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1.  Long-Term Exposure to Ambient Fine Particulate Matter and Renal Function in Older Men: The Veterans Administration Normative Aging Study 
Environmental Health Perspectives  2016;124(9):1353-1360.
It is unknown if ambient fine particulate matter (PM2.5) is associated with lower renal function, a cardiovascular risk factor.
We investigated whether long-term PM2.5 exposure was associated with estimated glomerular filtration rate (eGFR) in a cohort of older men living in the Boston Metropolitan area.
This longitudinal analysis included 669 participants from the Veterans Administration Normative Aging Study with up to four visits between 2000 and 2011 (n = 1,715 visits). Serum creatinine was measured at each visit, and eGFR was calculated according to the Chronic Kidney Disease Epidemiology Collaboration equation. One-year exposure to PM2.5 prior to each visit was assessed using a validated spatiotemporal model that utilized satellite remote-sensing aerosol optical depth data. eGFR was modeled in a time-varying linear mixed-effects regression model as a continuous function of 1-year PM2.5, adjusting for important covariates.
One-year PM2.5 exposure was associated with lower eGFRs; a 2.1-μg/m3 interquartile range higher 1-year PM2.5 was associated with a 1.87 mL/min/1.73 m2 lower eGFR [95% confidence interval (CI): –2.99, –0.76]. A 2.1 μg/m3-higher 1-year PM2.5 was also associated with an additional annual decrease in eGFR of 0.60 mL/min/1.73 m2 per year (95% CI: –0.79, –0.40).
In this longitudinal sample of older men, the findings supported the hypothesis that long-term PM2.5 exposure negatively affects renal function and increases renal function decline.
Mehta AJ, Zanobetti A, Bind MC, Kloog I, Koutrakis P, Sparrow D, Vokonas PS, Schwartz JD. 2016. Long-term exposure to ambient fine particulate matter and renal function in older men: the VA Normative Aging Study. Environ Health Perspect 124:1353–1360;
PMCID: PMC5010417  PMID: 26955062
2.  Lead-Related Genetic Loci, Cumulative Lead Exposure and Incident Coronary Heart Disease: The Normative Aging Study 
PLoS ONE  2016;11(9):e0161472.
Cumulative exposure to lead is associated with cardiovascular outcomes. Polymorphisms in the δ-aminolevulinic acid dehydratase (ALAD), hemochromatosis (HFE), heme oxygenase-1 (HMOX1), vitamin D receptor (VDR), glutathione S-transferase (GST) supergene family (GSTP1, GSTT1, GSTM1), apolipoprotein E (APOE),angiotensin II receptor-1 (AGTR1) and angiotensinogen (AGT) genes, are believed to alter toxicokinetics and/or toxicodynamics of lead.
We assessed possible effect modification by genetic polymorphisms in ALAD, HFE, HMOX1, VDR, GSTP1, GSTT1, GSTM1, APOE, AGTR1 and AGT individually and as the genetic risk score (GRS) on the association between cumulative lead exposure and incident coronary heart disease (CHD) events.
We used K-shell-X-ray fluorescence to measure bone lead levels. GRS was calculated on the basis of 22 lead-related loci. We constructed Cox proportional hazard models to compute adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for incident CHD. We applied inverse probability weighting to account for potential selection bias due to recruitment into the bone lead sub-study.
Significant effect modification was found by VDR, HMOX1, GSTP1, APOE, and AGT genetic polymorphisms when evaluated individually. Further, the bone lead-CHD associations became larger as GRS increases. After adjusting for potential confounders, a HR of CHD was 2.27 (95%CI: 1.50–3.42) with 2-fold increase in patella lead levels, among participants in the top tertile of GRS. We also detected an increasing trend in HRs across tertiles of GRS (p-trend = 0.0063).
Our findings suggest that lead-related loci as a whole may play an important role in susceptibility to lead-related CHD risk. These findings need to be validated in a separate cohort containing bone lead, lead-related genetic loci and incident CHD data.
PMCID: PMC5008632  PMID: 27584680
3.  Genome-Wide Association Study Identification of Novel Loci Associated with Airway Responsiveness in Chronic Obstructive Pulmonary Disease 
Increased airway responsiveness is linked to lung function decline and mortality in subjects with chronic obstructive pulmonary disease (COPD); however, the genetic contribution to airway responsiveness remains largely unknown. A genome-wide association study (GWAS) was performed using the Illumina (San Diego, CA) Human660W-Quad BeadChip on European Americans with COPD from the Lung Health Study. Linear regression models with correlated meta-analyses, including data from baseline (n = 2,814) and Year 5 (n = 2,657), were used to test for common genetic variants associated with airway responsiveness. Genotypic imputation was performed using reference 1000 Genomes Project data. Expression quantitative trait loci (eQTL) analyses in lung tissues were assessed for the top 10 markers identified, and immunohistochemistry assays assessed protein staining for SGCD and MYH15. Four genes were identified within the top 10 associations with airway responsiveness. Markers on chromosome 9p21.2 flanked by LINGO2 met a predetermined threshold of genome-wide significance (P < 9.57 × 10−8). Markers on chromosomes 3q13.1 (flanked by MYH15), 5q33 (SGCD), and 6q21 (PDSS2) yielded suggestive evidence of association (9.57 × 10−8 < P ≤ 4.6 × 10−6). Gene expression studies in lung tissue showed single nucleotide polymorphisms on chromosomes 5 and 3 to act as eQTL for SGCD (P = 2.57 × 10−9) and MYH15 (P = 1.62 × 10−6), respectively. Immunohistochemistry confirmed localization of SGCD protein to airway smooth muscle and vessels and MYH15 to airway epithelium, vascular endothelium, and inflammatory cells. We identified novel loci associated with airway responsiveness in a GWAS among smokers with COPD. Risk alleles on chromosomes 5 and 3 acted as eQTLs for SGCD and MYH15 messenger RNA, and these proteins were expressed in lung cells relevant to the development of airway responsiveness.
PMCID: PMC4566043  PMID: 25514360
COPD; airway reactivity; bronchial responsiveness; eQTL; δ-sarcoglycan
4.  Cumulative lead exposure is associated with reduced olfactory recognition performance in elderly men: the Normative Aging Study 
Neurotoxicology  2015;49:158-164.
Olfactory dysfunction has been identified as an early warning sign for Alzheimer’s disease, Parkinson’s disease, dementia and more. A few occupational and environmental exposures have also been associated with reduced olfactory function, although the effects of long term environmental exposure to lead on olfactory dysfunction have not been explored. Here we performed olfactory recognition testing in elderly men in a community-dwelling cohort and examined the association with cumulative lead exposure, as assessed by lead in tibial and patellar bone.
Olfactory recognition was measured in 165 men from the Normative Aging Study (NAS) who had previously taken part in bone lead measurements using K-X-Ray fluorescence (KXRF). Olfactory recognition was measured using the University of Pennsylvania Smell Identification Test (UPSIT). Associations between olfactory recognition, global cognition and cumulative lead exposure were estimated using linear regression, with additional adjustment for age, smoking, and functional polymorphism status for hemochromatosis (HFE), transferrin (TfC2), glutathione-s-transferase Pi1 (GSTP1) and apolipoprotein E (APOE) genotypes. Sensitivity analyses explored olfactory recognition in men with high global cognitive function as measured using the Mini-Mental Status Exam (MMSE).
The average age of the NAS participants at the time of olfactory recognition testing was 80.3 (standard deviation or SD = 5.7) years. Mean tibia lead was 16.3 (SD = 12.0) μg/g bone, mean patella lead was 22.4 (SD = 14.4) μg/g bone, and mean UPSIT score was 26.9 out of 40 (SD = 7.0). Consistent with previous findings, age at olfaction testing was negatively associated with UPSIT score. Tibia (but not patella) bone lead was negatively associated with olfaction recognition (per 15 μg/g tibia lead: β = −1.57; 95% CI: −2.93, −0.22; p = 0.02) in models adjusted for smoking and age. Additional adjustment for education did not significantly change results. Of all the genes explored, only the presence of one or more HFE variant alleles was significantly associated with olfaction recognition (HFE β = 2.26; 95% CI: 0.09, 4.43; p = 0.04). In a model containing the HFE term and a lead term, the tibia lead parameter estimate dropped by 21% (per 15 μg/g tibia lead: β = −1.25; 95% CI: −2.64, 0.14; p = 0.08) while the HFE term dropped 15% (β = 1.91; 95% CI: −0.28, 4.10; p=0.09). None of the other gene terms were associated with olfactory recognition in this cohort, nor were any gene-lead interaction terms significant. Additional sensitivity analysis in men with MMSE scores of 25 or higher (n = 149) showed a similar but slightly attenuated association between lead and olfactory recognition (per 15 μg/g tibia lead β = −1.39; 95% CI: −3.00, 0.22; p = 0.09)
Cumulative exposure to lead is associated with reduced olfactory recognition in a cohort of elderly men. The association was similar but not significant in men with better cognitive function as measured by the MMSE. Iron metabolism gene status may also affect olfactory function.
PMCID: PMC4523435  PMID: 26121922
Olfaction; aging; bone lead; HFE; ApoE; GSTP1
5.  Dietary anthocyanin intake and age-related decline in lung function: longitudinal findings from the VA Normative Aging Study123 
Background: It is unknown whether habitual intake of dietary flavonoids, known for their antioxidative and anti-inflammatory properties, affects longitudinal change in lung function.
Objective: We investigated whether different flavonoid subclasses present in the habitual diet were associated with beneficial changes in lung function over time in the elderly.
Design: This longitudinal analysis included 839 participants from the VA (Veterans Affairs) Normative Aging Study whose lung function [forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC)] was measured at 2 and up to 5 visits between 1992 and 2008 (n = 2623 measurements). Yearly average intake of major flavonoid subclasses (anthocyanins, flavanones, flavan-3-ols, flavonols, flavones, and polymers) was calculated from food-frequency questionnaires at each visit. We estimated adjusted differences in annual change in lung function associated with each flavonoid subclass, categorized into quartiles, in linear mixed-effects regression models after adjustment for lifestyle and dietary confounders.
Results: Strong inverse associations were found between anthocyanin intake and age-related decline in lung function. Independent of dietary and nondietary risk factors, slower rates of FEV1 and FVC decline by 23.6 (95% CI: 16.6, 30.7) and 37.3 (95% CI: 27.8, 46.8) mL/y, respectively, were observed in participants in the fourth quartile of intake compared with participants in the first quartile (P-trend < 0.0001). The protective associations observed for anthocyanin intake were present in both current/former and never smokers. Compared with no or very low intakes, an intake of ≥2 servings of anthocyanin-rich blueberries/wk was associated with slower decline in FEV1 and FVC by 22.5 (95% CI: 10.8, 34.2) and 37.9 (95% CI: 22.1, 53.7) mL/y, respectively. To a lesser extent, higher flavan-3-ol intake was also associated with slower lung function decline.
Conclusions: An attenuation of age-related lung function decline was associated with higher dietary anthocyanin intake in this longitudinal sample of predominantly elderly men. Further prospective studies are needed to confirm these novel associations.
PMCID: PMC4733262  PMID: 26791184
anthocyanins; clinical epidemiology; diet; flavonoids; lung function tests
6.  Psychological factors and DNA methylation of genes related to immune/inflammatory system markers: the VA Normative Aging Study 
BMJ Open  2016;6(1):e009790.
Although psychological factors have been associated with chronic diseases such as coronary heart disease (CHD), the underlying pathways for these associations have yet to be elucidated. DNA methylation has been posited as a mechanism linking psychological factors to CHD risk. In a cohort of community-dwelling elderly men, we explored the associations between positive and negative psychological factors with DNA methylation in promoter regions of multiple genes involved in immune/inflammatory processes related to atherosclerosis.
Prospective cohort study.
Greater Boston, Massachusetts area.
Samples of 538 to 669 men participating in the Normative Aging Study cohort with psychological measures and DNA methylation measures, collected on 1–4 visits between 1999 and 2006 (mean age=72.7 years at first visit).
Outcome measures
We examined anxiety, depression, hostility and life satisfaction as predictors of leucocyte gene-specific DNA methylation. We estimated repeated measures linear mixed models, controlling for age, smoking, education, history of heart disease, stroke or diabetes, % lymphocytes, % monocytes and plasma folate.
Psychological distress measured by anxiety, depression and hostility was positively associated, and happiness and life satisfaction were inversely associated with average Intercellular Adhesion Molecule-1 (ICAM-1) and coagulation factor III (F3) promoter methylation levels. There was some evidence that hostility was positively associated with toll-like receptor 2 (TLR-2) promoter methylation, and that life satisfaction was inversely associated with TLR-2 and inducible nitric oxide synthase (iNOS) promoter methylation. We observed less consistent and significant associations between psychological factors and average methylation for promoters of the genes for glucocorticoid receptor (NR3C1), interferon-γ (IFN-γ) and interleukin 6 (IL-6).
These findings suggest that positive and negative psychological factors affect DNA methylation of selected genes involved in chronic immune/inflammatory processes and inflammation-related endothelial dysfunction. Such epigenetic changes may represent biological pathways that mediate the effects of psychological factors on CHD.
PMCID: PMC4716233  PMID: 26733571
psycholoogical factors; methylation
7.  Use of the Adaptive LASSO Method to Identify PM2.5 Components Associated with Blood Pressure in Elderly Men: The Veterans Affairs Normative Aging Study 
Environmental Health Perspectives  2015;124(1):120-125.
PM2.5 (particulate matter ≤ 2.5 μm) has been associated with adverse cardiovascular outcomes, but it is unclear whether specific PM2.5 components, particularly metals, may be responsible for cardiovascular effects.
We aimed to determine which PM2.5 components are associated with blood pressure in a longitudinal cohort.
We fit linear mixed-effects models with the adaptive LASSO penalty to longitudinal data from 718 elderly men in the Veterans Affairs Normative Aging Study, 1999–2010. We controlled for PM2.5 mass, age, body mass index, use of antihypertensive medication (ACE inhibitors, non-ophthalmic beta blockers, calcium channel blockers, diuretics, and angiotensin receptor antagonists), smoking status, alcohol intake, years of education, temperature, and season as fixed effects in the models, and additionally applied the adaptive LASSO method to select PM2.5 components associated with blood pressure. Final models were identified by the Bayesian Information Criterion (BIC).
For systolic blood pressure (SBP), nickel (Ni) and sodium (Na) were selected by the adaptive LASSO, whereas only Ni was selected for diastolic blood pressure (DBP). An interquartile range increase (2.5 ng/m3) in 7-day moving-average Ni was associated with 2.48-mmHg (95% CI: 1.45, 3.50 mmHg) increase in SBP and 2.22-mmHg (95% CI: 1.69, 2.75 mmHg) increase in DBP, respectively. Associations were comparable when the analysis was restricted to study visits with PM2.5 below the 75th percentile of the distribution (12 μg/m3).
Our study suggested that exposure to ambient Ni was associated with increased blood pressure independent of PM2.5 mass in our study population of elderly men. Further research is needed to confirm our findings, assess generalizability to other populations, and identify potential mechanisms for Ni effects.
Dai L, Koutrakis P, Coull BA, Sparrow D, Vokonas PS, Schwartz JD. 2016. Use of the adaptive LASSO method to identify PM2.5 components associated with blood pressure in elderly men: the Veterans Affairs Normative Aging Study. Environ Health Perspect 124:120–125;
PMCID: PMC4710598  PMID: 26090776
8.  Biased Exposure–Health Effect Estimates from Selection in Cohort Studies: Are Environmental Studies at Particular Risk? 
Environmental Health Perspectives  2015;123(11):1113-1122.
The process of creating a cohort or cohort substudy may induce misleading exposure–health effect associations through collider stratification bias (i.e., selection bias) or bias due to conditioning on an intermediate. Studies of environmental risk factors may be at particular risk.
We aimed to demonstrate how such biases of the exposure–health effect association arise and how one may mitigate them.
We used directed acyclic graphs and the example of bone lead and mortality (all-cause, cardiovascular, and ischemic heart disease) among 835 white men in the Normative Aging Study (NAS) to illustrate potential bias related to recruitment into the NAS and the bone lead substudy. We then applied methods (adjustment, restriction, and inverse probability of attrition weighting) to mitigate these biases in analyses using Cox proportional hazards models to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs).
Analyses adjusted for age at bone lead measurement, smoking, and education among all men found HRs (95% CI) for the highest versus lowest tertile of patella lead of 1.34 (0.90, 2.00), 1.46 (0.86, 2.48), and 2.01 (0.86, 4.68) for all-cause, cardiovascular, and ischemic heart disease mortality, respectively. After applying methods to mitigate the biases, the HR (95% CI) among the 637 men analyzed were 1.86 (1.12, 3.09), 2.47 (1.23, 4.96), and 5.20 (1.61, 16.8), respectively.
Careful attention to the underlying structure of the observed data is critical to identifying potential biases and methods to mitigate them. Understanding factors that influence initial study participation and study loss to follow-up is critical. Recruitment of population-based samples and enrolling participants at a younger age, before the potential onset of exposure-related health effects, can help reduce these potential pitfalls.
Weisskopf MG, Sparrow D, Hu H, Power MC. 2015. Biased exposure–health effect estimates from selection in cohort studies: are environmental studies at particular risk? Environ Health Perspect 123:1113–1122;
PMCID: PMC4629739  PMID: 25956004
9.  Long-Term Effects of Traffic Particles on Lung Function Decline in the Elderly 
Rationale: Few studies have been performed on air pollution effects on lung function in the elderly, a vulnerable population with low reserve capacity, and even fewer have looked at changes in the rate of lung function decline.
Objectives: We evaluated the effect of long-term exposure to black carbon on levels and rates of decline in lung function in the elderly.
Methods: FVC and FEV1 were measured one to six times during the period 1995–2011 in 858 men participating in the Normative Aging Study. Exposure to black carbon, a tracer of traffic emissions, was estimated by a spatiotemporal land use regression model. We investigated the effects of moving averages of black carbon of 1–5 years before the lung function measurement using linear mixed models.
Measurements and Main Results: A 0.5 μg/m3 increase in long-term exposure to black carbon was associated with an additional rate of decline in FVC and FEV1 of between 0.5% and 0.9% per year, respectively, depending on the averaging time. In addition, black carbon exposure before the baseline visit was associated with lower levels of both FVC and FEV1, with effect estimates increasing up to 6–7% with a 5-year average exposure.
Conclusions: Our results support adverse effects of long-term exposure to traffic particles on lung function level and rate of decline in the elderly and suggest that functionally significant differences in health and risk of disability occur below the annual Environmental Protection Agency National Air Quality Standards.
PMCID: PMC4214085  PMID: 25028775
air pollution; black carbon; FEV1
10.  The effect of oxidative stress polymorphisms on the association between long-term black carbon exposure and lung function among elderly men 
Thorax  2014;70(2):133-137.
Black carbon (BC) is a pro-oxidant, traffic-related pollutant linked with lung function decline. We evaluated the influence of genetic variation in the oxidative stress pathway on the association between long-term BC exposure and lung function decline.
Lung function parameters (FVC and FEV1) were measured during one or more study visits between 1995 and 2011 (n=651 participants) among an elderly cohort: the Normative Aging Study. Residential BC exposure levels were estimated using a spatiotemporal land use regression model. We evaluated whether oxidative stress variants, combined into a genetic score, modify the association between 1-year and 5-year moving averages of BC exposure and lung function levels and rates of decline, using linear mixed models.
We report stronger associations between long-term BC exposure and increased rate of lung function decline, but not baseline lung function level, among participants with higher oxidative stress allelic risk profiles compared with participants with lower risk profiles. Associations were strongest when evaluating 5-year moving averages of BC exposure. A 0.5 μg/m3 increase in 5-year BC exposure was associated with a 0.1% yearly increase in FVC (95% CI −0.5 to 0.7) among participants with low genetic risk scores and a 1.3% yearly decrease (95% CI −1.8 to −0.8) among those with high scores (p-interaction=0.0003).
Our results suggest that elderly men with high oxidative stress genetic scores may be more susceptible to the effects of BC on lung function decline. The results, if confirmed, should inform air-quality recommendations in light of a potentially susceptible subgroup.
PMCID: PMC4509588  PMID: 25414198
11.  Variants of Asthma and Chronic Obstructive Pulmonary Disease Genes and Lung Function Decline in Aging 
A substantial proportion of the general population has low lung function, and lung function is known to decrease as we age. Low lung function is a feature of several pulmonary disorders, such as uncontrolled asthma and chronic obstructive pulmonary disease. The objective of this study is to investigate the association of polymorphisms in asthma and chronic obstructive pulmonary disease candidate genes with rates of lung function decline in a general population sample of aging men.
We analyzed data from a cohort of 1,047 Caucasian men without known lung disease, who had a mean of 25 years of lung function data, and on whom DNA was available. The cohort was randomly divided into two groups, and we tested a total of 940 single-nucleotide polymorphisms in 44 asthma and chronic obstructive pulmonary disease candidate genes in the first group (testing cohort, n = 545) for association with change in forced expiratory volume in 1 second over time.
One hundred nineteen single-nucleotide polymorphisms that showed nominal associations in the testing cohort were then genotyped and tested in the second group (replication cohort, n = 502). Evidence for association from the testing and replication cohorts were combined, and after adjustment for multiple testing, seven variants of three genes (DPP10, NPSR1, and ADAM33) remained significantly associated with change in forced expiratory volume in 1 second over time.
Our findings that genetic variants of genes involved in asthma and chronic obstructive pulmonary disease are associated with lung function decline in normal aging participants suggest that similar genetic mechanisms may underlie lung function decline in both disease and normal aging processes.
PMCID: PMC4111635  PMID: 24253534
Genetics; Pulmonary; Normative aging; Successful aging.
12.  Relationship between Outdoor Temperature and Blood Pressure 
Cardiovascular mortality has been linked to changes in outdoor temperature. However, the mechanisms behind these effects are not well established. We aimed to study the effect of outdoor temperature on blood pressure (BP), as increased BP is a risk factor of cardiovascular deaths.
The study population consisted of men aged 53–100 years living in the Boston area. We used a mixed effects model to estimate the effect of three temperature variables: ambient, apparent, and dew point temperature (DPT), on repeated measures (every 3–5 years) of diastolic and systolic blood pressure. Random intercepts for subjects and several possible confounders were used in the models, including black carbon (BC) and barometric pressure.
We found modest associations between diastolic BP and ambient temperature, and apparent temperature. In the basic models, increases in diastolic BP in association with a 5°C decrease in 7-day moving averages of temperatures were 1.01% (95% CI: −0.06 – 2.09), and 1.55% (95%, CI: 0.61 – 2.49) for ambient and apparent temperature, respectively. Excluding extreme temperatures made these associations stronger (2.13%, 95% CI: 0.66 – 3.63, and 1.65%, 95% CI: 0.41 – 2.90, for ambient and apparent temperature, respectively). Effect estimates for dew point temperature were close to null. The effect of apparent temperature on systolic BP was similar (1.30% increase (95% CI: 0.32 – 2.29) for a 5°C decrease in 7-day moving average).
Cumulative exposure to decreasing ambient and apparent temperature may increase BP. These findings suggest that increase in BP could be a mechanism behind cold-, but not heat-related cardiovascular mortality.
PMCID: PMC4437584  PMID: 20864465
Cardiovascular; Blood pressure; Climate; Epidemiology; Temperature
13.  Outdoor temperature is associated with serum HDL and LDL 
Environmental research  2010;111(2):281-287.
While exposures to high and low air temperatures are associated with cardiovascular mortality, the underlying mechanisms are poorly understood. The risk factors for cardiovascular disease include high levels of total cholesterol and low-density lipoprotein (LDL), and low levels of high-density lipoprotein (HDL). We investigated whether temperature was associated with changes in circulating lipid levels, and whether this might explain part of the association with increased cardiovascular events.
The study cohort consisted of 478 men in the greater Boston area with a mean age of 74.2 years. They visited the clinic every 3–5 years between 1995–2008 for physical examination and to complete questionnaires. We excluded from analyses all men taking statin medication and all days with missing data, resulting in a total of 862 visits. Associations between three temperature variables (ambient, apparent, and dew point temperature) and serum lipid levels (total cholesterol, HDL, LDL, and triglycerides) were studied with linear mixed models that included possible confounders such as air pollution and a random intercept for each subject.
We found that HDL decreased −1.76% (95% CI: −3.17 – −0.32, lag 2 days), and −5.58% (95% CI: −8.87 – −2.16, moving average of 4 weeks) for each 5°C increase in mean ambient temperature. For the same increase in mean ambient temperature, LDL increased by 1.74% (95% CI: 0.07 – 3.44, lag 1 day) and 1.87% (95% CI: 0.14 – 3.63, lag 2 days). These results were also similar for apparent and dew point temperatures. No changes were found in total cholesterol or triglycerides in relation to temperature increase.
Changes in HDL and LDL levels associated with an increase in ambient temperature may be among the underlying mechanisms of temperature-related cardiovascular mortality.
PMCID: PMC4437587  PMID: 21172696
cardiovascular; cholesterol; cohort; high-density lipoprotein; low-density lipoprotein; temperature
14.  Lead Exposure and Tremor among Older Men: The VA Normative Aging Study 
Environmental Health Perspectives  2015;123(5):445-450.
Background: Tremor is one of the most common neurological signs, yet its etiology is poorly understood. Case–control studies suggest an association between blood lead and essential tremor, and that this association is modified by polymorphisms in the δ-aminolevulinic acid dehydrogenase (ALAD) gene.
Objective: We aimed to examine the relationship between lead and tremor, including modification by ALAD, in a prospective cohort study, using both blood lead and bone lead—a biomarker of cumulative lead exposure.
Methods: We measured tibia (n = 670) and patella (n = 672) bone lead and blood lead (n = 807) among older men (age range, 50–98 years) in the VA Normative Aging Study cohort. A tremor score was created based on an approach using hand-drawing samples. ALAD genotype was dichotomized as ALAD-2 carriers or not. We used linear regression adjusted for age, education, smoking, and alcohol intake to estimate the associations between lead biomarkers and tremor score.
Results: In unadjusted analyses, there was a marginal association between quintiles of all lead biomarkers and tremor scores (p-values < 0.13), which did not persist in adjusted models. Age was the strongest predictor of tremor. Among those younger than the median age (68.9 years), tremor increased significantly with blood lead (p = 0.03), but this pattern was not apparent for bone lead. We did not see modification by ALAD or an association between bone lead and change in tremor score over time.
Conclusion: Our results do not strongly support an association between lead exposure and tremor, and suggest no association with cumulative lead biomarkers, although there is some suggestion that blood lead may be associated with tremor among the younger men in our cohort.
Citation: Ji JS, Power MC, Sparrow D, Spiro A III, Hu H, Louis ED, Weisskopf MG. 2015. Lead exposure and tremor among older men: the VA Normative Aging Study. Environ Health Perspect 123:445–450;
PMCID: PMC4421770  PMID: 25633720
15.  Occupational Determinants of Cumulative Lead Exposure: Analysis of Bone Lead Among Men in the VA Normative Aging Study 
To examine the relation between occupation and cumulative lead exposure—assessed by measuring bone lead—in a community-dwelling population
We measured bone lead concentration with K-shell X-Ray Fluorescence in 1,320 men in the Normative Aging Study. We categorized job titles into 14 broad US Census Bureau categories. We used ordinary least squares regression to estimate bone lead by job categories adjusted for other predictors.
Service Workers, Construction and Extractive Craft Workers, and Installation, Maintenance and Repair Craft Workers had the highest bone lead concentrations. Including occupations significantly improved the overall model (p<0.001) and reduced by −15% to −81% the association between bone lead and education categories.
Occupation significantly predicts cumulative lead exposure in a community-dwelling population, and accounts for a large proportion of the association between education and bone lead.
PMCID: PMC3982188  PMID: 24709766
biomarker; bone lead; job exposure matrix; job title; occupation
16.  Pessimistic orientation in relation to telomere length in older men: the VA Normative Aging Study 
Psychoneuroendocrinology  2014;42:68-76.
Recent research suggests pessimistic orientation is associated with shorter leukocyte telomere length (LTL). However, this is the first study to look not only at effects of pessimistic orientation on average LTL at multiple time points, but also at effects on the rate of change in LTL over time.
Participants were older men from the VA Normative Aging Study (n=490). The Life Orientation Test (LOT) was used to measure optimistic and pessimistic orientations at study baseline, and relative LTL by telomere to single copy gene ratio (T:S ratio) was obtained repeatedly over the course of the study (1999-2008). A total of 1,010 observations were included in the analysis. Linear mixed effect models with a random subject intercept were used to estimate associations.
Higher pessimistic orientation scores were associated with shorter average LTL (percent difference by 1-SD increase in pessimistic orientation (95% CI): -3.08 (-5.62, -0.46)), and the finding was maintained after adjusting for the higher likelihood that healthier individuals return for follow-up visits (-3.44 (-5.95,-0.86)). However, pessimistic orientation scores were not associated with rate of change in LTL over time. No associations were found between overall optimism and optimistic orientation subscale scores and LTL.
Higher pessimistic orientation scores were associated with shorter LTL in older men. While there was no evidence that pessimistic orientation was associated with rate of change in LTL over time, higher levels of pessimistic orientation were associated with shorter LTL at baseline and this association persisted over time.
PMCID: PMC4070424  PMID: 24636503
Optimism; Pessimism; Telomere length
17.  Associations between arrhythmia episodes and temporally and spatially resolved black carbon and particulate matter in elderly patients 
Ambient air pollution has been associated with sudden deaths, some of which are likely due to ventricular arrhythmias. Defibrillator discharge studies have examined the association of air pollution with arrhythmias in sensitive populations. No studies have assessed this association using residence-specific estimates of air pollution exposure.
In the Normative Aging Study, we investigated the association between temporally-and spatially-resolved black carbon (BC) and PM2.5 and arrhythmia episodes (bigeminy, trigeminy or couplets episodes) measured as ventricular ectopy (VE) by 4-min electrocardiogram (ECG) monitoring in repeated measures of 701 subjects, during the years 2000 to 2010.
We used a binomial distribution (having or not a VE episode) in a mixed effect model with a random intercept for subject, controlling for seasonality, temperature, day of the week, medication use, smoking, having diabetes, BMI and age. We also examined whether these associations were modified by genotype or phenotype.
We found significant increases in VE with both pollutants and lags; for the estimated concentration averaged over the three days prior to the health assessment we found increases in the odds of having VE with an OR of 1.52 (95% CI: 1.19–1.94) for an IQR (0.30 μg/m3) increase in BC and an OR of 1.39 (95% CI: 1.12–1.71) for an IQR (5.63 μg/m3) increase in PM2.5. We also found higher effects in subjects with the GSTT1 and GSTM1 variants and in obese (P-values<0.05).
Increased levels of short-term traffic related pollutants may increase the risk of ventricular arrhythmia in elderly subjects.
PMCID: PMC4371778  PMID: 24142987
arrhythmia episodes; spatially-resolved black carbon and particulate matter; traffic pollution; elderly
18.  Risk loci for chronic obstructive pulmonary disease: a genome-wide association study and meta-analysis 
The Lancet. Respiratory medicine  2014;2(3):214-225.
The genetic risk factors for susceptibility to chronic obstructive pulmonary disease (COPD) are still largely unknown. Additional genetic variants are likely to be identified by genome-wide association studies in larger cohorts or specific subgroups.
Genome-wide association analysis in COPDGene (non-Hispanic whites and African-Americans) was combined with existing data from the ECLIPSE, NETT/NAS, and GenKOLS (Norway) studies. Analyses were performed both using all moderate-to-severe cases and the subset of severe cases. Top loci not previously described as genome-wide significant were genotyped in the ICGN study, and results combined in a joint meta-analysis.
Analysis of a total of 6,633 moderate-to-severe cases and 5,704 controls confirmed association at three known loci: CHRNA3/CHRNA5/IREB2, FAM13A, and HHIP (10−12 < P < 10−14), and also showed significant evidence of association at a novel locus near RIN3 (overall P, including ICGN = 5•4×10−9). In the severe COPD analysis (n=3,497), the effects at two of three previously described loci were significantly stronger; we also identified two additional loci previously reported to affect gene expression of MMP12 and TGFB2 (overall P = 2•6x10−9 and 8•3×10−9). RIN3 and TGFB2 expression levels were reduced in a set of Lung Tissue Research Consortium COPD lung tissue samples compared with controls.
In a genome-wide study of COPD, we confirmed associations at three known loci and found additional genome-wide significant associations with moderate-to-severe COPD near RIN3 and with severe COPD near MMP12 and TGFB2. Genetic variants, apart from alpha-1 antitrypsin deficiency, increase the risk of COPD. Our analysis of severe COPD suggests additional genetic variants may be identified by focusing on this subgroup.
National Heart, Lung, and Blood Institute; the COPD Foundation through contributions from AstraZeneca, Boehringer Ingelheim, Novartis, and Sepracor; GlaxoSmithKline; Centers for Medicare and Medicaid Services; Agency for Healthcare Research and Quality; US Department of Veterans Affairs.
PMCID: PMC4176924  PMID: 24621683
19.  Associations between air pollution and perceived stress: the Veterans Administration Normative Aging Study 
Environmental Health  2015;14:10.
There is mixed evidence suggesting that air pollution may be associated with increased risk of developing psychiatric disorders. We aimed to investigate the association between air pollution and non-specific perceived stress, often a precursor to development of affective psychiatric disorders.
This longitudinal analysis consisted of 987 older men participating in at least one visit for the Veterans Administration Normative Aging Study between 1995 and 2007 (n = 2,244 visits). At each visit, participants were administered the 14-item Perceived Stress Scale (PSS), which quantifies stress experienced in the previous week. Scores ranged from 0–56 with higher scores indicating increased stress. Differences in PSS score per interquartile range increase in moving average (1, 2, and 4-weeks) of air pollution exposures were estimated using linear mixed-effects regression after adjustment for age, race, education, physical activity, anti-depressant medication use, seasonality, meteorology, and day of week. We also evaluated effect modification by season (April-September and March-October for warm and cold season, respectively).
Fine particles (PM2.5), black carbon (BC), nitrogen dioxide, and particle number counts (PNC) at moving averages of 1, 2, and 4-weeks were associated with higher perceived stress ratings. The strongest associations were observed for PNC; for example, a 15,997 counts/cm3 interquartile range increase in 1-week average PNC was associated with a 3.2 point (95%CI: 2.1-4.3) increase in PSS score. Season modified the associations for specific pollutants; higher PSS scores in association with PM2.5, BC, and sulfate were observed mainly in colder months.
Air pollution was associated with higher levels of perceived stress in this sample of older men, particularly in colder months for specific pollutants.
Electronic supplementary material
The online version of this article (doi:10.1186/1476-069X-14-10) contains supplementary material, which is available to authorized users.
PMCID: PMC4417295  PMID: 25627872
Aged; Air pollution; Male; Particulate matter; Prospective studies; Stress; Psychological
20.  Associations Between Short-term Changes in Air Pollution and Correlates of Arterial Stiffness: The Veterans Affairs Normative Aging Study, 2007–2011 
American Journal of Epidemiology  2013;179(2):192-199.
We investigated associations between short-term exposure to air pollution and central augmentation index and augmentation pressure, correlates of arterial stiffness, in a cohort of elderly men in the Boston, Massachusetts, metropolitan area. This longitudinal analysis included 370 participants from the Veterans Affairs Normative Aging Study with up to 2 visits between 2007 and 2011 (n = 445). Augmentation index (as %) and augmentation pressure (in mmHg) were measured at each visit by using radial artery applanation tonometry for pulse wave analysis and modeled in a mixed effects regression model as continuous functions of moving averages of air pollution exposures (over 4 hours and 1, 3, 7, and 14 days). The results suggest that short-term changes in air pollution were associated with augmentation index and augmentation pressure at several moving averages. Interquartile range (IQR) increases in 3-day average exposure to particles with aerodynamic diameter less than 2.5 μm (3.6-μg/m3 IQR increase) and sulfate (1.4-μg/m3 IQR increase) and 1-day average exposure to particle number counts (8,741-counts/cm3 IQR increase) were associated with augmentation index values that were 0.8% (95% confidence interval (CI): 0.2, 1.4), 0.6% (95% CI: 0.1, 1.2), and 1.7% (95% CI: 0.4, 2.9) higher, respectively. Overall, the findings were similar for augmentation pressure. The findings support the hypothesis that exposure to air pollution may affect vascular function.
PMCID: PMC3873113  PMID: 24227017
air pollution; particulate matter; pulse wave analysis
21.  Effect modification by vitamin D receptor genetic polymorphisms in the association between cumulative lead exposure and pulse pressure: a longitudinal study 
Environmental Health  2015;14:5.
Although the association between lead and cardiovascular disease is well established, potential mechanisms are still poorly understood. Calcium metabolism plays a role in lead toxicity and thus, vitamin D receptor (VDR) polymorphisms have been suggested to modulate the association between lead and health outcomes. We investigated effect modification by VDR genetic polymorphisms in the association between cumulative lead exposure and pulse pressure, a marker of arterial stiffness.
We examined 727 participants (3,100 observations from follow-ups from 1991 to 2011) from the Normative Aging Study (NAS), a longitudinal study of aging. Tibia and patella bone lead levels were measured using K-x-ray fluorescence. Four single nucleotide polymorphisms (SNPs) in the VDR gene, Bsm1, Taq1, Apa1, and Fok1, were genotyped. Linear mixed effects models with random intercepts were implemented to take into account repeated measurements.
Adjusting for potential confounders, pulse pressure was 2.5 mmHg (95% CI: 0.4-4.7) and 1.9 mmHg (95% CI: 0.1-3.8) greater per interquartile range (IQR) increase in tibia lead (15 μg/g) and patella lead (20 μg/g), respectively, in those with at least one minor frequency allele in Bsm1 compared with those with major frequency allele homozygotes. The observed interaction effect between bone lead and the Bsm1 genotype persists over time during the follow-up. Similar results were observed in effect modification by Taq1.
This study suggests that subjects with the minor frequency alleles of VDR Bsm1 or Taq1 may be more susceptible to cumulative lead exposure-related elevated pulse pressure.
Electronic supplementary material
The online version of this article (doi:10.1186/1476-069X-14-5) contains supplementary material, which is available to authorized users.
PMCID: PMC4417283  PMID: 25582168
Lead; Vitamin D receptor; Gene by environmental interaction; A longitudinal study
22.  Cardiac Autonomic Dysfunction: Particulate Air Pollution Effects Are Modulated by Epigenetic Immunoregulation of Toll‐like Receptor 2 and Dietary Flavonoid Intake 
Short‐term fine particles (PM2.5) exposure is associated with reduced heart rate variability, a strong predictor of cardiac mortality among older people. Identifying modifiable factors that confer susceptibility is essential for intervention. We evaluated whether Toll‐like receptor 2 (TLR2) methylation, a reversible immune‐epigenetic process, and its dietary modulation by flavonoids and methyl nutrients, modify susceptibility to heart rate variability effects following PM2.5 exposure.
Methods and Results
We measured heart rate variability and PM2.5 repeatedly over 11 years (1275 total observations) among 573 elderly men from the Normative Aging Study. Blood TLR2 methylation was analyzed using pyrosequencing. Daily flavonoid and methyl nutrients intakes were assessed through the Food Frequency Questionnaire (FFQ). Every 10 μg/m3 increase in 48‐hour PM2.5 moving average was associated with 7.74% (95% CI: −1.21% to 15.90%; P=0.09), 7.46% (95% CI: 0.99% to 13.50%; P=0.02), 14.18% (95% CI: 1.14% to 25.49%; P=0.03), and 12.94% (95% CI: −2.36% to 25.96%; P=0.09) reductions in root mean square of successive differences, standard deviation of normal‐to‐normal intervals, low‐frequency power, and high‐frequency power, respectively. Higher TLR2 methylation exacerbated the root mean square of successive differences, standard deviation of normal‐to‐normal intervals, low‐frequency, and high‐frequency reductions associated with heightened PM2.5 (Pinteraction=0.006, 0.03, 0.05, 0.04, respectively). Every interquartile‐range increase in flavonoid intake was associated with 5.09% reduction in mean TLR2 methylation (95% CI: 0.12% to 10.06%; P=0.05) and counteracted the effects of PM2.5 on low frequency (Pinteraction=0.05). No significant effect of methyl nutrients on TLR2 methylation was observed.
Higher TLR2 methylation may confer susceptibility to adverse cardiac autonomic effects of PM2.5 exposure in older individuals. Higher flavonoid intake may attenuate these effects, possibly by decreasing TLR2 methylation.
PMCID: PMC4330067  PMID: 25628407
epidemiology; epigenetics; heart rate variability; inflammation; nutrition
23.  Modifying roles of glutathione S-transferase polymorphisms on the association between cumulative lead exposure and cognitive function 
Neurotoxicology  2013;0:10.1016/j.neuro.2013.08.002.
Glutathione-S-transferase gene (GST) polymorphisms can result in variable ability of these enzymes to remove electrophilic substrates. We investigated whether the GSTP1 Val105 and GSTM1 deletion polymorphisms modify the lead-cognitive function association.
We used repeated measures analysis to compare the association between cumulative lead biomarkers—bone lead measured using K-shell X-Ray Fluorescence—and Mini-Mental State Exam (MMSE) score by GST variants, adjusted for covariates, among Normative Aging Study participants, a Boston-based prospective cohort of men. We had complete data for 698 men (providing 1292 observations) for GSTM1 analyses and 595 men (providing 1142 observations) for GSTP1 analyses.
A 15 μg/g higher tibia lead concentration (interquartile range of tibia lead) was associated with a 0.24 point decrement in MMSE score among GSTP1 Val105 variant carriers, which was significantly stronger than the association among men with only wild-type alleles (p=0.01). The association among GSTP1 Val105 carriers was comparable to that of 3 years of age in baseline MMSE scores. The association between tibia lead and MMSE score appeared progressively steeper in participants with increasingly more GSTP1 Val105 alleles. A modest association between tibia lead and lower MMSE score was seen among participants with the GSTM1 deletion polymorphism. Neither of the glutathione S-transferase variants was independently associated with cognitive function, nor with lead biomarker measures. The results pertaining to patella lead were similar to those observed for tibia lead.
Our results suggest that the GSTP1 Val105 polymorphism confers excess susceptibility to the cognitive effects of cumulative lead exposure.
PMCID: PMC3844089  PMID: 23958642
Lead; Glutathione S-transferase; Cognitive function; Environmental exposure; Gene-environment interaction
24.  Blood pressure and cognition:Factors that may account for their inconsistent association 
Epidemiology (Cambridge, Mass.)  2013;24(6):10.1097/EDE.0b013e3182a7121c.
Studies of hypertension and cognition variously report adverse, null and protective associations. We evaluated evidence supporting three potential explanations for this variation: an effect of hypertension duration, an effect of age at hypertension initiation, and selection bias due to dependent censoring.
The Normative Aging Study is a prospective cohort study of men in the greater Boston area. Participants completed study visits, including hypertension assessment, every 3-5 years starting in 1961. 758 of 1284 men eligible at baseline completed cognitive assessment between 1992 and 2005; we used the mean age-adjusted cognitive test z-score from their first assessment to quantify cognition. We estimated how becoming hypertensive and increasing age at onset and duration since hypertension initiation affect cognition. We used inverse probability of censoring weights to reduce and quantify selection bias.
A history of hypertension diagnosis predicted lower cognition. Increasing duration since hypertension initiation predicted lower mean cognitive z-score (-0.02 standard units per year increase [95% confidence interval= -0.04 to -0.001]), independent of age at onset. Comparing participants with and without hypertension, we observed noteworthy differences in mean cognitive score only for those with a long duration since hypertension initiation, regardless of age at onset. Age at onset was not associated with cognition independent of duration. Analyses designed to quantify selection bias suggested upward bias.
Previous findings of null or protective associations between hypertension and cognition likely reflect the study of persons with short duration since hypertension initiation. Selection bias may also contribute to cross-study heterogeneity.
PMCID: PMC3818218  PMID: 24030502
25.  Lead Exposure, B Vitamins, and Plasma Homocysteine in Men 55 Years of Age and Older: The VA Normative Aging Study 
Environmental Health Perspectives  2014;122(10):1066-1074.
Background: Lead (Pb) exposure may influence the plasma concentration of homocysteine, a one-carbon metabolite associated with cardiovascular and neurodegenerative diseases. Little is known about the associations between Pb and homocysteine over time, or the potential influence of dietary factors.
Objectives: We examined the longitudinal association of recent and cumulative Pb exposure with homocysteine concentrations and the potential modifying effect of dietary nutrients involved in one-carbon metabolism.
Methods: In a subcohort of the Veterans Affairs (VA) Normative Aging Study (1,056 men with 2,301 total observations between 1993 and 2011), we used mixed-effects models to estimate differences in repeated measures of total plasma homocysteine across concentrations of Pb in blood and tibia bone, assessing recent and cumulative Pb exposure, respectively. We also assessed effect modification by dietary intake and plasma concentrations of folate, vitamin B6, and vitamin B12.
Results: An interquartile range (IQR) increment in blood Pb (3 μg/dL) was associated with a 6.3% higher homocysteine concentration (95% CI: 4.8, 7.8%). An IQR increment in tibia bone Pb (14 μg/g) was associated with a 3.7% higher homocysteine (95% CI: 1.6, 5.6%), which was attenuated to 1.5% (95% CI: –0.5, 3.6%) after adjusting for blood Pb. For comparison, a 5-year increase in time from baseline was associated with a 5.7% increase in homocysteine (95% CI: 4.3, 7.1%). The association between blood Pb and homocysteine was significantly stronger among participants with estimated dietary intakes of vitamin B6 and folate below (vs. above) the study population medians, which were similar to the U.S. recommended dietary allowance intakes.
Conclusions: Pb exposure was positively associated with plasma homocysteine concentration. This association was stronger among men with below-median dietary intakes of vitamins B6 and folate. These findings suggest that increasing intake of folate and B6 might reduce Pb-associated increases in homocysteine, a risk factor for cardiovascular disease and neurodegeneration.
Citation: Bakulski KM, Park SK, Weisskopf MG, Tucker KL, Sparrow D, Spiro A III, Vokonas PS, Nie LH, Hu H, Weuve J. 2014. Lead exposure, B vitamins, and plasma homocysteine in men 55 years of age and older: the VA Normative Aging Study. Environ Health Perspect 122:1066–1074;
PMCID: PMC4181916  PMID: 24905780

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