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1.  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.
doi:10.1093/aje/kwt271
PMCID: PMC3873113  PMID: 24227017
air pollution; particulate matter; pulse wave analysis
2.  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.
Background
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.
Methods
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.
Results
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.
Conclusion
Our results suggest that the GSTP1 Val105 polymorphism confers excess susceptibility to the cognitive effects of cumulative lead exposure.
doi:10.1016/j.neuro.2013.08.002
PMCID: PMC3844089  PMID: 23958642
Lead; Glutathione S-transferase; Cognitive function; Environmental exposure; Gene-environment interaction
3.  Blood pressure and cognition:Factors that may account for their inconsistent association 
Epidemiology (Cambridge, Mass.)  2013;24(6):10.1097/EDE.0b013e3182a7121c.
Background
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1097/EDE.0b013e3182a7121c
PMCID: PMC3818218  PMID: 24030502
4.  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; http://dx.doi.org/10.1289/ehp.1306931
doi:10.1289/ehp.1306931
PMCID: PMC4181916  PMID: 24905780
5.  Associations between Changes in City and Address Specific Temperature and QT Interval - The VA Normative Aging Study 
PLoS ONE  2014;9(9):e106258.
Background
The underlying mechanisms of the association between ambient temperature and cardiovascular morbidity and mortality are not well understood, particularly for daily temperature variability. We evaluated if daily mean temperature and standard deviation of temperature was associated with heart rate-corrected QT interval (QTc) duration, a marker of ventricular repolarization in a prospective cohort of older men.
Methods
This longitudinal analysis included 487 older men participating in the VA Normative Aging Study with up to three visits between 2000–2008 (n = 743). We analyzed associations between QTc and moving averages (1–7, 14, 21, and 28 days) of the 24-hour mean and standard deviation of temperature as measured from a local weather monitor, and the 24-hour mean temperature estimated from a spatiotemporal prediction model, in time-varying linear mixed-effect regression. Effect modification by season, diabetes, coronary heart disease, obesity, and age was also evaluated.
Results
Higher mean temperature as measured from the local monitor, and estimated from the prediction model, was associated with longer QTc at moving averages of 21 and 28 days. Increased 24-hr standard deviation of temperature was associated with longer QTc at moving averages from 4 and up to 28 days; a 1.9°C interquartile range increase in 4-day moving average standard deviation of temperature was associated with a 2.8 msec (95%CI: 0.4, 5.2) longer QTc. Associations between 24-hr standard deviation of temperature and QTc were stronger in colder months, and in participants with diabetes and coronary heart disease.
Conclusion/Significance
In this sample of older men, elevated mean temperature was associated with longer QTc, and increased variability of temperature was associated with longer QTc, particularly during colder months and among individuals with diabetes and coronary heart disease. These findings may offer insight of an important underlying mechanism of temperature-related cardiovascular morbidity and mortality in an older population.
doi:10.1371/journal.pone.0106258
PMCID: PMC4169528  PMID: 25238150
6.  Lead Exposure and Fear-Potentiated Startle in the VA Normative Aging Study: A Pilot Study of a Novel Physiological Approach to Investigating Neurotoxicant Effects 
Background
Physiologically-based indicators of neural plasticity in humans could provide mechanistic insights into toxicant actions on learning in the brain, and perhaps prove more objective and sensitive measures of such effects than other methods.
Objectives
We explored the association between lead exposure and classical conditioning of the acoustic startle reflex (ASR)—a simple form of associative learning in the brain—in a population of elderly men. Fifty-one men from the VA Normative Aging Study with cumulative bone lead exposure measurements made with K-X-Ray-Fluorescence participated in a fear-conditioning protocol.
Results
The mean age of the men was 75.5 years (standard deviation [sd]=5.9) and mean patella lead concentration was 22.7μg/g bone (sd=15.9). Baseline ASR eyeblink response decreased with age, but was not associated with subsequent conditioning. Among 37 men with valid responses at the end of the protocol, higher patella lead was associated with decreased awareness of the conditioning contingency (declarative learning; adjusted odds ratio [OR] per 20 μg/g patella lead=0.91, 95% confidence interval [CI]: 0.84, 0.99, p=0.03). Eyeblink conditioning (non-declarative learning) was 0.44sd less (95% CI:−0.91, 0.02; p=0.06) per 20 μg/g patella lead after adjustment. Each result was stronger when correcting for the interval between lead measurement and startle testing (awareness: OR=0.88, 95% CI: 0.78, 0.99, p = 0.04; conditioning: −0.79sd less, 95% CI: −1.56, 0.03, p = 0.04).
Conclusions
This initial exploration suggests that lead exposure interferes with specific neural mechanisms of learning and offers the possibility that the ASR may provide a new approach to physiologically explore the effects of neurotoxicant exposures on neural mechanisms of learning in humans with a paradigm that is directly comparable to animal models.
doi:10.1016/j.ntt.2013.04.003
PMCID: PMC3774537  PMID: 23603705
lead; aging; acoustic startle response; psychophysiology; behavioral toxicology
7.  Epigenetic Influences on Associations between Air Pollutants and Lung Function in Elderly Men: The Normative Aging Study 
Environmental Health Perspectives  2014;122(6):566-572.
Background: Few studies have been performed on pulmonary effects of air pollution in the elderly—a vulnerable population with low reserve capacity—and mechanisms and susceptibility factors for potential effects are unclear.
Objectives: We evaluated the lag structure of air pollutant associations with lung function and potential effect modification by DNA methylation (< or ≥ median) at 26 individual CpG sites in nine candidate genes in a well-characterized cohort of elderly men.
Methods: We measured forced vital capacity (FVC), forced expiratory volume in 1 sec (FEV1), and blood DNA methylation one to four times between 1999 and 2009 in 776 men from the Normative Aging Study. Air pollution was measured at fixed monitors 4 hr to 28 days before lung function tests. We used linear mixed-effects models to estimate the main effects of air pollutants and effect modification by DNA methylation.
Results: An interquartile range (IQR) increase in subchronic exposure (3 to 28 days cumulated), but not in acute exposure (during the previous 4 hr, or the current or previous day), to black carbon, total and nontraffic particles with aerodynamic diameter ≤ 2.5 μm (PM2.5), carbon monoxide, and nitrogen dioxide was associated with a 1–5% decrease in FVC and FEV1 (p < 0.05). Slope estimates were greater for FVC than FEV1, and increased with cumulative exposure. The estimates slopes for air pollutants (28 days cumulated) were higher in participants with low (< median) methylation in TLR2 at position 2 and position 5 and high (≥ median) methylation in GCR.
Conclusions: Subchronic exposure to traffic-related pollutants was associated with significantly reduced lung function in the elderly; nontraffic pollutants (particles, ozone) had weaker associations. Epigenetic mechanisms related to inflammation and immunity may influence these associations.
Citation: Lepeule J, Bind MAC, Baccarelli AA, Koutrakis P, Tarantini L, Litonjua A, Sparrow D, Vokonas P, Schwartz JD. 2014. Epigenetic influences on associations between air pollutants and lung function in elderly men: the Normative Aging Study. Environ Health Perspect 122:566–572; http://dx.doi.org/10.1289/ehp.1206458
doi:10.1289/ehp.1206458
PMCID: PMC4050500  PMID: 24602767
8.  Dissecting direct and indirect genetic effects on chronic obstructive pulmonary disease (COPD) susceptibility 
Human genetics  2013;132(4):431-441.
Cigarette smoking is the major environmental risk factor for chronic obstructive pulmonary disease (COPD). Genome-wide association studies have provided compelling associations for three loci with COPD. In this study, we aimed to estimate direct, i.e., independent from smoking, and indirect effects of those loci on COPD development using mediation analysis. We included a total of 3,424 COPD cases and 1,872 unaffected controls with data on two smoking-related phenotypes: lifetime average smoking intensity and cumulative exposure to tobacco smoke (pack years). Our analysis revealed that effects of two linked variants (rs1051730 and rs8034191) in the AGPHD1/CHRNA3 cluster on COPD development are significantly, yet not entirely, mediated by the smoking-related phenotypes. Approximately 30 % of the total effect of variants in the AGPHD1/CHRNA3 cluster on COPD development was mediated by pack years. Simultaneous analysis of modestly (r2 = 0.21) linked markers in CHRNA3 and IREB2 revealed that an even larger (~42 %) proportion of the total effect of the CHRNA3 locus on COPD was mediated by pack years after adjustment for an IREB2 single nucleotide polymorphism. This study confirms the existence of direct effects of the AGPHD1/CHRNA3, IREB2, FAM13A and HHIP loci on COPD development. While the association of the AGPHD1/CHRNA3 locus with COPD is significantly mediated by smoking-related phenotypes, IREB2 appears to affect COPD independently of smoking.
doi:10.1007/s00439-012-1262-3
PMCID: PMC3600068  PMID: 23299987
9.  Air Pollution and Homocysteine: More Evidence that Oxidative Stress-related Genes Modify Effects of Particulate Air Pollution 
Epidemiology (Cambridge, Mass.)  2010;21(2):198-206.
Background
Ambient particles are associated with cardiovascular events, and recently with total plasma homocysteine. High total plasma homocysteine is a risk for human health. However, the biological mechanisms are not fully understood. One of putative pathways is through oxidative stress. We aimed to examine whether associations of PM2.5 and black carbon with homocysteine were modified by genotypes including HFE H63D, C282Y, CAT (rs480575, rs1001179, rs2284367 and rs2300181), NQO1 (rs1800566), GSTP1 I105V, GSTM1, GSTT1(deletion vs non-deletion) and HMOX-1 (any short vs both long). We attempted to replicate identified genes in an analysis of heart rate variability, and in other outcomes reported in the literature.
Methods
Study subjects were 1000 white non-Hispanic men in the Boston area, participating in a cohort study of aging. PM2.5, black carbon, total plasma homocysteine and other covariates were measured at several points in time between 1995 and 2006. We fit mixed models to examine effect modification of genes on associations of pollution with total plasma homocysteine.
Results
Interquartile range (IQR) increases in PM2.5 and black carbon (7-day moving averages) were associated with 1.5% (95% confidence interval = 0.2% to 2.8%) and 2.2% (0.6% to 3.9%) increases in total plasma homocysteine, respectively. GSTT1 and HFE C282Y modified effects of black carbon on total plasma homocysteine, and HFE C282Y and CAT (rs2300181) modified effects of PM2.5 on homocysteine. Several genotypes marginally modified effects of PM2.5 and black carbon on various endpoints. All genes with significant interactions with particulate air pollution had modest main effects on total plasma homocysteine.
Conclusions
Effects of PM2.5 and black carbon on various endpoints appeared to be mediated by genes related to oxidative stress pathways.
doi:10.1097/EDE.0b013e3181cc8bfc
PMCID: PMC3939788  PMID: 20110814
10.  Cumulative lead exposure in community-dwelling adults and fine motor function: comparing standard and novel tasks in the VA Normative Aging Study 
Neurotoxicology  2013;35:154-161.
Background and Aims
Lead exposure in children and occupationally-exposed adults has been associated with reduced visuomotor and fine motor function. However, associations in environmentally-exposed adults remain relatively unexplored. To address this, we examined the association between cumulative lead exposure—as measured by lead in bone—and performance on the Grooved Pegboard (GP) manual dexterity task, as well as on handwriting tasks using a novel assessment approach, among men in the VA Normative Aging Study (NAS).
Methods
GP testing was done with 362 NAS participants, and handwriting assessment with 328, who also had tibia and patella lead measurements made with K-X-Ray Fluorescence (KXRF). GP scores were time (sec) to complete the task with the dominant hand. The handwriting assessment approach assessed the production of signature and cursive lowercase l and m letter samples. Signature and lm task scores reflect consistency in repeated trials. We used linear regression to estimate associations and 95% confidence intervals (CI) with adjustment for age, smoking, education, income and computer experience. A backward elimination algorithm was used in the subset with both GP and handwriting assessment to identify variables predictive of each outcome.
Results
The mean (SD) participant age was 69.1 (7.2) years; mean patella and tibia concentrations were 25.0 (20.7) μg/g and 19.2 (14.6) μg/g, respectively. In multivariable-adjusted analyses, GP performance was associated with tibia (β per 15 μg/g bone = 4.66, 95% CI: 1.73, 7.58, p=0.002) and patella (β per 20 μg/g = 3.93, 95% CI: 1.11, 6.76, p = 0.006). In multivariable adjusted models of handwriting production, only the lm-pattern task showed a significant association with tibia (β per 15 μg/g bone = 1.27, 95% CI: 0.24, 2.29, p = 0.015), such that lm pattern production was more stable with increasing lead exposure. GP and handwriting scores were differentially sensitive to education, smoking, computer experience, financial stability, income and alcohol consumption.
Conclusions
Long-term cumulative environmental lead exposure was associated with deficits in GP performance, but not handwriting production. Higher lead appeared to be associated with greater consistency on the lm task. Lead sensitivity differences could suggest that lead affects neural processing speed rather than motor function per se, or could result from distinct brain areas involved in the execution of different motor tasks.
doi:10.1016/j.neuro.2013.01.005
PMCID: PMC3602137  PMID: 23370289
Grooved pegboard; lead; NAS; fine motor; visuomotor
11.  Lipid and endothelial related genes, ambient particulate matter, and heart rate variability --the VA Normative Aging Study 
Background
Many studies have shown that exposures to air pollution are associated with cardiovascular events although the mechanism remains to be clarified. To identify whether exposures to ambient particles act on autonomic function via the lipid/endothelial metabolism pathway, we evaluated whether the effects of particulate matter < 2.5 µm in aerodynamic diameter (PM2.5) on heart rate variability (HRV) were modified by gene polymorphisms related to those pathways.
Methods
We used HRV and gene data from the Normative Aging Study and PM2.5 from a monitor located a kilometer from the examination site. We fitted a mixed effect model to investigate the associations between PM2.5 and repeated measurements of HRV by gene polymorphisms of apolipoprotein E (APOE), lipoprotein lipase (LPL) and vascular endothelial growth factor (VEGF) adjusting for potential confounders chosen a priori.
Results
A 10-µg/m3 increase of PM2.5 in the two days before the examination was associated with 3.8% [95% confidence interval (CI): 0.2%, 7.4%], 7.8% [95 CI: 0.4%, 15.3%] and 10.6% [95% CI: 1.8 %, 19.4%] decreases of the standard deviation of normal-to-normal intervals, low frequency and high frequency, respectively. In general, carriers of wild type APOE, LPL and VEGF genes had stronger effects of particles on HRV compared to those with hetero- or homozygous types. Variations of LPL-N291S, LPL-D9N and APOE-G113C significantly modified effects of PM2.5 on HRV.
Conclusion
Associations between PM2.5 and HRV were modified by gene polymorphisms of APOE, LPL and VEGF and biological metabolism remains to be identified.
doi:10.1136/jech.2008.083295
PMCID: PMC3935361  PMID: 19602472
air pollution; heart rate variability; effect modification; apolipoprotein E; lipoprotein lipase; vascular endothelial growth factor
12.  Association between blood pressure and DNA methylation of retrotransposons and pro-inflammatory genes 
Background Methylation of deoxyribonucleic acid (DNA) is an epigenetic regulator of gene expression that changes with age, but its contribution to aging-related disorders, including high blood pressure (BP), is still largely unknown. We examined the relation of BP to the methylation of retrotransposon sequences of DNA and of selected candidate genes.
Methods This investigation included 789 elderly participants in the Normative Aging Study, ranging in age from 55 to 100 years, who had longitudinal measurements of DNA methylation. In these subjects’ DNA we measured the proportion of methylated sites in retrotransposable sequences and in pro-inflammatory genes, expressed as the percent of 5-methylated cytosines (%5mC) among all cytosines. From one to four methylation measurements were made for each subject between 1999 and 2009. We fit mixed-effects models, using repeated measures of BP as the outcome and DNA methylation as the explanatory variable, adjusting for confounding variables. We also fit a Bayesian mixed-effects structural equation model to account for heterogeneity in the effects of methylation sites within each gene.
Results An increase in inter-quartile range (IQR) in the methylation of Alu elements was associated with an increase of 0.97 mm Hg in diastolic blood pressure (DBP) (95% CI 0.32–1.57), but no such association was observed for long interspersed nuclear element-1 (LINE-1). We also found positive associations between DBP and methylation of the genes for toll-like receptor 2 (TLR2) and inducible nitric oxide synthase (iNOS), and a negative association between DBP and methylation of the gene for interferon-γ (IFN-γ). Associations between methylation and systolic blood pressure (SBP) were weaker than those between methylation and DBP. Bayesian mixed-effects structural equation model results were similar for both DBP and SBP models.
Conclusions The results of our study suggest that changes in DNA methylation of some pro-inflammatory genes and retrotransposable elements are related to small changes in BP.
doi:10.1093/ije/dys220
PMCID: PMC3600626  PMID: 23508416
Epigenetics; DNA methylation; blood pressure; inflammation; Bayesian model
13.  Allergen sensitization is associated with increased DNA methylation in older men 
Background
Variation in epigenetic modifications, arising from either environmental exposures or internal physiological changes, can influence gene expression, and may ultimately contribute to complex diseases such as asthma and allergies. We examined the association of asthma and allergic phenotypes with DNA methylation levels of retrotransposon-derived elements.
Methods
We used data from 704 men (mean age 73) in the longitudinal Normative Aging Study to assess the relationship between asthma, allergic phenotypes and DNA methylation levels of the retrotransposon derived elements Alu and LINE-1. Retrotransposons represent a large fraction of the genome (> 30%), and are heavily methylated to prevent expression. Percent methylation of Alu and LINE-1 elements in peripheral white blood cells was quantified using PCR pyrosequencing. Data on sensitization to common allergens by skin prick testing, asthma, and methacholine responsiveness was gathered approximately 8 years prior to DNA methylation analysis.
Results
Prior allergen sensitization was associated with increased methylation of Alu (β=0.32 [sensitized vs. non-sensitized], p value 0.003), in models adjusted for pack-years, BMI, smoking, air pollutants, percent eosinophils, white blood cell count and age. Of the men interviewed, 5 % of subjects reported diagnosis of asthma. Neither Alu, nor LINE-1 methylation was associated with asthma.
Conclusions
These data suggest that increased DNA methylation of repetitive elements may be associated with allergen sensitization, but does not appear to be associated with asthma. Future work is needed to identify potential underlying mechanisms for these relationships.
doi:10.1159/000343004
PMCID: PMC3730837  PMID: 23257623
allergen sensitization; DNA methylation; Alu; and LINE-1
14.  Bone Lead and Endogenous Exposure in an Environmentally Exposed Elderly Population: the Normative Aging Study 
Objective
The objective of this study is to investigate the mobilization of lead from bone to blood (endogenous exposure) in a large epidemiologic population.
Methods
Study subjects were 776 participants in the Normative Aging Study. The subjects had their tibia lead, patella lead, blood lead, and/or urinary N-telopeptide (NTx) levels measured 1-4 times from 1991 to 2002. Regression models were estimated to quantify the association between tibia and patella lead and blood lead. We studied nonlinearity of the association, and explored possible factors that may modify it, including age and NTx levels.
Results and conclusions
There is significant association between bone lead and blood lead, and the association is non-linear. The non-linear associations between blood lead and bone lead are not significantly modified by age and NTx.
doi:10.1097/JOM.0b013e3181aa0106
PMCID: PMC3800179  PMID: 19528829
15.  Vitamin D Deficiency, Smoking, and Lung Function in the Normative Aging Study 
Rationale: Vitamin D has immunomodulatory and antiinflammatory effects that may be modified by cigarette smoke and may affect lung function.
Objectives: To examine the effect of vitamin D deficiency and smoking on lung function and lung function decline.
Methods: A total of 626 men from the Normative Aging Study had 25-hydroxyvitamin D levels measured at three different times between 1984 and 2003 with concurrent spirometry. Vitamin D deficiency was defined as serum level ≤ 20 ng/ml. Statistical analysis was performed using multivariable linear regression and mixed effects models.
Measurements and Main Results: In the overall cohort, there was no significant effect of vitamin D deficiency on lung function or on lung function decline. In both cross-sectional and longitudinal multivariable models, there was effect modification by vitamin D status on the association between smoking and lung function. Cross-sectional analysis revealed lower lung function in current smokers with vitamin D deficiency (FEV1, FVC, and FEV1/FVC; P ≤ 0.0002), and longitudinal analysis showed more rapid rates of decline in FEV1 (P = 0.023) per pack-year of smoking in subjects with vitamin D deficiency as compared with subjects who were vitamin D sufficient.
Conclusions: Vitamin D deficiency was associated with lower lung function and more rapid lung function decline in smokers over 20 years in this longitudinal cohort of elderly men. This suggests that vitamin D sufficiency may have a protective effect against the damaging effects of smoking on lung function. Future studies should seek to confirm this finding in the context of smoking and other exposures that affect lung function.
doi:10.1164/rccm.201110-1868OC
PMCID: PMC3480523  PMID: 22822023
vitamin D; vitamin D deficiency; lung function decline; smoking; effect modification
16.  Forced Expiratory Volume in 1 Second and Cognitive Aging in Men 
OBJECTIVES
To evaluate forced expiratory volume in 1 second (FEV1, a measure of overall lung function), long-term average FEV1, and rate of decline in FEV1 in relation to cognition and cognitive decline in older men.
DESIGN
Prospective observational study.
SETTING
Community-based population.
PARTICIPANTS
Eight hundred sixty-four older men from the Normative Aging Study.
MEASUREMENTS
Starting in 1984, participants underwent triennial clinical evaluations. Lung function assessments provided estimates of FEV1. Cognitive assessments entailing tests of several cognitive abilities began in 1993. FEV1 measured approximately 12 years before baseline cognitive testing, average FEV1 over the 12-year period, and rate of change in FEV1 were all evaluated in relation to baseline and change in performance on the cognitive tests.
RESULTS
In multivariable-adjusted analyses, associations between FEV1 and baseline cognitive scores were mixed, although average FEV1 predicted significantly better performance on tests of visuospatial ability (P =.04) and general cognition (P =.03). Higher FEV1 was more consistently associated with slower cognitive decline, but only the association between historical FEV1 and attention was significant (difference per standard deviation in FEV1 = 0.056, P =.05). Rate of FEV1 decline was not consistently associated with cognitive function or decline. Findings were generally similar or stronger in men who had never smoked. To account for potential bias due to selective attrition, inverse probability of censoring weights were applied to the cognitive decline analyses, yielding slightly larger estimates; the inadequate prognostic power of the censoring models limited this approach.
CONCLUSION
Overall, the data provide limited evidence of an inverse association between FEV1 and cognitive aging.
doi:10.1111/j.1532-5415.2011.03487.x
PMCID: PMC3758858  PMID: 21718272
lung function; cognition; cognitive decline; epidemiology; aging
17.  Long-term Exposure to Black Carbon and Carotid Intima-Media Thickness: The Normative Aging Study 
Environmental Health Perspectives  2013;121(9):1061-1067.
Background: Evidence suggests that air pollution is associated with atherosclerosis and that traffic-related particles are a particularly important contributor to the association.
Objectives: We investigated the association between long-term exposure to black carbon, a correlate of traffic particles, and intima-media thickness of the common carotid artery (CIMT) in elderly men residing in the greater Boston, Massachusetts, area.
Methods: We estimated 1-year average exposures to black carbon at the home addresses of Normative Aging Study participants before their first CIMT measurement. The association between estimated black carbon levels and CIMT was estimated using mixed effects models to account for repeated outcome measures. In secondary analyses, we examined whether living close to a major road or average daily traffic within 100 m of residence was associated with CIMT.
Results: There were 380 participants (97% self-reported white race) with an initial visit between 2004 and 2008. Two or three follow-up CIMT measurements 1.5 years apart were available for 340 (89%) and 260 (68%) men, respectively. At first examination, the average ± SD age was 76 ± 6.4 years and the mean ± SD CIMT was 0.99 ± 0.18 mm. A one-interquartile range increase in 1-year average black carbon (0.26 µg/m3) was associated with a 1.1% higher CIMT (95% CI: 0.4, 1.7%) based on a fully adjusted model.
Conclusions: Annual mean black carbon concentration based on spatially resolved exposure estimates was associated with CIMT in a population of elderly men. These findings support an association between long-term air pollution exposure and atherosclerosis.
Citation: Wilker EH, Mittleman MA, Coull BA, Gryparis A, Bots ML, Schwartz J, Sparrow D. 2013. Long-term exposure to black carbon and carotid intima-media thickness: the Normative Aging Study. Environ Health Perspect 121:1061–1067; http://dx.doi.org/10.1289/ehp.1104845 [Online 2 July 2013]
doi:10.1289/ehp.1104845
PMCID: PMC3764069  PMID: 23820848
18.  Repetitive element hypomethylation in blood leukocyte DNA and cancer incidence, prevalence and mortality in elderly individuals: the Normative Aging Study 
Cancer causes & control : CCC  2010;22(3):437-447.
Background
Global genomic hypomethylation is a common epigenetic event in cancer that mostly results from hypomethylation of repetitive DNA elements. Case-control studies have associated blood leukocyte DNA hypomethylation with several cancers. Because samples in case-control studies are collected after disease development, whether DNA hypomethylation is causal or just associated with cancer development is still unclear.
Methods
In 722 elderly subjects from the Normative Aging Study cohort, we examined whether DNA methylation in repetitive elements (Alu, LINE-1) was associated with cancer incidence (30 new cases, median follow-up: 89 months), prevalence (205 baseline cases), and mortality (28 deaths, median follow-up: 85 months). DNA methylation was measured by bisulfite pyrosequencing.
Results
Individuals with low LINE-1 methylation (
Conclusion
These findings suggest that individuals with lower repetitive element methylation are at high risk of developing and dying from cancer.
doi:10.1007/s10552-010-9715-2
PMCID: PMC3752839  PMID: 21188491
Repetitive elements; DNA methylation; Epigenetics; Blood; Cancer risk
American Journal of Epidemiology  2012;176(3):224-232.
DNA methylation is a potential pathway linking air pollution to disease. Studies indicate that psychological functioning modifies the association between pollution and morbidity. The authors estimated the association of DNA methylation with ambient particulate matter less than 2.5 µm in diameter (PM2.5) and black carbon, using mixed models. DNA methylation of the inducible nitric oxide synthase gene, iNOS, and the glucocorticoid receptor gene, GCR, was measured by quantitative polymerase chain reaction pyrosequencing of 1,377 blood samples from 699 elderly male participants in the VA Normative Aging Study (1999–2009). The authors also investigated whether this association was modified by psychological factors including optimism or pessimism, anxiety, and depression. iNOS methylation was decreased after acute exposure to both black carbon and PM2.5. A 1-μg/m3 increase in exposure to black carbon in the 4 hours preceding the clinical examination was associated with a 0.9% decrease in 5-methylcytosine (95% CI: 0.4, 1.4) in iNOS, and a 10-μg/m3 increase in exposure to PM2.5 was associated with a 0.6% decrease in 5-methylcytosine (95% CI: 0.03, 1.1) in iNOS. Participants with low optimism and high anxiety had associations that were 3–4 times larger than those with high optimism or low anxiety. GCR methylation was not associated with particulate air pollution exposure.
doi:10.1093/aje/kwr523
PMCID: PMC3491965  PMID: 22798479
air pollution; DNA methylation; psychology
Epidemiology (Cambridge, Mass.)  2010;21(6):819-828.
Background
Epigenetic features such as DNA hypomethylation have been associated with conditions related to cardiovascular risk. We evaluated whether lower blood DNA methylation in heavily methylated repetitive sequences predicts the risk of ischemic heart disease and stroke.
Methods
We quantified blood DNA methylation of LINE-1 repetitive elements through PCR-pyrosequencing in 712 elderly individuals from the Boston-area Normative Aging Study. We estimated risk-factor adjusted relative risks (RRs) for ischemic heart disease and stroke at baseline (242 prevalent cases); as well as in incidence (44 new cases; median follow-up, 63 months); and subsequent mortality from ischemic heart disease (86 deaths; median follow-up, 75 months).
Results
Blood LINE-1 hypomethylation was associated with baseline ischemic heart disease (RR=2.1 [95% confidence interval = 1.2 to 4.0] for lowest vs. highest methylation quartile) and for stroke (2.5 [0.9 to 7.5]). Among participants free of baseline disease, individuals with methylation below the median also had higher risk of developing ischemic heart disease (4.0 [1.8 to 8.9]) or stroke (5.7 [0.8 to 39.5]). In the entire cohort, persons with methylation below the median had higher mortality from ischemic heart disease (3.3 [1.3 to 8.4]) and stroke (2.8 [0.6 to 14.3]). Total mortality was also increased (2.0 [1.2 to 3.3]). These results were confirmed in additional regression models using LINE-1 methylation as a continuous variable.
Conclusions
Subjects with prevalent IHD and stroke exhibited lower LINE-1 methylation. In longitudinal analyses, persons with lower LINE-1 methylation were at higher risk for incident ischemic heart disease and stroke, and for total mortality.
doi:10.1097/EDE.0b013e3181f20457
PMCID: PMC3690659  PMID: 20805753
Objective
We evaluated the modifying influence of a δ-aminolevulinic acid dehydratase (ALAD) polymorphism on the relation between lead burden and cognition among older men.
Methods
Information on ALAD genotype, lead measurements, potential confounders, and cognitive testing was collected from 982 participants. For each cognitive test and lead biomarker, we fit separate multiple linear regression models which included an interaction term for ALAD genotype and the lead biomarker, and adjusted for potential confounders.
Results
With higher levels of tibia lead, ALAD 1-2/2-2 carriers exhibited worse performance on a spatial copying test in comparison with ALAD 1-1 carriers (pinteraction=0.03). However, there was no consistent pattern of an ALAD genotype-lead interaction for the other tests.
Conclusions
The results provide some evidence that ALAD genotype modifies the relation between lead burden and cognition among older men with low lead burden, particularly for cognitive domains sensitive to the effects of cumulative lead burden.
doi:10.1097/JOM.0b013e3181792463
PMCID: PMC3664949  PMID: 18784554
blood; bone and blood; lead; environmental; polymorphism; genetic; cognition; neuropsychological tests
Epigenetics  2012;7(3):261-269.
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.
doi:10.4161/epi.7.3.19216
PMCID: PMC3335949  PMID: 22430802
DNA methylation; genes; spirometry; FEV1; lungs; TLR2; F3; INOS; GCR; OGG1
Human Molecular Genetics  2011;21(4):947-957.
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.
doi:10.1093/hmg/ddr524
PMCID: PMC3298111  PMID: 22080838
Epigenetics  2012;7(1):63-70.
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.
doi:10.4161/epi.7.1.18749
PMCID: PMC3329504  PMID: 22207354
aging; DNA Mmthylation; epigenesis; genetic
American Journal of Epidemiology  2011;174(12):1345-1353.
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.
doi:10.1093/aje/kwr269
PMCID: PMC3276297  PMID: 22071587
depression; lead; metals; orientation; psychology; socioeconomic factors

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