Gene promoter methylation is associated with lung function in the elderly: the Normative Aging Study.
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ABSTRACT:
SUBMITTER: Lepeule J
PROVIDER: S-EPMC3335949 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Elderly individuals who are never smokers but have the same height and chronological age can have substantial differences in lung function. The underlying biological mechanisms are unclear. To evaluate the associations of different biomarkers of aging (BoA) and lung function, we performed a repeated-measures analysis in the Normative Aging Study using linear mixed-effect models. We generated GrimAgeAccel, PhenoAgeAccel, extrinsic and intrinsic epigenetic age acceleration using a publically available online calculator. We calculated Zhang's DNAmRiskScore based on 10 CpGs. We measured telomere length (TL) and mitochondrial DNA copy number (mtDNA-CN) using quantitative real-time polymerase chain reaction. A pulmonary function test was performed measuring forced expiratory volume in 1 second / forced vital capacity (FEV1/FVC), FEV1, and maximum mid-expiratory flow (MMEF). Epigenetic-based BoA were associated with lower lung function. For example, a one-year increase in GrimAgeAccel was associated with a 13.64 mL [95% confidence interval (CI), 5.11 to 22.16] decline in FEV1; a 0.2 increase in Zhang's DNAmRiskScore was associated with a 0.009 L/s (0.005 to 0.013) reduction in MMEF. No association was found between TL/mtDNA-CN and lung function. Overall, this paper shows that epigenetics might be a potential mechanism underlying pulmonary dysfunction in the elderly.
| S-EPMC7343502 | biostudies-literature
Project description:Few studies have been performed on pulmonary effects of air pollution in the elderly--a vulnerable population with low reserve capacity--and mechanisms and susceptibility factors for potential effects are unclear.We evaluated the lag structure of air pollutant associations with lung function and potential effect modification by DNA methylation (< or ? median) at 26 individual CpG sites in nine candidate genes in a well-characterized cohort of elderly men.We measured forced vital capacity (FVC), forced expiratory volume in 1 sec (FEV1), and blood DNA methylation one to four times between 1999 and 2009 in 776 men from the Normative Aging Study. Air pollution was measured at fixed monitors 4 hr to 28 days before lung function tests. We used linear mixed-effects models to estimate the main effects of air pollutants and effect modification by DNA methylation.An interquartile range (IQR) increase in subchronic exposure (3 to 28 days cumulated), but not in acute exposure (during the previous 4 hr, or the current or previous day), to black carbon, total and nontraffic particles with aerodynamic diameter ? 2.5 ?m (PM2.5), carbon monoxide, and nitrogen dioxide was associated with a 1-5% decrease in FVC and FEV1 (p < 0.05). Slope estimates were greater for FVC than FEV1, and increased with cumulative exposure. The estimates slopes for air pollutants (28 days cumulated) were higher in participants with low (< median) methylation in TLR2 at position 2 and position 5 and high (? median) methylation in GCR.Subchronic exposure to traffic-related pollutants was associated with significantly reduced lung function in the elderly; nontraffic pollutants (particles, ozone) had weaker associations. Epigenetic mechanisms related to inflammation and immunity may influence these associations.
| S-EPMC4050500 | biostudies-other
Project description:Decreased lung function has been linked to increased inflammation and oxidative stress. Statins have demonstrated antiinflammatory and antioxidant properties.We investigated the effect of statin use on decline in lung function in the elderly, and whether smoking modified this effect.Our study population included 2,136 measurements on 803 elderly men from the Normative Aging Study whose lung function (FVC and FEV(1)) was measured two to four times between 1995 and 2005. Subjects indicated statin use and smoking history at each visit. We used mixed linear models to estimate the effects of each covariate, adjusting for subject and possible confounders.For those not using statins, the estimated decline in FEV(1) was 23.9 ml/year (95% confidence interval [CI], -27.8 to -20.1 ml/yr), whereas those taking statins had an estimated 10.9-ml/year decline in FEV(1) (95% CI, -16.9 to -5.0 ml/yr). We also examined the effect of statins with smoking by dividing the cohort into four groups: never-smokers, longtime quitters (quit >or= 10 yr ago), recent quitters (quit < 10 yr ago), and current smokers. We found a significant three-way interaction between time since first visit, statin use, and smoking status (P < 0.001). Within each smoking category, the effect of statins was always estimated to be beneficial, but the size of the improvement in the decline rate varied among smoking groups. We found similar results for FVC decline.Our results indicate that statin use attenuates decline in lung function in the elderly, with the size of the beneficial effect modified by smoking status.
| S-EPMC2020828 | biostudies-other
Project description:RationaleVitamin D has immunomodulatory and antiinflammatory effects that may be modified by cigarette smoke and may affect lung function.ObjectivesTo examine the effect of vitamin D deficiency and smoking on lung function and lung function decline.MethodsA total of 626 men from the Normative Aging Study had 25-hydroxyvitamin D levels measured at three different times between 1984 and 2003 with concurrent spirometry. Vitamin D deficiency was defined as serum level ≤ 20 ng/ml. Statistical analysis was performed using multivariable linear regression and mixed effects models.Measurements and main resultsIn the overall cohort, there was no significant effect of vitamin D deficiency on lung function or on lung function decline. In both cross-sectional and longitudinal multivariable models, there was effect modification by vitamin D status on the association between smoking and lung function. Cross-sectional analysis revealed lower lung function in current smokers with vitamin D deficiency (FEV(1), FVC, and FEV(1)/FVC; P ≤ 0.0002), and longitudinal analysis showed more rapid rates of decline in FEV(1) (P = 0.023) per pack-year of smoking in subjects with vitamin D deficiency as compared with subjects who were vitamin D sufficient.ConclusionsVitamin D deficiency was associated with lower lung function and more rapid lung function decline in smokers over 20 years in this longitudinal cohort of elderly men. This suggests that vitamin D sufficiency may have a protective effect against the damaging effects of smoking on lung function. Future studies should seek to confirm this finding in the context of smoking and other exposures that affect lung function.
| S-EPMC3480523 | biostudies-literature
Project description:To investigate the association between methylation of transposable elements Alu and long-interspersed nuclear elements (LINE-1) and lung function.Cohort study.Outpatient Veterans Administration facilities in greater Boston, Massachusetts, USA.Individuals from the Veterans Administration Normative Aging Study, a longitudinal study of aging in men, evaluated between 1999 and 2007. The majority (97%) were white.Primary predictor was methylation, assessed using PCR-pyrosequencing after bisulphite treatment. Primary outcome was lung function as assessed by spirometry, performed according to American Thoracic Society/European Respiratory Society guidelines at the same visit as the blood draws.In multivariable models adjusted for age, height, body mass index (BMI), pack-years of smoking, current smoking and race, Alu hypomethylation was associated with lower forced expiratory volume in 1 s (FEV(1)) (?=28 ml per 1% change in Alu methylation, p=0.017) and showed a trend towards association with a lower forced vital capacity (FVC) (?=27 ml, p=0.06) and lower FEV(1)/FVC (?=0.3%, p=0.058). In multivariable models adjusted for age, height, BMI, pack-years of smoking, current smoking, per cent lymphocytes, race and baseline lung function, LINE-1 hypomethylation was associated with more rapid decline of FEV(1) (?=6.9 ml/year per 1% change in LINE-1 methylation, p=0.005) and of FVC (?=9.6 ml/year, p=0.002).In multiple regression analysis, Alu hypomethylation was associated with lower lung function, and LINE-1 hypomethylation was associated with more rapid lung function decline in a cohort of older and primarily white men from North America. Future studies should aim to replicate these findings and determine if Alu or LINE-1 hypomethylation may be due to specific and modifiable environmental exposures.
| S-EPMC3488751 | biostudies-literature
Project description:Variation in healthy aging and lifespan is ascribed more to various non-genetic factors than to inherited genetic determinants, and a major goal in aging research is to reveal the epigenetic basis of aging. One approach to this goal is to find genomic sites or regions where DNA methylation correlates with biological age. Using health data from 134 elderly twins, we calculated a frailty index as a quantitative indicator of biological age, and by applying the Infinium HumanMethylation450K BeadChip technology to their leukocyte DNA samples, we obtained quantitative DNA methylation data on genome-wide CpG sites. We analyzed the health and epigenome data by taking two independent associative approaches: the parametric regression-based approach and a non-parametric machine learning approach followed by GO ontology analysis. Our results indicate that DNA methylation at CpG sites in the promoter region of PCDHGA3 is associated with biological age. PCDHGA3 belongs to clustered protocadherin genes, which are all located in a single locus on chromosome 5 in human. Previous studies of the clustered protocadherin genes showed that (1) DNA methylation is associated with age or age-related phenotypes; (2) DNA methylation can modulate gene expression; (3) dysregulated gene expression is associated with various pathologies; and (4) DNA methylation patterns at this locus are associated with adverse lifetime experiences. All these observations suggest that DNA methylation at the clustered protocadherin genes, including PCDHGA3, is a key mediator of healthy aging.
| S-EPMC6294724 | biostudies-literature
Project description:The mechanisms by which air pollution has multiple systemic effects in humans are not fully elucidated, but appear to include inflammation and thrombosis. This study examines whether concentrations of ozone and components of fine particle mass are associated with changes in methylation on tissue factor (F3), interferon gamma (IFN-?), interleukin 6 (IL-6), toll-like receptor 2 (TLR-2), and intercellular adhesion molecule 1 (ICAM-1). We investigated associations between air pollution exposure and gene-specific methylation in 777 elderly men participating in the Normative Aging Study (1999-2009). We repeatedly measured methylation at multiple CpG sites within each gene's promoter region and calculated the mean of the position-specific measurements. We examined intermediate-term associations between primary and secondary air pollutants and mean methylation and methylation at each position with distributed-lag models. Increase in air pollutants concentrations was significantly associated with F3, ICAM-1, and TLR-2 hypomethylation, and IFN-? and IL-6 hypermethylation. An interquartile range increase in black carbon concentration averaged over the four weeks prior to assessment was associated with a 12% reduction in F3 methylation (95% CI: -17% to -6%). For some genes, the change in methylation was observed only at specific locations within the promoter region. DNA methylation may reflect biological impact of air pollution. We found some significant mediated effects of black carbon on fibrinogen through a decrease in F3 methylation, and of sulfate and ozone on ICAM-1 protein through a decrease in ICAM-1 methylation.
| S-EPMC4053463 | biostudies-literature
Project description:The transcription of ribosomal RNA genes (rDNA) is subject to epigenetic regulation, as it is abrogated by the methylation of CpG dinucleotides within their promoter region. Here, we investigated, through Sequenom platform, the age-related methylation status of the CpG island falling into the rDNA promoter in 472 blood samples from 20- to 105-year-old humans and in different tissues (blood, heart, liver, kidney, and testis) of 15 rats 3-96 weeks old. In humans, we did not find a consistently significant correlation between CpG site methylation and chronological age. Furthermore, the methylation levels of one of the analyzed CpG sites were negatively associated with both cognitive performance and survival chance measured in a 9-year follow-up study. We consistently confirmed such result in a replication sample. In rats, the analysis of the homologous region in the tissues revealed the existence of increased methylation in old rats. rRNA expression data, in both humans and rats, were consistent with observed methylation patterns, with a lower expression of rRNA in highly methylated samples. As chronological and biological ages in rats of a given strain are likely to be much closer to each other than in humans, these results seem to provide the first evidence that epigenetic modifications of rDNA change over time according to the aging decline. Thus, the methylation profile of rDNA may represent a potential biomarker of aging.
| S-EPMC5595699 | biostudies-literature
Project description:BackgroundEnvironmental metal exposures have been associated with multiple deleterious health endpoints. DNA methylation (DNAm) may provide insight into the mechanisms underlying these relationships. Toenail metals are non-invasive biomarkers, reflecting a medium-term time exposure window.ObjectivesThis study examined variation in leukocyte DNAm and toenail arsenic (As), cadmium (Cd), lead (Pb), manganese (Mn), and mercury (Hg) among elderly men in the Normative Aging Study, a longitudinal cohort.MethodsWe repeatedly collected samples of blood and toenail clippings. We measured DNAm in leukocytes with the Illumina HumanMethylation450 K BeadChip. We first performed median regression to evaluate the effects of each individual toenail metal on DNAm at three levels: individual cytosine-phosphate-guanine (CpG) sites, regions, and pathways. Then, we applied a Bayesian kernel machine regression (BKMR) to assess the joint and individual effects of metal mixtures on DNAm. Significant CpGs were identified using a multiple testing correction based on the independent degrees of freedom approach for correlated outcomes. The approach considers the effective degrees of freedom in the DNAm data using the principal components that explain >95% variation of the data.ResultsWe included 564 subjects (754 visits) between 1999 and 2013. The numbers of significantly differentially methylated CpG sites, regions, and pathways varied by metals. For example, we found six significant pathways for As, three for Cd, and one for Mn. The As-associated pathways were associated with cancer (e.g., skin cancer) and cardiovascular disease, whereas the Cd-associated pathways were related to lung cancer. Metal mixtures were also associated with 47 significant CpG sites, as well as pathways, mainly related to cancer and cardiovascular disease.ConclusionsThis study provides an approach to understanding the potential epigenetic mechanisms underlying observed relations between toenail metals and adverse health endpoints.
| S-EPMC9825663 | biostudies-literature
Project description:Recent studies have reported robust associations of long-term PM2.5 exposure with DNA methylation-based measures of aging; yet, the molecular implications of these relationships remain poorly understood. We evaluated if genetic variation in 3 biological pathways implicated in PM2.5-related disease-oxidative stress, endothelial function, and metal processing-could modify the effect of PM2.5 on DNAm-age, one prominent DNA methylation-based measure of biological age. This analysis was based on 552 individuals from the Normative Aging Study with at least one visit between 2000 and 2011 (n?=?940 visits). A genetic-score approach was used to calculate aging-risk variant scores for endothelial function, oxidative stress, and metal processing pathways. One-year PM2.5 and PM2.5 component (sulfate and ammonium) levels at participants' addresses were estimated using the GEOS-chem transport model. Blood DNAm-age was calculated using CpG sites on the Illumina HumanMethylation450 BeadChip. In fully-adjusted linear mixed-effects models, the effects of sulfate on DNAm-age (in years) were greater in individuals with high aging-risk endothelial function variant scores when compared with individuals with low aging-risk endothelial function variant scores (Pinteraction = 0.0007; ?High = 1.09, 95% CIHigh: 0.70, 1.48; ?Low = 0.40, 95% CILow: 0.14, 0.67). Similar trends were observed in fully adjusted models of ammonium and total PM2.5 alone. No effect modification was observed by oxidative stress and metal processing variant scores. Secondary analyses revealed significant associations of serum endothelial markers, intercellular adhesion molecule-1 (??=?0.01, 95% CI: 0.002, 0.012) and vascular cell adhesion molecule-1 (??=?0.002, 95% CI: 0.0005, 0.0026), with DNAm-age. Our results add novel evidence that endothelial physiology may be important to DNAm-age relationships, but further research is required to establish their generalizability.
| S-EPMC6075375 | biostudies-literature