Global genomic hypomethylation is a common epigenetic event in cancer that mostly results from hypomethylation of repetitive DNA elements. Case-control studies have associated blood leukocyte DNA hypomethylation with several cancers. Because samples in case-control studies are collected after disease development, whether DNA hypomethylation is causal or just associated with cancer development is still unclear.
In 722 elderly subjects from the Normative Aging Study cohort, we examined whether DNA methylation in repetitive elements (Alu, LINE-1) was associated with cancer incidence (30 new cases, median follow-up: 89 months), prevalence (205 baseline cases), and mortality (28 deaths, median follow-up: 85 months). DNA methylation was measured by bisulfite pyrosequencing.
Individuals with low LINE-1 methylation (
These findings suggest that individuals with lower repetitive element methylation are at high risk of developing and dying from cancer.
Repetitive elements; DNA methylation; Epigenetics; Blood; Cancer risk
DNA methylation is a potential pathway linking air pollution to disease. Studies indicate that psychological functioning modifies the association between pollution and morbidity. The authors estimated the association of DNA methylation with ambient particulate matter less than 2.5 µm in diameter (PM2.5) and black carbon, using mixed models. DNA methylation of the inducible nitric oxide synthase gene, iNOS, and the glucocorticoid receptor gene, GCR, was measured by quantitative polymerase chain reaction pyrosequencing of 1,377 blood samples from 699 elderly male participants in the VA Normative Aging Study (1999–2009). The authors also investigated whether this association was modified by psychological factors including optimism or pessimism, anxiety, and depression. iNOS methylation was decreased after acute exposure to both black carbon and PM2.5. A 1-μg/m3 increase in exposure to black carbon in the 4 hours preceding the clinical examination was associated with a 0.9% decrease in 5-methylcytosine (95% CI: 0.4, 1.4) in iNOS, and a 10-μg/m3 increase in exposure to PM2.5 was associated with a 0.6% decrease in 5-methylcytosine (95% CI: 0.03, 1.1) in iNOS. Participants with low optimism and high anxiety had associations that were 3–4 times larger than those with high optimism or low anxiety. GCR methylation was not associated with particulate air pollution exposure.
air pollution; DNA methylation; psychology
Epigenetic features such as DNA hypomethylation have been associated with conditions related to cardiovascular risk. We evaluated whether lower blood DNA methylation in heavily methylated repetitive sequences predicts the risk of ischemic heart disease and stroke.
We quantified blood DNA methylation of LINE-1 repetitive elements through PCR-pyrosequencing in 712 elderly individuals from the Boston-area Normative Aging Study. We estimated risk-factor adjusted relative risks (RRs) for ischemic heart disease and stroke at baseline (242 prevalent cases); as well as in incidence (44 new cases; median follow-up, 63 months); and subsequent mortality from ischemic heart disease (86 deaths; median follow-up, 75 months).
Blood LINE-1 hypomethylation was associated with baseline ischemic heart disease (RR=2.1 [95% confidence interval = 1.2 to 4.0] for lowest vs. highest methylation quartile) and for stroke (2.5 [0.9 to 7.5]). Among participants free of baseline disease, individuals with methylation below the median also had higher risk of developing ischemic heart disease (4.0 [1.8 to 8.9]) or stroke (5.7 [0.8 to 39.5]). In the entire cohort, persons with methylation below the median had higher mortality from ischemic heart disease (3.3 [1.3 to 8.4]) and stroke (2.8 [0.6 to 14.3]). Total mortality was also increased (2.0 [1.2 to 3.3]). These results were confirmed in additional regression models using LINE-1 methylation as a continuous variable.
Subjects with prevalent IHD and stroke exhibited lower LINE-1 methylation. In longitudinal analyses, persons with lower LINE-1 methylation were at higher risk for incident ischemic heart disease and stroke, and for total mortality.
Particulate air pollution is associated with cardiovascular events, but the mechanisms are not fully understood. The main objective was to assess the relationship between long-term exposure to traffic-related air pollution and blood pressure (BP).
The authors used longitudinal data from 853 elderly men participating in the Veterans Administration Normative Aging Study, followed during 1996–2008. Long-term average exposures to traffic particles were created from daily predictions of black carbon (BC) exposure at the geocoded address of each subject, using a validated spatiotemporal model based on ambient monitoring at 82 Boston-area locations. The authors examined the association of these exposures with BP using a mixed model. The authors included the following covariates: age, body mass index, smoking, alcohol, fasting glucose, creatinine clearance, use of cardiovascular medication, education, census-level poverty, day of week and season of clinical visit.
The authors found significant positive associations between 1-year average BC exposure and both systolic and diastolic blood pressure. An IQR increase in 1-year average BC exposure (0.32 µg/m3) was associated with a 2.64 mm Hg increase in systolic blood pressure (95% CI 1.47 to 3.80) and a 2.41 mm Hg increase in diastolic blood pressure (95% CI 1.77 to 3.05).
Long-term exposure to traffic particles is associated with increased BP, which may explain part of the association with myocardial infarctions and cardiovascular deaths reported in cohort studies.
Previous studies suggest that air pollution is related to thrombosis, inflammation, and endothelial dysfunction. Mechanisms and sources of susceptibility are still unclear. One possibility is that these associations can be modified by DNA methylation states.
We conducted a cohort study with repeated measurements of fibrinogen, C-reactive protein, intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) in 704 elderly men participating in the Veterans Administration Normative Aging Study (2000-2009). We investigated short- and intermediate-term air pollution effects on these blood markers, and epigene-environment interactions by DNA methylation of Alu, LINE-1, tissue factor (F3), Toll-Like Receptor 2 (TLR-2), and ICAM-1.
We found effects of particle number, black carbon, nitrogen dioxide (NO2), and carbon monoxide (CO) on fibrinogen. Ozone was a significant predictor of C-reactive protein and ICAM-1. Particle number, black carbon, NO2, CO, PM2.5, and sulfates were associated with ICAM-1and VCAM-1. An interquartile range increase in 24-hour exposure for NO2; was associated with a 1.7% (95% confidence interval = 0.2% to 3.3%) increase in fibrinogen for ozone a 10.8% (2.2% to 20.0%) increase in C-reactive protein for particle number, a 5.9% (3.6% to 8.3%) increase in ICAM-1; and for PM2.5 a 3.7% (1.7% to 5.8%) increase in VCAM-1. The air pollution effect was stronger among subjects having higher Alu, lower LINE-1, tissue factor, or TLR-2 methylation status.
We observed associations of traffic-related pollutants on fibrinogen, and both traffic and secondary particles on C-reactive protein, ICAM-1, and VCAM-1. There was effect modification by DNA methylation status, indicating that epigenetic states can convey susceptibility to air pollution.
Lung function is a strong predictor of mortality. While inflammatory markers have been associated with lung function decrease, pathways are still poorly understood and epigenetic changes may participate in lung function decline mechanisms. We studied the cross-sectional association between DNA methylation in nine inflammatory genes and lung function in a cohort of 756 elderly men living in the metropolitan area of Boston. Participants donated a blood sample for DNA methylation analysis and underwent spirometry at each visit every 3 to 5 y from 1999–2006. We used separate multivariate mixed effects regression models to study the association between each lung function measurement and DNA methylation within each gene. Decreased CRAT, F3 and TLR2 methylation was significantly associated with lower lung function. One interquartile range (IQR) decrease in DNA methylation was associated with lower forced vital capacity (FVC) and forced expiratory volume in one second (FEV1), respectively by 2.94% (p < 10−4) and 2.47% (p < 10−3) for F3 and by 2.10% (p < 10−2) and 2.42% (p < 10−3) for TLR2. Decreased IFNγ and IL6 methylation was significantly associated with better lung function. One IQR decrease in DNA methylation was associated with higher FEV1 by 1.75% (p = 0.02) and 1.67% (p = 0.05) for IFNγ and IL6, respectively. These data demonstrate that DNA methylation may be part of the biological processes underlying the lung function decline and that IFNγ and IL6 may have ambivalent roles through activation of negative feedback.
DNA methylation; genes; spirometry; FEV1; lungs; TLR2; F3; INOS; GCR; OGG1
Background Estimates of global DNA methylation from repetitive DNA elements, such as Alu and LINE-1, have been increasingly used in epidemiological investigations because of their relative low-cost, high-throughput and quantitative results. Nevertheless, determinants of these methylation measures in healthy individuals are still largely unknown. The aim of this study was to examine whether age, gender, smoking habits, alcohol drinking and body mass index (BMI) are associated with Alu or LINE-1 methylation levels in blood leucocyte DNA of healthy individuals.
Methods Individual data from five studies including a total of 1465 healthy subjects were combined. DNA methylation was quantified by PCR-pyrosequencing.
Results Age [β = −0.011% of 5-methyl-cytosine (%5mC)/year, 95% confidence interval (CI) −0.020 to −0.001%5mC/year] and alcohol drinking (β = −0.214, 95% CI −0.415 to −0.013) were inversely associated with Alu methylation. Compared with females, males had lower Alu methylation (β = −0.385, 95% CI −0.665 to −0.104) and higher LINE-1 methylation (β = 0.796, 95% CI 0.261 to 1.330). No associations were found with smoking or BMI. Percent neutrophils and lymphocytes in blood counts exhibited a positive (β = 0.036, 95% CI 0.010 to 0.061) and negative (β = −0.038, 95% CI −0.065 to −0.012) association with LINE-1 methylation, respectively.
Conclusions Global methylation measures in blood DNA vary in relation with certain host and lifestyle characteristics, including age, gender, alcohol drinking and white blood cell counts. These findings need to be considered in designing epidemiological investigations aimed at identifying associations between DNA methylation and health outcomes.
Blood; DNA methylation; epigenetics; meta-analysis; repetitive elements
DNA methylation has been associated with age-related disease. Intra-individual changes in gene-specific DNA methylation over time in a community-based cohort has not been well described. We estimated the change in DNA methylation due to aging for nine genes in an elderly, community-dwelling cohort of men. Seven hundred and eighty four men from the Veterans Administration Normative Aging Study who were living in metropolitan Boston from 1999–2009 donated a blood sample for DNA methylation analysis at clinical examinations repeated at approximately 3-5 year intervals. We used mixed effects regression models. Aging was significantly associated with decreased methylation of GCR, iNOS and TLR2 and with increased methylation of IFNγ, F3, CRAT and OGG. Obstructive pulmonary disease at baseline modified the effect of aging on methylation of IFNγ (interaction p = 0.04). For participants who had obstructive pulmonary disease at their baseline visit, the rate of change of methylation of IFNγ was -0.05% 5-methyl-cytosine (5-mC) per year (95% CI: -0.22, 0.13), but was 0.14% 5-mC per year (95% CI: 0.05, 0.24) for those without this condition. Models with random slopes indicated significant heterogeneity in the effect of aging on methylation of GCR, iNOS and OGG. These findings suggest that DNA methylation may reflect differential biological aging.
aging; DNA Mmthylation; epigenesis; genetic
To investigate the association between methylation of transposable elements Alu and long-interspersed nuclear elements (LINE-1) and lung function.
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 and secondary outcome measures
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 (FEV1) (β=28 ml per 1% change in Alu methylation, p=0.017) and showed a trend towards association with a lower forced vital capacity (FVC) (β=27 ml, p=0.06) and lower FEV1/FVC (β=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 FEV1 (β=6.9 ml/year per 1% change in LINE-1 methylation, p=0.005) and of FVC (β=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.
Bone lead is a cumulative measure of lead exposure that can also be remobilized. We examined repeated measures of bone lead over 11 years to characterize long-term changes and identify predictors of tibia and patella lead stores in an elderly male population.
Lead was measured every 3–5 years by k-x-ray fluorescence and mixed-effect models with random effects were used to evaluate change over time.
554 participants provided up to 4 bone lead measurements. Final models predicted a −1.4% annual decline (95%CI: −2.2,−0.7) for tibia lead and piecewise linear model for patella with an initial decline of 5.1% per year (95%CI: −6.2,−3.9) during the first 4.6 years but no significant change thereafter (−0.4% (95% CI: −2.4, 1.7)).
These results suggest that bone lead half-life may be longer than previously reported.
It has come to the attention of the authors that Table 5 was not included in Epigenetics Volume 7, Issue 3 in the manuscript: Lepeule J, Baccarelli A, Tarantini L, Motta V, Cantone L, Litonjua AA, et al. Gene promoter methylation is associated with lung function in the elderly: The normative aging study. Epigenetics 2012; 7:261-9.
The citation for Table 5 should have appeared on p. 264, “Sensitivity analyses. The sensitivity analyses including participants with chronic lung diseases showed similar associations between lung function and DNA methylation as the main analyses, with only slight variations in significance (Table 5).”
Studies show that ambient temperature and air pollution are associated with cardiovascular disease and that they may interact to affect cardiovascular events. However, few epidemiologic studies have examined mechanisms through which ambient temperature may influence cardiovascular function. The authors examined whether temperature was associated with heart rate variability (HRV) in a Boston, Massachusetts, study population and whether such associations were modified by ambient air pollution concentrations. The population was a cohort of 694 older men examined between 2000 and 2008. The authors fitted a mixed model to examine associations between temperature and air pollution and their interactions with repeated HRV measurements, adjusting for covariates selected a priori on the basis of their previous studies. Results showed that higher ambient temperature was associated with decreases in HRV measures (standard deviation of normal-to-normal intervals, low-frequency power, and high-frequency power) during the warm season but not during the cold season. These warm-season associations were significantly greater when ambient ozone levels were higher (>22.3 ppb) but did not differ according to levels of ambient fine (≤2.5 μm) particulate matter. The authors conclude that temperature and ozone, exposures to both of which are expected to increase with climate change, might act together to worsen cardiovascular health and/or precipitate cardiovascular events via autonomic nervous system dysfunction.
air pollution; heart rate; interaction; ozone; particulate matter; temperature
Background: Traffic-related particles (TRPs) are associated with adverse cardiovascular events. The exact mechanisms are unclear, but systemic inflammatory responses likely play a role.
Objectives: We conducted a repeated measures study among male participants of the Normative Aging Study in the greater Boston, Massachusetts, area to determine whether individual-level residential black carbon (BC), a marker of TRPs, is associated with systemic inflammation and whether coronary heart disease (CHD), diabetes, and obesity modify associations.
Methods: We quantified markers of inflammation in 1,163 serum samples from 580 men. Exposure to BC up to 4 weeks prior was predicted from a validated spatiotemporal land-use regression model. Linear mixed effects models estimated the effects of BC on each marker while adjusting for potential confounders.
Results: Associations between BC and blood markers were not observed in main effects models or when stratified by obesity status. However, BC was positively associated with markers of inflammation in men with CHD (particularly vascular endothelial growth factor) and in men with diabetes (particularly interleukin-1β and tumor necrosis factor-α). Significant exposure time windows varied by marker, although in general the strongest associations were observed with moving averages of 2–7 days after a lag of several days.
Conclusions: In an elderly male population, estimated BC exposures were positively associated with markers of systemic inflammation but only in men with CHD or diabetes.
air pollution; black carbon; cardiovascular disease; coronary heart disease; diabetes; inflammation; land-use regression model; particulate matter; susceptible; traffic
Background: Lead exposure has been associated with cardiovascular disease (CVD) in animal and human studies. However, the mechanisms of action have not been fully elucidated. We therefore examined the relationship between lead and multiple biomarkers of CVD.
Methods: Participants were older men from the Normative Aging Study without preexisting coronary heart disease, diabetes, or active infection at baseline (n = 426). Serum biomarkers included lipid profile [total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), and triglycerides] and inflammatory markers [C-reactive protein, intercellular adhesion molecule-1, interleukin-6, and tumor necrosis factor receptor-2 (TNF-R2)]. We measured lead in blood and in bone by K-shell X-ray fluorescence. In this sample, 194 men (44.3%) had two or more repeated measures, resulting in 636 observations for analysis. We conducted analyses using mixed effects models with random subject intercepts.
Results: Lead levels were associated with several CVD biomarkers, including levels of TNF-R2 and lipid markers. Specifically, in multivariable models, a 50% increase in blood lead level was associated with 26% increased odds of high TNF-R2 levels (> 5.52 ng/mL; odds ratio = 1.26; 95% confidence interval: 1.09, 1.45). There were positive associations of blood lead level with total cholesterol and HDL levels, and these associations were more evident when modeled as continuous outcomes than when categorized using clinically relevant cut points. In addition, longitudinal analyses indicated a significant increase in TNF-R2 levels over time to be associated with high blood lead level at the preceding visit.
Conclusions: Blood lead level may be related with CVD in healthy older men through its association with TNF-R2 levels. In addition, the magnitude of the association of blood lead level with TNF-R2 level increased with age in the study population.
aging; biomarkers; cardiovascular; cholesterol; inflammation; lead; metals
Background: Arsenic, cadmium, mercury, and lead are associated with cardiovascular disease in epidemiologic research. These associations may be mediated by direct effects of the metals on blood pressure (BP) elevation. Manganese is associated with cardiovascular dysfunction and hypotension in occupational cohorts.
Objectives: We hypothesized that chronic arsenic, cadmium, mercury, and lead exposures elevate BP and that manganese lowers BP.
Methods: We conducted a cross-sectional analysis of associations between toenail metals and BP among older men from the Normative Aging Study (n = 639), using linear regression and adjusting for potential confounders.
Results: An interquartile range increase in toenail arsenic was associated with higher systolic BP [0.93 mmHg; 95% confidence interval (CI): 0.25, 1.62] and pulse pressure (0.76 mmHg; 95% CI: 0.22, 1.30). Positive associations between arsenic and BP and negative associations between manganese and BP were strengthened in models adjusted for other toenail metals.
Conclusions: Our findings suggest associations between BP and arsenic and manganese. This may be of public health importance because of prevalence of both metal exposure and cardiovascular disease. Results should be interpreted cautiously given potential limitations of toenails as biomarkers of metal exposure.
arsenic; blood pressure; cadmium; epidemiology; lead; manganese; mercury; metals
Particulate matter (PM) has been associated with acute cardiovascular outcomes, but our understanding of the mechanism is incomplete. We examined the association between PM and cell adhesion molecules. We also investigated the modifying effect of genotype and phenotype variation to gain insight into the relevant biological pathways for this association.
We used mixed regression models to examine the association of PM2.5 and black carbon (BC) with serum concentrations of soluble Intercellular Adhesion Molecule (sICAM-1) and soluble Vascular Cell Adhesion Molecule (sVCAM-1), markers of endothelial function and inflammation, in a longitudinal study of 809 participants in the Normative Aging Study (1819 total observations). We also examined whether this association was modified by genotype, obesity, or diabetes status. Genes selected for analyses were either related to oxidative stress, endothelial function, lipid metabolism or metal processing.
BC during the 2 days prior to blood draw was significantly associated with increased sVCAM-1 (4.5% increase per 1μg/m3 95% CI 1.1, 8.0). Neither pollutant was associated with sICAM-1. Larger effects of BCon sVCAM were seen in subjects with obesity (p=0.007) and who were GSTM1 null (p=0.02).
BC is associated with markers of endothelial function and inflammation. Genes related to oxidative defense may modify this association.
air pollution; epidemiology; genetic susceptibility; particulates
Although lead has been associated with hearing loss in occupational settings and in children, little epidemiologic research has been conducted on the impact of cumulative lead exposure on age-related hearing loss in the general population. We determined whether bone lead levels, a marker of cumulative lead exposure, are associated with decreased hearing ability in 448 men from the Normative Aging Study, seen between 1962 and 1996 (2,264 total observations). Air conduction hearing thresholds were measured at 0.25 to 8 kHz and pure tone averages (PTA) (mean of 0.5, 1, 2 and 4 kHz) were computed. Tibia and patella lead levels were measured using K x-ray fluorescence between 1991 and 1996. In cross-sectional analyses, after adjusting for potential confounders including occupational noise, patella lead levels were significantly associated with poorer hearing thresholds at 2, 3, 4, 6 and 8 kHz and PTA. The odds of hearing loss significantly increased with patella lead levels. We also found significant positive associations between tibia lead and the rate change in hearing thresholds at 1, 2, and 8 kHz and PTA in longitudinal analyses. Our results suggest that chronic low-level lead exposure may be an important risk factor for age-related hearing loss and reduction of lead exposure could help prevent or delay development of age-related hearing loss.
bone lead; general population; hearing loss; occupational noise
Lower blood DNA methylation has been associated with atherosclerosis and high cardiovascular risk. Mechanisms linking DNA hypomethylation to increased cardiovascular risk are still largely unknown.
In a population of community-dwelling elderly individuals, we evaluated whether DNA methylation in LINE-1 repetitive element, heavily methylated sequences dispersed throughout the human genome, was associated with circulating Vascular Cell Adhesion Molecule-1 (VCAM-1), Inter-Cellular Adhesion Molecule-1 (ICAM-1), and C-reactive protein (CRP).
METHODS AND RESULTS
We measured LINE-1 methylation by bisulfite PCR-Pyrosequencing on 742 blood DNA samples from male participants in the Boston area Normative Aging Study (mean age=74.8 years). Mean serum VCAM-1 increased progressively in association with LINE-1 hypomethylation (from 975.2 to 1063.4 ng/ml in the highest vs. lowest methylation quintiles; p-trend=0.004). The association between VCAM-1 and LINE-1 hypomethylation was significant in individuals without ischemic heart disease or stroke (n=480; p=0.001), but not in those with prevalent disease (n=262; p=0.57). Serum ICAM-1 and CRP were not associated with LINE-1 methylation (p-trend=>0.25). All results were confirmed by multivariable analyses adjusting for age, BMI, smoking, pack-years, and ischemic heart disease/stroke.
LINE-1 element hypomethylation is associated with higher serum VCAM-1. Our data provide new insights into epigenetic events that may accompany the development of cardiovascular disease.
cell adhesion molecules; epidemiology; cardiovascular diseases; risk factors; LINE-1; VCAM-1
Background: DNA methylation is a potential pathway linking environmental exposures to disease. Exposure to particulate air pollution has been associated with increased cardiovascular morbidity and mortality, and lower blood DNA methylation has been found in processes related to cardiovascular morbidity.
Objective: We hypothesized that prolonged exposure to particulate pollution would be associated with hypomethylation of repetitive DNA elements and that this association would be modified by genes involved in glutathione metabolism and other host characteristics.
Methods: DNA methylation of the long interspersed nucleotide element–1 (LINE-1) and the short interspersed nucleotide element Alu were measured by quantitative polymerase chain reaction pyrosequencing in 1,406 blood samples from 706 elderly participants in the Normative Aging Study. We estimated changes in repetitive element DNA methylation associated with ambient particles (particulate matter ≤ 2.5 µm in aerodynamic diameter), black carbon (BC), and sulfates (SO4), with mixed models. We examined multiple exposure windows (1–6 months) before DNA methylation measurement. We investigated whether this association was modified by genotype and phenotype.
Results: An interquartile range (IQR) increase in BC over a 90-day period was associated with a decrease of 0.31% 5-methylcytosine (5mC) (95% confidence interval, 0.12–0.50%) in Alu. An IQR increase in SO4 over a 90-day period was associated with a decrease of 0.27% 5mC (0.02–0.52%) in LINE-1. The glutathione S-transferase mu-1–null genotype strengthened the association between BC and Alu hypomethylation.
Conclusion: Prolonged exposure to BC and SO4 particles was associated with hypomethylation of two types of repetitive elements.
air pollution; DNA methylation; epigenetics; gene–environment. Environ Health Perspect 119:977–982 (2011). doi:10.1289/ehp.1002773 [Online 8 March 2011]
Background: No studies have examined the association between cumulative low-level lead exposure and the prospective development of electrocardiographic conduction abnormalities, which may mediate the association between lead and several cardiovascular end points.
Objective: We prospectively examined the association between lead exposure and the development of electrocardiographic conduction abnormalities.
Methods: We assessed blood lead, bone lead—a biomarker of cumulative lead exposure—measured with K-shell X-ray fluorescence, and electrocardiographic end points among 600 men in the Normative Aging Study who were free of electrocardiographic abnormalities at the time of the baseline ECG. Of these men, we had follow-up data from a second electrocardiogram for 496 men 8.1 (SD = 3.1) years later, on average. We used repeated measures linear regression to analyze change in electrocardiographic conduction timing and logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for developing specific conduction disturbances and adjusted for potential confounders.
Results: Mean (± SD) blood (5.8 ± 3.6), patella bone (30.3 ± 17.7), and tibia bone (21.6 ± 12.0) lead concentrations were similar to those found in samples from the general U.S. population and much lower than those reported in occupationally exposed groups. Compared with those in the lowest tertile of tibia lead, those in the highest had a 7.94-ms (95% CI, 1.42–14.45) increase in heart rate–corrected QT (QTc) interval and a 5.94-ms increase in heart rate–corrected QRS (95% CI, 1.66–10.22) duration > 8 years. Those in the highest tertile of tibia lead also had increased odds of QT prolongation (QTc ≥ 440 msec; OR = 2.53; 95% CI, 1.22–5.25) and JT prolongation (heart rate–corrected JT > 360 msec; OR = 2.53; 95% CI, 0.93–6.91). Results were weaker for patella lead. No associations were identified with blood lead.
Conclusions: This study suggests that low-level cumulative exposure to lead is associated with worse future cardiac conductivity in the ventricular myocardium, as reflected in QT interval characteristics.
ECG; electrocardiographic conduction; environmental exposure; epidemiology; lead; prospective study
Particulate air pollution has been associated with cardiovascular morbidity and mortality, but it remains unclear which time windows and pollutant sources are most critical. MicroRNA (miRNA) is thought to be involved in cardiovascular regulation. However, little is known about whether polymorphisms in genes that process microRNAs influence response to pollutant exposure. We hypothesized that averaging times longer than routinely measured one or two day moving averages are associated with higher soluble intercellular adhesion molecule-1 (sICAM-1) and vascular cell adhesion molecule-1 (sVCAM-1) levels, and that stationary and mobile sources contribute differently to these effects. We also investigated whether single nucleotide polymorphisms (SNPs) in miRNA-processing genes modify these associations.
sICAM-1 and sVCAM-1 were measured from 1999-2008 and matched to air pollution monitoring for fine particulate matter (PM2.5) black carbon, and sulfates (SO42-). We selected 17 SNPs in five miRNA-processing genes. Mixed-effects models were used to assess effects of pollutants, SNPs, and interactions under recessive inheritance models using repeated measures.
723 participants with 1652 observations and 1-5 visits were included in our analyses for black carbon and PM2.5. Sulfate data was available for 672 participants with 1390 observations. An interquartile range change in seven day moving average of PM2.5 (4.27 μg/m3) was associated with 3.1% (95%CI: 1.6, 4.6) and 2.5% (95%CI: 0.6, 4.5) higher sICAM-1 and sVCAM-1. Interquartile range changes in sulfates (1.39 μg/m3) were associated with 1.4% higher (95%CI: 0.04, 2.7) and 1.6% (95%CI: -0.4, 3.7) higher sICAM-1 and sVCAM-1 respectively. No significant associations were observed for black carbon. In interaction models with PM2.5, both sICAM-1 and sVCAM-1 levels were lower in rs1062923 homozygous carriers. These interactions remained significant after multiple comparisons adjustment.
PM2.5 seven day moving averages are associated with higher sICAM-1 and sVCAM-1 levels. SO4-2 seven day moving averages are associated with higher sICAM-1 and a suggestive association was observed with sVCAM-1 in aging men. SNPs in miRNA-processing genes may modify associations between ambient pollution and sICAM-1 and sVCAM-1, which are correlates of atherosclerosis and cardiovascular disease.
Particulate air pollution is associated with cardiovascular mortality and morbidity. To help identify mechanisms of action and protective/susceptibility factors, we evaluated whether the effect of particulate matter <2.5 µm in aerodynamic diameter (PM2.5) on heart rate variability (HRV) was modified by dietary intakes of methyl nutrients (folate, vitamin B6, B12, methionine) and related gene polymorphisms (C677T MTHFR and C1420T cSHMT).
Methods and Results
HRV and dietary data were obtained between 2000–2005 from 549 elderly men from the Normative Aging Study. In carriers of [CT/TT] MTHFR genotypes, the standard deviation of normal-to-normal intervals (SDNN) was 17.1% (95% CI, 6.5, 26.4; p=0.002) lower than in CC MTHFR subjects. In the same [CT/TT] MTHFR subjects, each 10 µg/m3 increase in PM2.5 in the 48 hours before the examination was associated with a further 8.8% (95%CI: 0.2, 16.7; p=0.047) decrease in SDDN. In [CC] cSHMT carriers, PM2.5 was associated with a 11.8% (95%CI: 1.8, 20.8; p=0.02) decrease in SDDN. No PM2.5-SSDN association was found in subjects with either [CC] MTHFR or [CT/TT] cSHMT genotypes. The negative effects of PM2.5 were abrogated in subjects with higher intakes (>median levels) of B6, B12, or methionine. PM2.5 was negatively associated with HRV in subjects with lower intakes, but no PM2.5 effect was found in the higher intake groups.
Genetic and nutritional variations in the methionine cycle affect HRV, either independently or by modifying the effects of PM2.5.
heart rate; nervous system; autonomic; metabolism; aging; epidemiology