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1.
Epigenomics ; 2019 09 19.
Artigo em Inglês | MEDLINE | ID: mdl-31536415

RESUMO

Aim: Cigarette smoking influences DNA methylation genome wide, in newborns from pregnancy exposure and in adults from personal smoking. Whether a unique methylation signature exists for in utero exposure in newborns is unknown. Materials & methods: We separately meta-analyzed newborn blood DNA methylation (assessed using Illumina450k Beadchip), in relation to sustained maternal smoking during pregnancy (9 cohorts, 5648 newborns, 897 exposed) and adult blood methylation and personal smoking (16 cohorts, 15907 participants, 2433 current smokers). Results & conclusion: Comparing meta-analyses, we identified numerous signatures specific to newborns along with many shared between newborns and adults. Unique smoking-associated genes in newborns were enriched in xenobiotic metabolism pathways. Our findings may provide insights into specific health impacts of prenatal exposure on offspring.

2.
Epigenetics ; : 1-13, 2019 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-31506003

RESUMO

DNA methylation (DNAm) has a well-established association with age in many tissues, including peripheral blood mononuclear cells (PBMCs). Compared to DNAm, the closely related epigenetic modification known as DNA hydroxymethylation (DNAhm) was much more recently discovered in mammals. Preliminary investigations have observed a positive correlation between gene body DNAhm and cis-gene expression. While some of these studies have observed an association between age and global DNAhm, none have investigated region-specific age-related DNAhm in human blood samples. In this study, we investigated DNAhm and gene expression in PBMCs of 10 young and 10 old, healthy female volunteers. Thousands of regions were differentially hydroxymethylated in the old vs. young individuals in gene bodies, exonic regions, enhancers, and promoters. Consistent with previous work, we observed directional consistency between age-related differences in DNAhm and gene expression. Further, age-related DNAhm and genes with high levels of DNAhm were enriched for immune system processes which may support a role of age-related DNAhm in immunosenescence.

4.
Epigenetics ; : 1-9, 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31538540

RESUMO

DNA methylation microarrays have been the platform of choice for epigenome-wide association studies in epidemiology, but declining costs have rendered targeted bisulphite sequencing a feasible alternative. Nonetheless, the literature for researchers seeking guidance on which platform to choose is sparse. To fill this gap, we conducted a comparison study in which we processed cord blood samples from four newborns in duplicates using both the Illumina HumanMethylationEPIC BeadChip and the Illumina TruSeq Methyl Capture EPIC Kit, and evaluated both platforms in regard to coverage, reproducibility, and identification of differential methylation. We conclude that with current analytic goals microarrays still outperform bisulphite sequencing for precise quantification of DNA methylation.

5.
J Am Coll Cardiol ; 74(10): 1329-1331, 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31488270
6.
Aging (Albany NY) ; 11(16): 5895-5923, 2019 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-31422385

RESUMO

Telomere length (TL) is associated with several aging-related diseases. Here, we present a DNA methylation estimator of TL (DNAmTL) based on 140 CpGs. Leukocyte DNAmTL is applicable across the entire age spectrum and is more strongly associated with age than measured leukocyte TL (LTL) (r ~-0.75 for DNAmTL versus r ~ -0.35 for LTL). Leukocyte DNAmTL outperforms LTL in predicting: i) time-to-death (p=2.5E-20), ii) time-to-coronary heart disease (p=6.6E-5), iii) time-to-congestive heart failure (p=3.5E-6), and iv) association with smoking history (p=1.21E-17). These associations are further validated in large scale methylation data (n=10k samples) from the Framingham Heart Study, Women's Health Initiative, Jackson Heart Study, InChianti, Lothian Birth Cohorts, Twins UK, and Bogalusa Heart Study. Leukocyte DNAmTL is also associated with measures of physical fitness/functioning (p=0.029), age-at-menopause (p=0.039), dietary variables (omega 3, fish, vegetable intake), educational attainment (p=3.3E-8) and income (p=3.1E-5). Experiments in cultured somatic cells show that DNAmTL dynamics reflect in part cell replication rather than TL per se. DNAmTL is not only an epigenetic biomarker of replicative history of cells, but a useful marker of age-related pathologies that are associated with it.

7.
Am J Public Health ; 109(9): 1188, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31390254
8.
Aging (Albany NY) ; 11(14): 4970-4989, 2019 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-31322503

RESUMO

Evidence indicates associations between higher optimism and reduced risk of age-related conditions and premature mortality. This suggests optimism is a positive health asset, but research identifying potential biological mechanisms underlying these associations remains limited. One potential pathway is slower cellular aging, which may delay age-related deterioration in health. Data were from the Women's Health Initiative (WHI) (N=3,298) and the Veterans Affairs Normative Aging Study (NAS) (N=514), and included dispositional and explanatory style optimism measures. We evaluated whether higher optimism was associated with metrics suggestive of less cellular aging, as indicated by two DNA methylation algorithms, intrinsic (IEAA) and extrinsic epigenetic age acceleration (EEAA); these algorithms represent accelerated biologic aging that exceeds chronological age. We used linear regression models to test our hypothesis while considering several covariates (sociodemographics, depressive symptoms, health behaviors). In both cohorts, we found consistently null associations of all measures of optimism with both measures of DNA methylation aging, regardless of covariates considered. For example, in fully-adjusted models, dispositional optimism was not associated with either IEAA (WHI:ß=0.02; 95% Confidence Interval [CI]:-0.15-0.20; NAS:ß=-0.06; 95% CI:-0.56-0.44) or EEAA (WHI:ß=-0.04; 95% CI: -0.26-0.17; NAS:ß=-0.17; 95% CI: -0.80-0.46). Higher optimism was not associated with reduced cellular aging as measured in this study.

9.
Artigo em Inglês | MEDLINE | ID: mdl-31315170

RESUMO

Essential hypertension is the leading preventable cause of death in the world. Epidemiological studies have shown that physical training can reduce blood pressure (BP), both in hypertensive and healthy individuals. Increasing evidence is emerging that DNA methylation is involved in alteration of the phenotype and of vascular function in response to environmental stimuli. We evaluated repetitive element and gene-specific DNA methylation in peripheral blood leukocytes of 68 volunteers, taken before (T0) and after (T1) a three-month intervention protocol of continuative aerobic physical exercise. DNA methylation was assessed by bisulfite-PCR and pyrosequencing. Comparing T0 and T1 measurements, we found an increase in oxygen consumption at peak of exercise (VO2peak) and a decrease in diastolic BP at rest. Exercise increased the levels of ALU and Long Interspersed Nuclear Element 1 (LINE-1) repetitive elements methylation, and of Endothelin-1 (EDN1), Inducible Nitric Oxide Synthase (NOS2), and Tumour Necrosis Factor Alpha (TNF) gene-specific methylation. VO2peak was positively associated with methylation of ALU, EDN1, NOS2, and TNF; systolic BP at rest was inversely associated with LINE-1, EDN1, and NOS2 methylation; diastolic BP was inversely associated with EDN1 and NOS2 methylation. Our findings suggest a possible role of DNA methylation for lowering systemic BP induced by the continuative aerobic physical training program.

10.
Environ Int ; 131: 105018, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31336254

RESUMO

BACKGROUND: Whole-body and thoracic ionizing radiation exposure are both associated with the development of renal dysfunction. However, whether low-level environmental radiation from air pollution affects renal function remains unknown. OBJECTIVES: We investigated the association of particle radioactivity (PR) with renal function defined by the estimated glomerular filtration rate (eGFR) and chronic kidney disease (CKD) in the Normative Aging Study. METHODS: This longitudinal analysis included 2491 medical visits from 809 white males enrolled between 1999 and 2013. The eGFR was calculated using the CKD-EPI and MDRD equations, and CKD cases were identified as those with an eGFR <60 mL/min/1.73 m2. Gross ß activity measured by five monitors of the U.S. Environmental Protection Agency's RadNet monitoring network was utilized to represent PR. RESULTS: Ambient PR levels from 1 to 28 days prior to clinical visit demonstrated robust negative associations with both forms of eGFR, but not with the increased odds of CKD. An interquartile range higher 28-day average ambient PR level was significantly associated with 0.83-mL/min/1.73 m2 lower eGFR estimated by the CKD-EPI equation (95% confidence interval: -1.46, -0.20, p-value = 0.01). Controlling for PM2.5 or black carbon in the model slightly attenuated the PR effects on eGFR. However, in individuals with the highest levels (3rd tertile) of C-reactive protein (CRP) or fibrinogen, we observed robust associations of PR with eGFR and CKD, suggesting that systemic inflammation may modify the PR-eGFR and PR-CKD relationships. CONCLUSIONS: Our study reveals adverse health effects of short-term low-level ambient PR on the renal function, providing evidence to guide further study of the interplay between PR, inflammation, and renal health.

11.
Artigo em Inglês | MEDLINE | ID: mdl-31277270

RESUMO

DNA methylation may play a critical role in aging and age-related diseases. DNA methylation phenotypic age (DNAmPhenoAge) is a new aging biomarker and predictor of chronic disease risk. While smoking is a strong risk factor for chronic diseases and influences methylation, its influence on DNAmPhenoAge is unknown. We investigated associations of self-reported and epigenetic smoking indicators with DNAmPhenoAge acceleration in a longitudinal aging study in eastern Massachusetts. DNA methylation was measured in whole blood samples from multiple visits for 692 male participants in the Veterans Affairs Normative Aging Study during 1999-2013. Acceleration was defined using residuals from linear regression of the DNAmPhenoAge on the chronological age. Cumulative smoking (pack-years) was significantly associated with DNAmPhenoAge acceleration, whereas self-reported smoking status was not. We observed significant validated associations between smoking-related loci and DNAmPhenoAge acceleration for 52 CpG sites, where 18 were hypomethylated and 34 were hypermethylated, mapped to 16 genes. The AHRR gene had the most loci (N = 8) among the 16 genes. We generated a smoking aging index based on these 52 loci, which showed positive significant associations with DNAmPhenoAge acceleration. These epigenetic biomarkers may help to predict age-related risks driven by smoking.

12.
Nat Commun ; 10(1): 3095, 2019 07 12.
Artigo em Inglês | MEDLINE | ID: mdl-31300640

RESUMO

The nasal cellular epigenome may serve as biomarker of airway disease and environmental response. Here we collect nasal swabs from the anterior nares of 547 children (mean-age 12.9 y), and measure DNA methylation (DNAm) with the Infinium MethylationEPIC BeadChip. We perform nasal Epigenome-Wide Association analyses (EWAS) of current asthma, allergen sensitization, allergic rhinitis, fractional exhaled nitric oxide (FeNO) and lung function. We find multiple differentially methylated CpGs (FDR < 0.05) and Regions (DMRs; ≥ 5-CpGs and FDR < 0.05) for asthma (285-CpGs), FeNO (8,372-CpGs; 191-DMRs), total IgE (3-CpGs; 3-DMRs), environment IgE (17-CpGs; 4-DMRs), allergic asthma (1,235-CpGs; 7-DMRs) and bronchodilator response (130-CpGs). Discovered DMRs annotated to genes implicated in allergic asthma, Th2 activation and eosinophilia (EPX, IL4, IL13) and genes previously associated with asthma and IgE in EWAS of blood (ACOT7, SLC25A25). Asthma, IgE and FeNO were associated with nasal epigenetic age acceleration. The nasal epigenome is a sensitive biomarker of asthma, allergy and airway inflammation.

13.
Fertil Steril ; 112(2): 387-396.e3, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31146888

RESUMO

OBJECTIVE: To study whether increased body mass index is associated with altered expression of extracellular vesicle microRNAs (EV-linked miRNAs) in human follicular fluid. DESIGN: Cross-sectional study. SETTING: Tertiary-care university-affiliated center. PATIENT(S): One hundred thirty-three women undergoing in vitro fertilization (IVF) were recruited from January 2014 to August 2016. INTERVENTIONS(S): None. MAIN OUTCOME MEASURE(S): EV-linked miRNAs were isolated from follicular fluid and their expression profiles were measured with the use of the Taqman Open Array Human miRNA panel. EV-linked miRNAs were globally normalized and inverse-normal transformed. Associations between body mass index (BMI) and EV-linked miRNA outcomes were analyzed by means of multivariate linear regression and principal component analysis. RESULT(S): Eighteen EV-linked miRNAs were associated with an increase in BMI after adjusting for age, ethnicity, smoking status, and batch effects. Hsa-miR-328 remained significant after false discovery rate adjustments. Principal component analyses identified the first principal component to account for 40% of the variation in our EV-linked miRNA dataset, and adjusted linear regression found that the first principal component was significantly associated with BMI after multiple testing adjustments. Using Kyoto Encyclopedia of Genes and Genomes enrichment analyses, we predicted gene targets of EV-linked miRNA in silico and identified PI3K-Akt signaling, ECM-receptor interaction, focal adhesion, FoxO signaling, and oocyte meiosis pathways. CONCLUSION(S): These results show that a 1-unit increase in BMI is associated with altered follicular fluid expression of EV-linked miRNAs that may influence follicular and oocyte developmental pathways. Our findings provide potential insight into a mechanistic explanation for the reduced fertility rates associated with increased BMI.

14.
Environ Int ; 132: 104723, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31208937

RESUMO

BACKGROUND: DNA methylation (DNAm) may contribute to processes that underlie associations between air pollution and poor health. Therefore, our objective was to evaluate associations between DNAm and ambient concentrations of particulate matter (PM) ≤2.5, ≤10, and 2.5-10 µm in diameter (PM2.5; PM10; PM2.5-10). METHODS: We conducted a methylome-wide association study among twelve cohort- and race/ethnicity-stratified subpopulations from the Women's Health Initiative and the Atherosclerosis Risk in Communities study (n = 8397; mean age: 61.5 years; 83% female; 45% African American; 9% Hispanic/Latino American). We averaged geocoded address-specific estimates of daily and monthly mean PM concentrations over 2, 7, 28, and 365 days and 1 and 12 months before exams at which we measured leukocyte DNAm in whole blood. We estimated subpopulation-specific, DNAm-PM associations at approximately 485,000 Cytosine-phosphate-Guanine (CpG) sites in multi-level, linear, mixed-effects models. We combined subpopulation- and site-specific estimates in fixed-effects, inverse variance-weighted meta-analyses, then for associations that exceeded methylome-wide significance and were not heterogeneous across subpopulations (P < 1.0 × 10-7; PCochran's Q > 0.10), we characterized associations using publicly accessible genomic databases and attempted replication in the Cooperative Health Research in the Region of Augsburg (KORA) study. RESULTS: Analyses identified significant DNAm-PM associations at three CpG sites. Twenty-eight-day mean PM10 was positively associated with DNAm at cg19004594 (chromosome 20; MATN4; P = 3.33 × 10-8). One-month mean PM10 and PM2.5-10 were positively associated with DNAm at cg24102420 (chromosome 10; ARPP21; P = 5.84 × 10-8) and inversely associated with DNAm at cg12124767 (chromosome 7; CFTR; P = 9.86 × 10-8). The PM-sensitive CpG sites mapped to neurological, pulmonary, endocrine, and cardiovascular disease-related genes, but DNAm at those sites was not associated with gene expression in blood cells and did not replicate in KORA. CONCLUSIONS: Ambient PM concentrations were associated with DNAm at genomic regions potentially related to poor health among racially, ethnically and environmentally diverse populations of U.S. women and men. Further investigation is warranted to uncover mechanisms through which PM-induced epigenomic changes may cause disease.

15.
Int J Epidemiol ; 2019 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-31038702

RESUMO

BACKGROUND: A 'mortality risk score' (MS) based on ten prominent mortality-related cytosine-phosphate-guanine (CpG) sites was previously associated with all-cause mortality, but has not been verified externally. We aimed to validate the association of MS with mortality and to compare MS with three aging biomarkers: telomere length (TL), DNA methylation age (DNAmAge) and phenotypic age (DNAmPhenoAge) to explore whether MS can serve as a reliable measure of biological aging and mortality. METHODS: Among 534 males aged 55-85 years from the US Normative Aging Study, the MS, DNAmAge and DNAmPhenoAge were derived from blood DNA methylation profiles from the Illumina HumanMethylation450 BeadChip, and TL was measured by quantitative real-time polymerase chain reaction (qRT-PCR). RESULTS: A total of 147 participants died during a median follow-up of 9.4 years. The MS showed strong associations with all-cause, cardiovascular disease (CVD) and cancer mortality. After controlling for all potential covariates, participants with high MS (>5 CpG sites with aberrant methylation) had almost 4-fold all-cause mortality (hazard ratio: 3.84, 95% confidence interval: 1.92-7.67) compared with participants with a low MS (0-1 CpG site with aberrant methylation). Similar patterns were observed with respect to CVD and cancer mortality. MS was associated with TL and DNAmPhenoAge acceleration but not with DNAmAge acceleration. Although the MS and DNAmPhenoAge acceleration were independently associated with all-cause mortality, the former exhibited a higher predictive accuracy of mortality than the latter. CONCLUSIONS: MS has the potential to be a prominent predictor of mortality that could enhance survival prediction in clinical settings.

16.
Ann Epidemiol ; 35: 48-52.e2, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31060895

RESUMO

PURPOSE: Cognitive development during adolescence affects health long term. We investigated whether level of and change in language-based cognition during adolescence are associated with cognitive performance in midlife. METHODS: Participants were enrolled in the Child Health and Development Study and followed during midlife (47-52 years). Adolescent cognition was measured with the Peabody Picture Vocabulary Test at ages 9-11 years (PPVT-9) and 15-17 years (PPVT-15). We examined PPVT-9, as well as a PPVT change score (derived using the standardized regression-based method) in relation to midlife cognition measures of Wechsler Test of Adult Reading, Verbal Fluency, and Digit Symbol tests. Linear regression models were adjusted for childhood socioeconomic status, age, sex, race, and midlife marital status, education, and occupational score. RESULTS: In 357 participants (52.1% female, 25.6% African American), both PPVT-9 (ß [95% confidence interval [CI] = 0.26 [0.18, 0.34]) and PPVT change score (ß [95% CI] = 2.03 [1.27, 2.80]) were associated with Wechsler Test of Adult Reading at midlife. PPVT-9 was associated with midlife Verbal Fluency (ß [95% CI] = 0.18 [0.10, 0.25]), whereas PPVT change score was not (ß [95% CI] = -0.01 [-0.68, 0.67]). Neither PPVT-9 nor PPVT change score was associated with midlife Digit Symbol. CONCLUSIONS: Both level of and change in language-based cognition during adolescence were associated with midlife vocabulary and language function, even after controlling for midlife occupation and education.

18.
Int J Hyg Environ Health ; 222(5): 756-764, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31103472

RESUMO

BACKGROUND: Ambient particulate air pollution is a major threat to the cardiovascular health of people. Inflammation is an important component of the pathophysiological process that links air pollution and cardiovascular disease (CVD). A classical marker of inflammation-C-reactive protein (CRP), has been recognized as an independent predictor of CVD risk. Exposure to ambient particulate matter (PM) may cause systemic inflammatory response but its association with CRP has been inconsistently reported. OBJECTIVES: To estimate the potential effects of short-term and long-term exposures to ambient particulate air pollution on circulating CRP level based on previous epidemiological studies. METHODS: A systematic literature search of PubMed, Web of Science, Embase, and Scopus databases for publications up to January 2018 was conducted for studies reporting the association between ambient PM (PM2.5 or PM10, or both) and circulating CRP level. We performed a meta-analysis for the associations reported in individual studies using a random-effect model and evaluated the effect modification by major potential modifiers. RESULTS: This meta-analysis comprised data from 40 observational studies conducted on 244,681 participants. These included 32 (27 PM2.5 studies and 13 PM10 studies) and 11 (9 PM2.5 studies and 5 PM10 studies) studies that investigated the associations of CRP with short-term and long-term exposure to particulate air pollution, respectively. A 10 µg/m3 increase in short-term exposure to PM2.5 and PM10 was associated with increases of 0.83 % (95% CI: 0.30%, 1.37%) and 0.39% (95% CI: -0.04%, 0.82%) in CRP level, respectively, and a 10 µg/m3 increase in long-term exposure to PM2.5 and PM10 was associated with much higher increases of 18.01% (95% CI: 5.96%, 30.06%) and 5.61% (95% CI: 0.79%, 10.44%) in CRP level, respectively. The long-term exposure to particulate air pollution was more strongly associated with CRP level than short-term exposure and PM2.5 had a greater effect on CRP level than PM10. CONCLUSION: Exposure to ambient particulate air pollution is associated with elevated circulating CRP level suggesting an activated systemic inflammatory state upon exposure, which may explain the association between particulate air pollution and CVD risk.

19.
J Perinatol ; 39(7): 941-948, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31110244

RESUMO

OBJECTIVE: To determine whether prenatal sex hormones from maternal saliva are associated with birth-weight-for-gestational age. STUDY DESIGN: We measured salivary progesterone, testosterone, estradiol, dehydroepiandrosterone (DHEA), and cortisone in 504 pregnant women in a Mexico City cohort. We performed linear and modified Poisson regression to examine associations of log-transformed hormones with birth-weight-for-gestational age z-scores and the risk of small-for-gestational age (SGA) and large-for-gestational age (LGA) adjusting for maternal age, sex, BMI, parity, smoking, education, and socioeconomic status. RESULTS: In total, 15% of infants were SGA and 2% were LGA. Each interquartile range increment in testosterone/estradiol ratio was associated with a 0.12 decrement in birth-weight-for-gestational age z-score (95% CI: -0.27 to -0.02) and a 50% higher risk of SGA versus appropriate-for-gestational age (AGA) (95% CI: 1.13-1.99). CONCLUSION: Higher salivary testosterone/estradiol ratios may affect fetal growth, and identifying the predictors of hormone levels may be important to optimizing fetal growth.

20.
Environ Int ; 126: 395-405, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30826618

RESUMO

BACKGROUND: Exploring the associations of air pollution and weather variables with blood leukocyte distribution is critical to understand the impacts of environmental exposures on the human immune system. OBJECTIVES: As previous analyses have been mainly based on data from cell counters, which might not be feasible in epidemiologic studies including large populations of long-stored blood samples, we aimed to expand the understanding of this topic by employing the leukocyte distribution estimated by DNA methylation profiles. METHODS: We measured DNA methylation profiles in blood samples using Illumina HumanMethylation450 BeadChip from 1519 visits of 774 Caucasian males participating in the Normative Aging Study. Leukocyte distribution was estimated using Houseman's and Horvath's algorithms. Data on air pollution exposure, temperature, and relative humidity within 28 days before each blood draw was obtained. RESULTS: After fully adjusting for potential covariates, PM2.5, black carbon, particle number, carbon monoxide, nitrogen dioxide, sulfur dioxide, temperature, and relative humidity were associated with the proportions of at least one subtype of leukocytes. Particularly, an interquartile range-higher 28-day average exposure of PM2.5 was associated with 0.147-, 0.054- and 0.101-unit lower proportions (z-scored) of plasma cells, naïve CD8+ T cells, and natural killers, respectively, and 0.059- and 0.161-unit higher proportions (z-scored) of naïve CD4+ T cells and CD8+ T cells, respectively. CONCLUSIONS: Our study suggests that short-term air pollution exposure, temperature, and relative humidity are associated with leukocyte distribution. Our study further provides a successful attempt to use epigenetic patterns to assess the influences of environmental exposures on human immune profiles.

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