to overall PM2.5 (β = 6.57, 95% CI: 2.68, 10.47), and an almost 2-year acceleration in a cluster characterized by relatively low sulfur fractions (β = 1.88, 95% CI: 0.51, 3.25). In a cluster distinguished by lower relative nitrate concentrations, PM2.5 was inversely associated with age acceleration (β = −1.33, 95% CI: −2.43, −0.23). Across the epigenome, NO2 was associated with methylation at 2 CpG sites.
Air pollution was associated with epigenetic age, a marker of mortality and disease risk, among certain PM2.5 component profiles.
•Associations between PM2.5 and age acceleration varied by PM2.5 component profiles.•NO2 was inversely associated with Hannum clock-defined age acceleration.•NO2 was associated with methylation at 2 individual CpG sites.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The Sister Study was designed to address gaps in the study of environment and breast cancer by taking advantage of more frequent breast cancer diagnoses among women with a sister history of breast ...cancer and the presumed enrichment of shared environmental and genetic exposures.
The Sister Study sought a large cohort of women never diagnosed with breast cancer but who had a sister (full or half) diagnosed with breast cancer.
A multifaceted national effort employed novel strategies to recruit a diverse cohort, and collected biological and environmental samples and extensive data on potential breast cancer risk factors.
The Sister Study enrolled 50,884 U.S. and Puerto Rican women 35-74y of age (median 56 y). Although the majority were non-Hispanic white, well educated, and economically well off, substantial numbers of harder-to-recruit women also enrolled (race/ethnicity other than non-Hispanic white: 16%; no college degree: 35%; household income <$50,000: 26%). Although all had a biologic sister with breast cancer, 16.5% had average or lower risk of breast cancer according to the Breast Cancer Risk Assessment Tool (Gail score). Most were postmenopausal (66%), parous with a first full-term pregnancy <30y of age (79%), never-smokers (56%) with body mass indexes (BMIs) of <29.9
kg/m
(70%). Few (5%) reported any cancer prior to enrollment.
The Sister Study is a unique cohort designed to efficiently study environmental and genetic risk factors for breast cancer. Extensive exposure data over the life-course and baseline specimens provide important opportunities for studying breast cancer and other health outcomes in women. Collaborations are welcome. https://doi.org/10.1289/EHP1923.
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CEKLJ, DOBA, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
Abstract
Background
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 tested this hypothesis for breast cancer.
Methods
Using a case-cohort approach, we measured baseline blood DNA methylation of 2764 women enrolled in the Sister Study, 1566 of whom subsequently developed breast cancer after an average of 6 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 and 95% confidence intervals for breast cancer risk were estimated using Cox regression models. All statistical tests were two-sided.
Results
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: hazard ratio HR = 1.10, 95% confidence interval CI = 1.00 to 1.21, P = .04; Horvath’s clock: HR = 1.08, 95% CI = 1.00 to 1.17, P = .04; Levine’s clock: HR = 1.15, 95% CI = 1.07 to 1.23, P < .001). For Levine’s clock, each 5-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 (odds ratio for invasive = 1.09, 95% CI = 0.98 to 1.22, P = .10).
Conclusions
DNA methylation-based measures of biological age may be important predictors of breast cancer risk.
The biological mechanisms driving associations between alcohol consumption and chronic diseases might include epigenetic modification of DNA methylation. We explored the hypothesis that alcohol ...consumption is associated with methylation in an epigenome-wide association study of blood and normal breast tissue DNA. Infinium HumanMethylation450 BeadChip (Illumina Inc., San Diego, California) array data on blood DNA methylation was examined in a discovery set of 2,878 non-Hispanic white women from the Sister Study (United States, 2004-2015) who provided detailed questionnaire information on lifetime alcohol use. Robust linear regression modeling was used to identify significant associations (false discovery rate of Q < 0.05) between the number of alcoholic drinks per week and DNA methylation at 5,458 cytosine-phosphate-guanine (CpG) sites. Associations were replicated (P < 0.05) for 677 CpGs in an independent set of 187 blood DNA samples from the Sister Study and for 628 CpGs in an independent set of 171 normal breast DNA samples; 1,207 CpGs were replicated in either blood or normal breast, with 98 CpGs replicated in both tissues. Individual gene effects were notable for phosphoglycerate dehydrogenase (PGHDH), peptidyl-prolyl cis-trans isomerase (PPIF), solute carrier 15 (SLC15), solute carrier family 43 member 1 (SLC43A1), and solute carrier family 7 member 11 (SLC7A11). We also found that high alcohol consumption was associated with significantly lower global methylation as measured by the average of CpGs on the entire array.
The development and consequences of hypertension involve multiple biological systems that may include changes in immune profiles. Whether hypertension is related to peripheral immune cell composition ...has not been examined in large human cohorts.
We estimated circulating proportions of 12 leukocyte subsets from the lymphoid and myeloid lineages by deconvolving cell-type-specific DNA methylation data from 4124 women. Hypertension status at baseline was defined by current use of antihypertensive medication and blood pressure measurements while new incident cases were identified during follow-up via annual health questionnaires.
Among hypertension-free women at baseline, higher B cell and lower naïve CD4+ helper T cell proportions were associated with subsequent increased hazard of hypertension incidence (B cells; adjusted HR: 1.17 95% CI: 1.02-1.35;
=0.03; naïve CD4+ T cell, adjusted HR: 0.88 95% CI: 0.78-0.99;
=0.04). Blood pressure measurements at baseline were similarly positively associated with B cells and inversely associated with naïve CD4+ helper T cells. Compared to normotensive women, women with hypertension had higher circulating proportions of neutrophils (adjusted odds ratio: 1.18 95% CI: 1.07-1.31;
=0.001) and lower proportions of CD4+ helper T cells (adjusted odds ratio: 0.90 95% CI: 0.81-1.00
=0.05), natural killers (adjusted odds ratio: 0.82 95% CI: 0.74-0.91;
<0.001), and B cells (adjusted odds ratio: 0.84 95% CI: 0.74-0.96;
=0.01).
These observations suggest that shifts in lymphocyte subsets occur before hypertension development, followed by later changes to neutrophils and additional lymphocytes.
Hypertension is common in older individuals and is a major risk factor for cardiovascular disease. Blood DNA methylation profiles have been used to derive metrics of biological age that capture ...age-related physiological change, disease risk, and mortality. The relationships between hypertension and DNA methylation-based biological age metrics have yet to be carefully described.
Among 4419 women enrolled in the prospective Sister Study cohort, DNA methylation data generated from whole blood samples collected at baseline were used to calculate 3 biological age metrics (PhenoAgeAccel, GrimAgeAccel, DunedinPACE). Women were classified as hypertensive at baseline if they had high blood pressure (systolic blood pressure ≥140 mm Hg or diastolic blood pressure ≥90 mm Hg) or reported current use of antihypertensive medication. New incident cases of hypertension during follow-up were identified via self-report on annual health questionnaires.
All 3 DNA methylation metrics of biological age were positively associated with prevalent hypertension at baseline (per 1-SD increase; PhenoAgeAccel, adjusted odds ratio, 1.16 95% CI, 1.05-1.28; GrimAgeAccel, adjusted odds ratio, 1.28 95% CI, 1.14-1.45; DunedinPACE, adjusted odds ratio, 1.16 95% CI, 1.03-1.30). Among 2610 women who were normotensive at baseline, women with higher biological age were more likely to be diagnosed with incident hypertension (per 1-SD increase; PhenoAgeAccel, adjusted hazard ratio, 1.09 95% CI, 0.97-1.23; GrimAgeAccel, adjusted hazard ratio, 1.16 95% CI, 0.99-1.36; DunedinPACE, adjusted hazard ratio, 1.16 95% CI, 1.01-1.33).
Methylation-based biological age metrics increase before a hypertension diagnosis and appear to remain elevated in the years after clinical diagnosis and treatment.
The results of this large study involving more than 64,500 U.S. women in the general population and 28 genes that have been previously implicated in conferring risk of breast cancer (when variant) ...have implications for the interpretation of results obtained by multigene panel testing.
The Routledge Handbook of Corpus Approaches to Discourse Analysis highlights the diversity, breadth, and depth of corpus approaches to discourse analysis, compiling new and original research from ...notable scholars across the globe. Chapters showcase recent developments influenced by the exponential growth in linguistic computing, advances in corpus design and compilation, and the applications of sound quantitative and interpretive techniques in analyzing text and discourse patterns. Key discourse domains covered by 35 empirical chapters include:
Research contexts and methodological considerations;
The Routledge Handbook of Corpus Approaches to Discourse Analysis is key reading for both experienced and novice researchers working at the intersection of corpus linguistics and discourse analysis, as well as anyone interested in related fields and adjacent research approaches.
Naturally occurring spoken, professional, and academic discourse;
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Vitamin D has anticarcinogenic and immune-related properties and may protect against some diseases, including breast cancer. Vitamin D affects gene transcription and may influence DNA methylation.
We ...studied the relationships between serum vitamin D, DNA methylation, and breast cancer using a case-cohort sample (1070 cases, 1277 in subcohort) of non-Hispanic white women. For our primary analysis, we used robust linear regression to examine the association between serum 25-hydroxyvitamin D (25(OH)D) and methylation within a random sample of the cohort ("subcohort"). We focused on 198 CpGs in or near seven vitamin D-related genes. For these 198 candidate CpG loci, we also examined how multiplicative interactions between methylation and 25(OH)D were associated with breast cancer risk. This was done using Cox proportional hazards models and the full case-cohort sample. We additionally conducted an exploratory epigenome-wide association study (EWAS) of the association between 25(OH)D and DNA methylation in the subcohort.
Of the CpGs in vitamin D-related genes, cg21201924 (RXRA) had the lowest p value for association with 25(OH)D (p = 0.0004). Twenty-two other candidate CpGs were associated with 25(OH)D (p < 0.05; RXRA, NADSYN1/DHCR7, GC, or CYP27B1). We observed an interaction between 25(OH)D and methylation at cg21201924 in relation to breast cancer risk (ratio of hazard ratios = 1.22, 95% confidence interval 1.10-1.34; p = 7 × 10
), indicating a larger methylation-breast cancer hazard ratio in those with high serum 25(OH)D concentrations. We also observed statistically significant (p < 0.05) interactions for six other RXRA CpGs and CpGs in CYP24A1, CYP27B1, NADSYN1/DHCR7, and VDR. In the EWAS of the subcohort, 25(OH)D was associated (q < 0.05) with methylation at cg24350360 (EPHX1; p = 3.4 × 10
), cg06177555 (SPN; p = 9.8 × 10
), and cg13243168 (SMARCD2; p = 2.9 × 10
).
25(OH)D concentrations were associated with DNA methylation of CpGs in several vitamin D-related genes, with potential links to immune function-related genes. Methylation of CpGs in vitamin D-related genes may interact with 25(OH)D to affect the risk of breast cancer.
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