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
The genetic risk factors for chronic obstructive pulmonary disease (COPD) are still largely unknown. To date, genome-wide association studies (GWASs) of limited size have identified several novel risk loci for COPD at CHRNA3/CHRNA5/IREB2, HHIP and FAM13A; additional loci may be identified through larger studies. We performed a GWAS using a total of 3499 cases and 1922 control subjects from four cohorts: the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE); the Normative Aging Study (NAS) and National Emphysema Treatment Trial (NETT); Bergen, Norway (GenKOLS); and the COPDGene study. Genotyping was performed on Illumina platforms with additional markers imputed using 1000 Genomes data; results were summarized using fixed-effect meta-analysis. We identified a new genome-wide significant locus on chromosome 19q13 (rs7937, OR = 0.74, P = 2.9 × 10−9). Genotyping this single nucleotide polymorphism (SNP) and another nearby SNP in linkage disequilibrium (rs2604894) in 2859 subjects from the family-based International COPD Genetics Network study (ICGN) demonstrated supportive evidence for association for COPD (P = 0.28 and 0.11 for rs7937 and rs2604894), pre-bronchodilator FEV1 (P = 0.08 and 0.04) and severe (GOLD 3&4) COPD (P = 0.09 and 0.017). This region includes RAB4B, EGLN2, MIA and CYP2A6, and has previously been identified in association with cigarette smoking behavior.
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
Pessimism, a general tendency toward negative expectancies, is a risk factor for depression and also heart disease, stroke, and reduced cancer survival. There is evidence that individuals with higher lead exposure have poorer health. However, low socioeconomic status (SES) is linked with higher lead levels and greater pessimism, and it is unclear whether lead influences psychological functioning independently of other social factors. The authors considered interrelations among childhood and adult SES, lead levels, and psychological functioning in data collected on 412 Boston area men between 1991 and 2002 in a subgroup of the VA Normative Aging Study. Pessimism was measured by using the Life Orientation Test. Cumulative (tibia) lead was measured by x-ray fluorescence. Structural equation modeling was used to quantify the relations as mediated by childhood and adult SES, controlling for age, health behaviors, and health status. An interquartile range increase in lead quartile was associated with a 0.37 increase in pessimism score (P < 0.05). Low childhood and adult SES were related to higher tibia lead levels, and both were also independently associated with higher pessimism. Lead maintained an independent association with pessimism even after childhood and adult SES were considered. Results demonstrate an interrelated role of lead burden and SES over the life course in relation to psychological functioning in older age.
depression; lead; metals; orientation; psychology; socioeconomic factors
Resistance training programs have been found to improve muscle strength, physical function, and depressive symptoms in middle-aged and older adults. These programs have typically been provided in clinical facilities, health clubs, and senior centers, which may be inconvenient and/or cost prohibitive for some older adults. The purpose of this study was to investigate the effectiveness of an automated telemedicine intervention that provides real-time guidance and monitoring of resistance training in the home.
A randomized clinical trial in 103 middle-aged or older participants. Participants were assigned to use of a theory-driven interactive voice response system designed to promote resistance training (Telephone-Linked Computer-based Long-term Interactive Fitness Trainer; n = 52) or to an attention control (n = 51) for a period of 12 months. Measurements of muscle strength, balance, walk distance, and mood were obtained at baseline, 3, 6, and 12 months.
We observed increased strength, improved balance, and fewer depressive symptoms in the intervention group than in the control group. Using generalized estimating equations modeling, group differences were statistically significant for knee flexion strength (p = .035), single-leg stance time (p = .029), and Beck Depression Inventory (p = .030).
This computer-based telecommunications exercise intervention led to improvements in participants’ strength, balance, and depressive symptoms. Because of their low cost and easy accessibility, computer-based interventions may be a cost-effective way of promoting exercise in the home.
Muscle strength; Balance; Resistance training
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.
Rationale: Chromosome 12p has been linked to chronic obstructive pulmonary disease (COPD) in the Boston Early-Onset COPD Study (BEOCOPD), but a susceptibility gene in that region has not been identified.
Objectives: We used high-density single-nucleotide polymorphism (SNP) mapping to implicate a COPD susceptibility gene and an animal model to determine the potential role of SOX5 in lung development and COPD.
Methods: On chromosome 12p, we genotyped 1,387 SNPs in 386 COPD cases from the National Emphysema Treatment Trial and 424 control smokers from the Normative Aging Study. SNPs with significant associations were then tested in the BEOCOPD study and the International COPD Genetics Network. Based on the human results, we assessed histology and gene expression in the lungs of Sox5−/− mice.
Measurements and Main Results: In the case-control analysis, 27 SNPs were significant at P ≤ 0.01. The most significant SNP in the BEOCOPD replication was rs11046966 (National Emphysema Treatment Trial–Normative Aging Study P = 6.0 × 10−4, BEOCOPD P = 1.5 × 10−5, combined P = 1.7 × 10−7), located 3′ to the gene SOX5. Association with rs11046966 was not replicated in the International COPD Genetics Network. Sox5−/− mice showed abnormal lung development, with a delay in maturation before the saccular stage, as early as E16.5. Lung pathology in Sox5−/− lungs was associated with a decrease in fibronectin expression, an extracellular matrix component critical for branching morphogenesis.
Conclusions: Genetic variation in the transcription factor SOX5 is associated with COPD susceptibility. A mouse model suggests that the effect may be due, in part, to its effects on lung development and/or repair processes.
chronic obstructive pulmonary disease; emphysema; knockout mice; lung development; single nucleotide polymorphism
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: 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
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
Rationale: Several family-based studies have identified genetic linkage for lung function and airflow obstruction to chromosome 2q.
Objectives: We hypothesized that merging results of high-resolution single nucleotide polymorphism (SNP) mapping in four separate populations would lead to the identification of chronic obstructive pulmonary disease (COPD) susceptibility genes on chromosome 2q.
Methods: Within the chromosome 2q linkage region, 2,843 SNPs were genotyped in 806 COPD cases and 779 control subjects from Norway, and 2,484 SNPs were genotyped in 309 patients with severe COPD from the National Emphysema Treatment Trial and 330 community control subjects. Significant associations from the combined results across the two case-control studies were followed up in 1,839 individuals from 603 families from the International COPD Genetics Network (ICGN) and in 949 individuals from 127 families in the Boston Early-Onset COPD Study.
Measurements and Main Results: Merging the results of the two case-control analyses, 14 of the 790 overlapping SNPs had a combined P < 0.01. Two of these 14 SNPs were consistently associated with COPD in the ICGN families. The association with one SNP, located in the gene XRCC5, was replicated in the Boston Early-Onset COPD Study, with a combined P = 2.51 × 10−5 across the four studies, which remains significant when adjusted for multiple testing (P = 0.02). Genotype imputation confirmed the association with SNPs in XRCC5.
Conclusions: By combining data from COPD genetic association studies conducted in four independent patient samples, we have identified XRCC5, an ATP-dependent DNA helicase, as a potential COPD susceptibility gene.
emphysema; genetic linkage; metaanalysis; single nucleotide polymorphism
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 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
Exposure to traffic-related air pollution (TRAP) contributes to increased cardiovascular risk. Land-use regression models can improve exposure assessment for TRAP.
We examined the association between medium-term concentrations of black carbon (BC) estimated by land-use regression and levels of soluble intercellular adhesion molecule-1 (sICAM-1) and soluble vascular cell adhesion molecule-1 (sVCAM-1), both markers of inflammatory and endothelial response.
We studied 642 elderly men participating in the Veterans Administration (VA) Normative Aging Study with repeated measurements of sICAM-1 and sVCAM-1 during 1999–2008. Daily estimates of BC exposure at each geocoded participant address were derived using a validated spatiotemporal model and averaged to form 4-, 8-, and 12-week exposures. We used linear mixed models to estimate associations, controlling for confounders. We examined effect modification by statin use, obesity, and diabetes.
We found statistically significant positive associations between BC and sICAM-1 for averages of 4, 8, and 12 weeks. An interquartile-range increase in 8-week BC exposure (0.30 μg/m3) was associated with a 1.58% increase in sICAM-1 (95% confidence interval, 0.18–3.00%). Overall associations between sVCAM-1 and BC exposures were suggestive but not statistically significant. We found a significant interaction with diabetes—where diabetics were more susceptible to the effect of BC—for both sICAM-1 and sVCAM-1. We also observed an interaction with statin use, which was statistically significant for sVCAM-1 and suggestive for sICAM-1. We found no evidence of an interaction with obesity.
Our results suggest that medium-term exposure to TRAP may induce an increased inflammatory/endothelial response, especially among diabetics and those not using statins.
adhesion molecules; air; cardiovascular; environmental; outdoor air; roadway proximity
We developed prediction models for bone lead using blood lead levels and other standard covariates in a community-based cohort of older men.
Participants having bone lead levels measured by K-x-ray fluorescence were included in the model selection process (n=825). Predictors of each tibia and patella lead were identified in three quarters of the population and then predicted the bone lead levels in the remaining one quarter and in the Community Lead Study.
18 predictors were selected for tibia (blood lead, age, education, occupation, smoking status, pack-years of cigarette, serum levels of phosphorus, uric acid, calcium, creatinine and total and high-density lipoprotein cholesterols, hematocrit, body mass index, systolic and diastolic blood pressure, diagnoses of cancer and diabetes; R2=0.32) and 16 for patella lead (among the predictors included in the tibia model diagnosis of cancer, serum levels of calcium and total cholesterol were not included in patella lead model, but diagnosis of hypertension was included; R2=0.34), respectively. The correlation coefficients between the observed and predicted values were 0.43-0.50 for tibia and 0.52-0.58 for patella lead in internal and external validation. We applied these predicted bone lead models to the Third National Health and Nutrition Examination Survey (NHANES-III) to examine associations with hypertension and found relatively more significant associations compared to blood lead.
This study suggests that the prediction equations may be used to predict bone lead levels in other community-based cohorts with reasonable accuracy.
Loss of genomic DNA methylation has been found in a variety of common human age-related diseases. Whether DNA methylation decreases over time as individuals age is unresolved. We measured DNA methylation in 1,097 blood DNA samples from 718 elderly subjects between 55–92 years of age (1–3 samples/subjects), who have been repeatedly evaluated over an 8-year time span in the Boston area Normative Aging Study. DNA methylation was measured using quantitative PCR-Pyrosequencing analysis in Alu and LINE-1 repetitive elements, heavily methylated sequences with high representation throughout the human genome. Age at the visit was negatively associated with Alu element methylation (β=−.12 %5mC/year, p=0.0005). A weaker association was observed with LINE-1 elements (β=−.06 %5mC/year, p=0.049). We observed a significant decrease in average Alu methylation over time, with a −0.2 %5mc change (p=0.012) compared to blood samples collected up to 8 years earlier. The longitudinal decline in Alu methylation was linear and highly correlated with time since the first measurement (β=−.089 %5mC/year, p<0.0001). In contrast, average LINE-1 methylation did not vary over time [p=0.51]. Our results demonstrate a progressive loss of DNA methylation in repetitive elements dispersed throughout the genome.
Inflammation and endothelial dysfunction are important risk factors for cardiovascular disease (CVD). We hypothesized that candidate genes selected for a study of asthma and chronic obstructive pulmonary disorder (COPD) are associated with markers of systemic inflammation and endothelial dysfunction in an aging population.
Plasma levels of circulating C-reactive protein (CRP), fibrinogen, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) were obtained from 679 elderly male participants in the Normative Aging Study. Blood samples were analyzed for 202 SNPs in 25 candidate genes and included both haplotype tagSNPs and functional SNPs based on literature review. Data were stratified into discovery and replication cohorts for 2-stage analysis. In the discovery cohort, the relationship between biomarker level and genotype was analyzed using linear mixed effects with random intercepts for each subject and models were adjusted for age and BMI. A positive outcome in the discovery cohort was defined as a p-value <0.1 for the SNP. SNPs that met this criterion were analyzed in the replication cohort and confirmed for those which met a criterion of significance (p<0.025).
In our analyses, SNPs in the CRHR1, ITPR2, and VDR genes met criteria of significant effects.
Our results suggest that genes thought to play a role in the pathogenesis of asthma and COPD may influence levels of serum markers of inflammation and endothelial dysfunction via novel SNP associations which have not previously been associated with cardiovascular disease.
biomarkers; cardiovascular disease; SNPs; inflammation; endothelial dysfunction
Blood lead concentration has been associated with mortality from different causes in several studies. Many effects of lead exposure that might increase risk of death are likely to result from cumulative exposure, for which bone lead is a better biomarker than blood lead. The association between bone lead levels and mortality has not been explored.
Methods and Results
We prospectively assessed the association between both blood lead and bone lead—analyzed using K-x-ray fluorescence—and mortality among 868 men in the Normative Aging Study. We identified 241 deaths over an average of 8.9 (sd=3.9) years of follow-up. We calculated adjusted hazard ratios (HR) and 95% confidence intervals (CI) using Cox proportional hazards. Compared to the lowest tertile of patella bone lead, the fully adjusted HR in the highest tertile for all cause and cardiovascular mortality (n=137 deaths) were 2.52 (95% CI: 1.17–5.41) and 5.63 (95% CI: 1.73–18.3), respectively. The age, smoking, and race-adjusted HR for ischemic heart disease mortality (n=62 deaths) in the highest tertile was 8.37 (95% CI: 1.29–54.4). Results were similar for tibia lead. Bone lead was not associated with cancer, and blood lead was not associated with any mortality category.
We found bone lead to be associated with all-cause and cardiovascular mortality in an environmentally-exposed population with low blood lead levels. This study suggests that cumulative lead exposure from prior decades of high environmental exposures continues to significantly impact risk of death despite recent declines in environmental lead exposure.
cardiovascular diseases; epidemiology; mortality; population; bone lead
High-level arsenic exposure is consistently associated with QT prolongation, a risk factor for arrhythmia and sudden cardiac death. Arsenic may act on QT by increasing cardiac calcium currents. The authors hypothesized that low-level arsenic exposure would be associated with QT duration and that this effect would be stronger among persons not using calcium channel blockers. They performed a cross-sectional analysis in elderly men from the Normative Aging Study to analyze associations between toenail arsenic and QT and heart rate-corrected QT (QTc) durations and to examine effect modification by calcium channel blocker use, using linear regression and adjusting for potential confounders. Participants were examined in Boston, Massachusetts, between 2000 and 2002 or in 2006. An interquartile range increase in arsenic concentration was associated with a 3.8-millisecond increase in QT (95% confidence interval: 0.82, 6.8) and a 2.5-millisecond increase in QTc (95% confidence interval: 0.11, 4.9). There was no evidence of effect modification by medication use for either QT (P = 0.93) or QTc (P = 0.58). The authors observed positive associations between a biomarker of arsenic exposure and QT duration but found no evidence of effect modification by calcium channel blocker use, possibly because of modest power.
antioxidants; arrhythmias, cardiac; arsenic; calcium channel blockers; cardiovascular diseases; environmental health; long QT syndrome
Chronic obstructive pulmonary disease (COPD) is a heterogeneous syndrome, including emphysema and airway disease. Phenotypes defined on the basis of chest computed tomography (CT) may decrease disease heterogeneity and aid in the identification of candidate genes for COPD subtypes. To identify these genes, we performed genome-wide linkage analysis in extended pedigrees from the Boston Early-Onset COPD Study, stratified by emphysema status (defined by chest CT scans) of the probands, followed by genetic association analysis of positional candidate genes. A region on chromosome 1p showed strong evidence of linkage to lung function traits in families of emphysema-predominant probands in the stratified analysis (LOD score = 2.99 in families of emphysema-predominant probands versus 1.98 in all families). Association analysis in 949 individuals from 127 early-onset COPD pedigrees revealed association for COPD-related traits with an intronic single-nucleotide polymorphism (SNP) in transforming growth factor-β receptor-3 (TGFBR3) (P = 0.005). This SNP was significantly associated with COPD affection status comparing 389 cases from the National Emphysema Treatment Trial to 472 control smokers (P = 0.04), and with FEV1 (P = 0.004) and CT emphysema (P = 0.05) in 3,117 subjects from the International COPD Genetics Network. Gene-level replication of association with lung function was seen in 427 patients with COPD from the Lung Health Study. In conclusion, stratified linkage analysis followed by association testing identified TGFBR3 (betaglycan) as a potential susceptibility gene for COPD. Published human microarray and murine linkage studies have also demonstrated the importance of TGFBR3 in emphysema and lung function, and our group and others have previously found association of COPD-related traits with TGFB1, a ligand for TGFBR3.
betaglycan; chronic obstructive pulmonary disease; computed tomography; linkage; single nucleotide polymorphism