Associations between solar and geomagnetic activity and cognitive function in the Normative Aging study.

BACKGROUND: Studies show that changes in solar and geomagnetic activity (SGA) influence melatonin secretion and the autonomic nervous system. We evaluated associations between solar and geomagnetic activity and cognitive function in the Normative Aging Study from 1992 to 2013. METHODS: We used logistic and linear generalized estimating equations and regressions to evaluate the associations between moving averages of sunspot number (SSN) and Kp index (a measure of geomagnetic activity) and a binary measure for Mini-Mental State Examination (MMSE) scores (≤25 or > 25) and six other cognitive tests as continuous measures, combined into one global composite score and considered separately. RESULTS: A one-IQR increase in same-day SSN and Kp index were associated with 17% (95% CI: 3%, 34%) and 19% (95% CI: 4%, 36%) increases in the odds of low MMSE score. We observed small increases in the global cognitive score with increasing SSN, although we observed decreases specifically in relation to the backwards digit span test. CONCLUSIONS: Periods of high SGA were associated with cognitive function. SGA may not equally impact all aspects of cognitive function, as evidenced by differences in associations observed for the MMSE, global cognitive score, and individual cognitive tests. Given that much of the pathology of cognitive decline in the elderly remains unexplained, studies specifically targeting decline and with longer follow-up periods are warranted.

Dysanapsis is differentially related to lung function trajectories with distinct structural and functional patterns in COPD and variable risk for adverse outcomes.

Background: Abnormal lung function trajectories are associated with increased risk of chronic obstructive pulmonary disease (COPD) and premature mortality; several risk factors for following these trajectories have been identified. Airway under-sizing dysanapsis (small airway lumens relative to lung size), is associated with an increased risk for COPD. The relationship between dysanapsis and lung function trajectories at risk for adverse outcomes of COPD is largely unexplored. We test the hypothesis that dysanapsis differentially affects distinct lung function trajectories associated with adverse outcomes of COPD. Methods: To identify lung function trajectories, we applied Bayesian trajectory analysis to longitudinal FEV1 and FVC Z-scores in the COPDGene Study, an ongoing longitudinal study that collected baseline data from 2007 to 2012. To ensure clinical relevance, we selected trajectories based on risk stratification for all-cause mortality and prospective exacerbations of COPD (ECOPD). Dysanapsis was measured in baseline COPDGene CT scans as the airway lumen-to-lung volume (a/l) ratio. We compared a/l ratios between trajectories and evaluated their association with trajectory assignment, controlling for previously identified risk factors. We also assigned COPDGene participants for whom only baseline data is available to their most likely trajectory and repeated our analysis to further evaluate the relationship between trajectory assignment and a/l ratio measures. Findings: We identified seven trajectories: supranormal, reference, and five trajectories at increased risk for mortality and exacerbations. Three at-risk trajectories are characterized by varying degrees of concomitant FEV1 and FVC impairments and exhibit airway predominant COPD patterns as assessed by quantitative CT imaging. These trajectories have lower a/l ratio values and increased risk for mortality and ECOPD compared to the reference trajectory. Two at-risk trajectories are characterized by disparate levels of FEV1 and FVC impairment and exhibit mixed airway and emphysema COPD patterns on quantitative CT imaging. These trajectories have markedly lower a/l ratio values compared to both the reference trajectory and airway-predominant trajectories and are at greater risk for mortality and ECOPD compared to the airway-predominant trajectories. These findings were observed among the participants with baseline-only data as well. Interpretation: The degree of dysanapsis appears to portend patterns of progression leading to COPD. Assignment of individuals-including those without spirometric obstruction-to distinct trajectories is possible in a clinical setting and may influence management strategies. Strategies that combine CT-assessed dysanapsis together with spirometric measures of lung function and smoke exposure assessment are likely to further improve trajectory assignment accuracy, thereby improving early detection of those most at risk for adverse outcomes. Funding: United States National Institute of Health, COPD Foundation, and Brigham and Women's Hospital.

Design issues in crossover trials involving patients with Parkinson's disease.

Background and objectives: Crossover designs are frequently used to assess treatments for patients with Parkinson's disease. Typically, two-period two-treatment trials include a washout period between the 2 periods and assume that the washout period is sufficiently long to eliminate carryover effects. A complementary strategy might be to jointly model carryover and treatment effects, though this has rarely been done in Parkinson's disease crossover studies. The primary objective of this research is to demonstrate a modeling approach that assesses treatment and carryover effects in one unified mixed model analysis and to examine how it performs in a simulation study and a real data analysis example, as compared to other data analytic approaches used in Parkinson's disease crossover studies. Methods: We examined how three different methods of analysis (standard crossover t-test, mixed model with a carryover term included in model statement, and mixed model with no carryover term) performed in a simulation study and illustrated the methods in a real data example in Parkinson's disease. Results: The simulation study based on the presence of a carryover effect indicated that mixed models with a carryover term and an unstructured correlation matrix provided unbiased estimates of treatment effect and appropriate type I error. The methods are illustrated in a real data example involving Parkinson's disease. Our literature review revealed that a majority of crossover studies included a washout period but did not assess whether the washout was sufficiently long to eliminate the possibility of carryover. Discussion: We recommend using a mixed model with a carryover term and an unstructured correlation matrix to obtain unbiased estimates of treatment effect.

Metabolomics and Self-Reported Depression, Anxiety, and Phobic Symptoms in the VA Normative Aging Study.

Traditional approaches to understanding metabolomics in mental illness have focused on investigating a single disorder or comparisons between diagnoses, but a growing body of evidence suggests substantial mechanistic overlap in mental disorders that could be reflected by the metabolome. In this study, we investigated associations between global plasma metabolites and abnormal scores on the depression, anxiety, and phobic anxiety subscales of the Brief Symptom Inventory (BSI) among 405 older males who participated in the Normative Aging Study (NAS). Our analysis revealed overlapping and distinct metabolites associated with each mental health dimension subscale and four metabolites belonging to xenobiotic, carbohydrate, and amino acid classes that were consistently associated across all three symptom dimension subscales. Furthermore, three of these four metabolites demonstrated a higher degree of alteration in men who reported poor scores in all three dimensions compared to men with poor scores in only one, suggesting the potential for shared underlying biology but a differing degree of perturbation when depression and anxiety symptoms co-occur. Our findings implicate pathways of interest relevant to the overlap of mental health conditions in aging veterans and could represent clinically translatable targets underlying poor mental health in this high-risk population.

Epigenome-wide DNA methylation in leukocytes and toenail metals: The normative aging study.

BACKGROUND: Environmental metal exposures have been associated with multiple deleterious health endpoints. DNA methylation (DNAm) may provide insight into the mechanisms underlying these relationships. Toenail metals are non-invasive biomarkers, reflecting a medium-term time exposure window. OBJECTIVES: This study examined variation in leukocyte DNAm and toenail arsenic (As), cadmium (Cd), lead (Pb), manganese (Mn), and mercury (Hg) among elderly men in the Normative Aging Study, a longitudinal cohort. METHODS: We repeatedly collected samples of blood and toenail clippings. We measured DNAm in leukocytes with the Illumina HumanMethylation450 K BeadChip. We first performed median regression to evaluate the effects of each individual toenail metal on DNAm at three levels: individual cytosine-phosphate-guanine (CpG) sites, regions, and pathways. Then, we applied a Bayesian kernel machine regression (BKMR) to assess the joint and individual effects of metal mixtures on DNAm. Significant CpGs were identified using a multiple testing correction based on the independent degrees of freedom approach for correlated outcomes. The approach considers the effective degrees of freedom in the DNAm data using the principal components that explain >95% variation of the data. RESULTS: We included 564 subjects (754 visits) between 1999 and 2013. The numbers of significantly differentially methylated CpG sites, regions, and pathways varied by metals. For example, we found six significant pathways for As, three for Cd, and one for Mn. The As-associated pathways were associated with cancer (e.g., skin cancer) and cardiovascular disease, whereas the Cd-associated pathways were related to lung cancer. Metal mixtures were also associated with 47 significant CpG sites, as well as pathways, mainly related to cancer and cardiovascular disease. CONCLUSIONS: This study provides an approach to understanding the potential epigenetic mechanisms underlying observed relations between toenail metals and adverse health endpoints.

Extracellular Vesicle-Encapsulated microRNAs as Novel Biomarkers of Lung Health.

Rationale: Early detection of respiratory diseases is critical to facilitate delivery of disease-modifying interventions. Extracellular vesicle-enriched microRNAs (EV-miRNAs) may represent reliable markers of early lung injury. Objectives: Evaluate associations of plasma EV-miRNAs with lung function. Methods: The prospective NAS (Normative Aging Study) collected plasma EV-miRNA measurements from 1996-2015 and spirometry every 3-5 years through 2019. Associations of EV-miRNAs with baseline lung function were modeled using linear regression. To complement the individual miRNA approach, unsupervised machine learning was used to identify clusters of participants with distinct EV-miRNA profiles. Associations of EV-miRNA profiles with multivariate latent longitudinal lung function trajectories were modeled using log binomial regression. Biological functions of significant EV-miRNAs were explored using pathway analyses. Results were replicated in an independent sample of NAS participants and in the HEALS (Health Effects of Arsenic Longitudinal Study). Measurements and Main Results: In the main cohort of 656 participants, 51 plasma EV-miRNAs were associated with baseline lung function (false discovery rate-adjusted P value < 0.05), 28 of which were replicated in the independent NAS sample and/or in the HEALS cohort. A subset of participants with distinct EV-miRNA expression patterns had increased risk of declining lung function over time, which was replicated in the independent NAS sample. Significant EV-miRNAs were shown in pathway analyses to target biological pathways that regulate respiratory cellular immunity, the lung inflammatory response, and airway structural integrity. Conclusions: Plasma EV-miRNAs may represent a robust biomarker of subclinical lung injury and may facilitate early identification and treatment of patients at risk of developing overt lung disease.

Predicting risk of lung function impairment and all-cause mortality using a DNA methylation-based classifier of tobacco smoke exposure.

BACKGROUND: The Epigenetic Smoking Status Estimator (EpiSmokEr) predicts smoking phenotypes based on DNA methylation at 121 CpG sites. OBJECTIVE: Evaluate associations of EpiSmokEr-predicted versus self-reported smoking phenotypes with lung function and all-cause mortality in a cohort of older adults. METHODS: The prospective Normative Aging Study collected DNA methylation measurements from 1999 to 2012 with follow-up through 2016. The R package EpiSmokEr derived predicted smoking phenotypes based on DNA methylation levels assayed by the Illumina HumanMethylation450 Beadchip. Spirometry was collected every 3-5 years. Airflow limitation was defined as forced expiratory volume in 1 s/forced vital capacity <0.7. Vital status was monitored through periodic mailings. RESULTS: Among 784 participants contributing 5414 person-years of follow-up, the EpiSmokEr-predicted smoking phenotypes matched the self-reported phenotypes for 228 (97%) never smokers and 22 (71%) current smokers. In contrast, EpiSmokEr classified 407 (79%) self-reported former smokers as never smokers. Nonetheless, the EpiSmokEr-predicted former smoking phenotype was more strongly associated with incident airflow limitation (hazard ratio [HR] = 3.15, 95% confidence interval [CI] = 1.50-6.59) and mortality (HR = 2.11, 95% CI = 1.56-2.85) compared to the self-reported former smoking phenotype (airflow limitation: HR = 2.21, 95% CI = 1.13-4.33; mortality: HR = 1.08, 95% CI = 0.86-1.36). Risk of airflow limitation and death did not differ among self-reported never smokers and former smokers who were classified as never smokers. The discriminative accuracy of EpiSmokEr-predicted phenotypes for incident airflow limitation and mortality was improved compared to self-reported phenotypes. CONCLUSIONS: The DNA methylation-based EpiSmokEr classifier may be a useful surrogate of smoking-induced lung damage and may identify former smokers most at risk of adverse smoking-related health effects.

Metabolomic differences in lung function metrics: evidence from two cohorts.

RATIONALE: The biochemical mechanisms underlying lung function are incompletely understood. OBJECTIVES: To identify and validate the plasma metabolome of lung function using two independent adult cohorts: discovery-the European Prospective Investigation into Cancer-Norfolk (EPIC-Norfolk, n=10 460) and validation-the VA Normative Aging Study (NAS) metabolomic cohort (n=437). METHODS: We ran linear regression models for 693 metabolites to identify associations with forced expiratory volume in one second (FEV1) and the ratio of FEV1 to forced vital capacity (FEV1/FVC), in EPIC-Norfolk then validated significant findings in NAS. Significance in EPIC-Norfolk was denoted using an effective number of tests threshold of 95%; a metabolite was considered validated in NAS if the direction of effect was consistent and p<0.05. MEASUREMENTS AND MAIN RESULTS: Of 156 metabolites that associated with FEV1 in EPIC-Norfolk after adjustment for age, sex, body mass index, height, smoking and asthma status, 34 (21.8%) validated in NAS, including several metabolites involved in oxidative stress. When restricting the discovery sample to men only, a similar percentage, 18 of 79 significant metabolites (22.8%) were validated. A smaller number of metabolites were validated for FEV1/FVC, 6 of 65 (9.2%) when including all EPIC-Norfolk as the discovery population, and 2 of 34 (5.9%) when restricting to men. These metabolites were characterised by involvement in respiratory track secretants. Interestingly, no metabolites were validated for both FEV1 and FEV1/FVC. CONCLUSIONS: The validation of metabolites associated with respiratory function can help to better understand mechanisms of lung health and may assist the development of biomarkers.

Blood DNA methylation biomarkers of cumulative lead exposure in adults.

BACKGROUND: Lead is a ubiquitous toxicant following three compartment kinetics with the longest half-life found in bones. Patella and tibia lead levels-validated measures of cumulative exposure-require specialized X-ray-fluorescence-spectroscopy available only in a few centers worldwide. We developed minimally invasive biomarkers reflecting individual cumulative lead exposure using blood DNA methylation profiles-obtainable via Illumina 450K or IlluminaEPIC bead-chip assays. METHODS: We developed and tested two methylation-based biomarkers from 348 Normative Aging Study (NAS) elderly men. We selected methylation sites with strong associations with bone lead levels via robust regressions analysis and constructed the biomarkers using elastic nets. Results were validated in a NAS subset, reporting specificity, and sensitivity. FINDINGS: Participants were 73 years old on average (standard deviation, SD = 6), with moderate lead levels of (mean ± SD patella: 27 ± 18 µg/g; tibia:21 ± 13 µg/g). Methylation-based biomarkers for lead in patella and tibia included 59 and 138 DNA methylation sites, respectively. Estimated lead levels were significantly correlated with actual measured values, (r = 0.62 patella, r = 0.59 tibia) and had low mean square error (MSE) (MSE = 0.68 patella, MSE = 0.53 tibia). Means and distributions of the estimated and actual lead levels were not significantly different across patella and tibia bones (p > 0.05). Methylation-based biomarkers discriminated participants highly exposed (>median) to lead with a specificity of 74 and 73% for patella and tibia lead levels, respectively, with 70% sensitivity. INTERPRETATION: DNA methylation-based lead biomarkers are novel tools that can be used to reconstruct decades' worth of individual cumulative lead exposure using only blood DNA methylation profiles and may help identify the consequences of cumulative exposure.

Metabolomic signatures of lead exposure in the VA Normative Aging Study.

BACKGROUND: Lead (Pb) is widespread and exposure to this non-essential heavy metal can cause multiple negative health effects; however the mechanisms underlying these effects remain incompletely understood. OBJECTIVES: To identify plasma metabolomic signatures of Pb exposure, as measured in blood and toenails. METHODS: In a subset of men from the VA Normative Aging Study, mass-spectrometry based plasma metabolomic profiling was performed. Pb levels were measured in blood samples and toenail clippings collected concurrently. Multivariable linear regression models, smoothing splines and Pathway analyses were employed to identify metabolites associated with Pb exposure. RESULTS: In 399 men, 858 metabolites were measured and passed QC, of which 154 (17.9%) were significantly associated with blood Pb (p < 0.05). Eleven of these passed stringent correction for multiple testing, including pro-hydroxy-pro (ß(95%CI): 1.52 (0.93,2.12), p = 7.18x10-7), N-acetylglycine (ß(95%CI): 1.44 (0.85,2.02), p = 1.12x10-6), tartarate (ß(95%CI): 0.68 (0.35,1.00), p = 4.84x10-5), vanillylmandelate (ß(95%CI): 1.05 (0.47,1.63), p = 4.44x10-7), and lysine (ß(95%CI): 1.88 (-2.8,-0.95), p = 9.10x10-5). A subset of 48 men had a second blood sample collected a mean of 6.1 years after their first. Three of the top eleven metabolites were also significant in this second blood sample. Furthermore, we identified 70 plasma metabolites associated with Pb as measured in toenails. Twenty-three plasma metabolites were significantly associated with both blood and toenail measures, while others appeared to be specific to the biosample in which Pb was measured. For example, benzanoate metabolism appeared to be of importance with the longer-term exposure assessed by toenails. DISCUSSION: Pb exposure is responsible for 0.6% of the global burden of disease and metabolomics is particularly well-suited to explore its pathogenic mechanisms. In this study, we identified metabolites and metabolomic pathways associated with Pb exposure that suggest that Pb exposure acts through oxidative stress and immune dysfunction. These findings help us to better understand the biology of this important public health burden.

Accelerated epigenetic aging as a risk factor for chronic obstructive pulmonary disease and decreased lung function in two prospective cohort studies.

Chronic obstructive pulmonary disease (COPD) is a frequent diagnosis in older individuals and contributor to global morbidity and mortality. Given the link between lung disease and aging, we need to understand how molecular indicators of aging relate to lung function and disease. Using data from the population-based KORA (Cooperative Health Research in the Region of Augsburg) surveys, we associated baseline epigenetic (DNA methylation) age acceleration with incident COPD and lung function. Models were adjusted for age, sex, smoking, height, weight, and baseline lung disease as appropriate. Associations were replicated in the Normative Aging Study. Of 770 KORA participants, 131 developed incident COPD over 7 years. Baseline accelerated epigenetic aging was significantly associated with incident COPD. The change in age acceleration (follow-up - baseline) was more strongly associated with COPD than baseline aging alone. The association between the change in age acceleration between baseline and follow-up and incident COPD replicated in the Normative Aging Study. Associations with spirometric lung function parameters were weaker than those with COPD, but a meta-analysis of both cohorts provide suggestive evidence of associations. Accelerated epigenetic aging, both baseline measures and changes over time, may be a risk factor for COPD and reduced lung function.

Association of Neutrophil to Lymphocyte Ratio With Pulmonary Function in a 30-Year Longitudinal Study of US Veterans.

Importance: Chronic obstructive pulmonary disease (COPD) is a critical public health burden. The neutrophil to lymphocyte ratio (NLR), an inflammation biomarker, has been associated with COPD morbidity and mortality; however, its associations with lung function decline and COPD development are poorly understood. Objective: To explore the associations of NLR with lung function decline and COPD risks. Design, Setting, and Participants: This longitudinal cohort study included white male veterans in the US with more than 30 years of follow-up to investigate the associations of NLR with lung function, COPD, and hypomethylation of cg05575921, the top DNA methylation marker of lung function changes in response to tobacco smoking. This study included 7466 visits from 1549 participants, each examined up to 13 times between 1982 and 2018. A subgroup of 1411 participants without COPD at baseline were selected to analyze the association of NLR with incident COPD. Data were analyzed from September 2019 to January 2020. Exposures: The primary exposure was NLR, which was estimated using automated whole blood cell counts based on a blood sample collected at each visit. The methylation level of cg05575921 was measured in blood DNA from a subgroup of 1228 visits. Main Outcomes and Measures: The outcomes of interest were lung function, measured as forced respiratory volume in the first second (FEV1) in liters, forced vital capacity (FVC) in liters, percentage of FVC exhaled in the first second (FEV1/FVC), and maximal midexpiratory flow rate (MMEF) in liters per minute and COPD status, defined as meeting the Global Initiative for Chronic Obstructive Lung Diseases stage II (or higher) criteria. Both outcomes were measured as each visit. Results: Among 1549 included men (mean [SD] age, 68.3 [9.3] years) with 7466 visits from 1982 to 2018, a 1-unit increase in NLR was associated with statistically significant mean (SE) decreases of 0.021 (0.004) L in FEV1, 0.016 (0.005) L in FVC, 0.290% (0.005) L in FVC, 0.290% (0.065%) in FEV1/FVC, and 3.65 (0.916) L/min MMEF. Changes in NLR up to approximately 10 years were associated with corresponding longitudinal changes in lung function. Furthermore, this increase in NLR was associated with 9% higher odds of COPD (odds ratio, 1.09 [95% CI, 1.03-1.15]) for all visits and 27% higher risk of incident COPD (odds ratio, 1.07 [95% CI, 1.07-1.51]) for participants without COPD at baseline. Additionally, a 1-unit increase in NLR was associated with a mean (SE) decrease of 0.0048 (0.0021 in cg05575921 hypomethylation, which may mediate the adverse association of NLR-related inflammation on lung function. Conclusions and Relevance: These findings suggest that NLR may be a clinically relevant biomarker associated with high risk of lung function impairment and COPD alone or in combination with DNA methylation profiles.

Biomarkers of aging and lung function in the normative aging study.

Elderly individuals who are never smokers but have the same height and chronological age can have substantial differences in lung function. The underlying biological mechanisms are unclear. To evaluate the associations of different biomarkers of aging (BoA) and lung function, we performed a repeated-measures analysis in the Normative Aging Study using linear mixed-effect models. We generated GrimAgeAccel, PhenoAgeAccel, extrinsic and intrinsic epigenetic age acceleration using a publically available online calculator. We calculated Zhang's DNAmRiskScore based on 10 CpGs. We measured telomere length (TL) and mitochondrial DNA copy number (mtDNA-CN) using quantitative real-time polymerase chain reaction. A pulmonary function test was performed measuring forced expiratory volume in 1 second / forced vital capacity (FEV1/FVC), FEV1, and maximum mid-expiratory flow (MMEF). Epigenetic-based BoA were associated with lower lung function. For example, a one-year increase in GrimAgeAccel was associated with a 13.64 mL [95% confidence interval (CI), 5.11 to 22.16] decline in FEV1; a 0.2 increase in Zhang's DNAmRiskScore was associated with a 0.009 L/s (0.005 to 0.013) reduction in MMEF. No association was found between TL/mtDNA-CN and lung function. Overall, this paper shows that epigenetics might be a potential mechanism underlying pulmonary dysfunction in the elderly.

Effect of Dietary Sodium and Potassium Intake on the Mobilization of Bone Lead among Middle-Aged and Older Men: The Veterans Affairs Normative Aging Study.

Bone is a major storage site as well as an endogenous source of lead in the human body. Dietary sodium and potassium intake may play a role in the mobilization of lead from bone to the circulation. We examined whether association between bone lead and urinary lead, a marker of mobilized lead in plasma, was modified by dietary intake of sodium and potassium among 318 men, aged 48-93 years, in the Veterans Affairs (VA) Normative Aging Study. Dietary sodium and potassium were assessed by flame photometry using 24-h urine samples, and a sodium-to-potassium ratio was calculated from the resulting measures. Patella and tibia bone lead concentrations were measured by K-shell-x-ray fluorescence. Urinary lead was measured by inductively coupled plasma mass spectroscopy in 24-h urine samples. Linear regression models were used to regress creatinine clearance-corrected urinary lead on bone lead, testing multiplicative interactions with tertiles of sodium, potassium, and sodium-to-potassium ratio, separately. After adjustment for age, body mass index, smoking, vitamin C intake, calcium, and total energy intake, participants in the highest tertile of sodium-to-potassium ratio showed 28.1% (95% CI: 12.5%, 45.9%) greater urinary lead per doubling increase in patella lead, whereas those in the second and lowest tertiles had 13.8% (95% CI: -1.7%, 31.7%) and 5.5% (95% CI: -8.0%, 21.0%) greater urinary lead, respectively (p-for-interaction = 0.04). No statistically significant effect modification by either sodium or potassium intake alone was observed. These findings suggest that relatively high intake of sodium relative to potassium may play an important role in the mobilization of lead from bone into the circulation.

Genetic landscape of chronic obstructive pulmonary disease identifies heterogeneous cell-type and phenotype associations.

Chronic obstructive pulmonary disease (COPD) is the leading cause of respiratory mortality worldwide. Genetic risk loci provide new insights into disease pathogenesis. We performed a genome-wide association study in 35,735 cases and 222,076 controls from the UK Biobank and additional studies from the International COPD Genetics Consortium. We identified 82 loci associated with P < 5 × 10-8; 47 of these were previously described in association with either COPD or population-based measures of lung function. Of the remaining 35 new loci, 13 were associated with lung function in 79,055 individuals from the SpiroMeta consortium. Using gene expression and regulation data, we identified functional enrichment of COPD risk loci in lung tissue, smooth muscle, and several lung cell types. We found 14 COPD loci shared with either asthma or pulmonary fibrosis. COPD genetic risk loci clustered into groups based on associations with quantitative imaging features and comorbidities. Our analyses provide further support for the genetic susceptibility and heterogeneity of COPD.

Dietary patterns, bone lead and incident coronary heart disease among middle-aged to elderly men.

BACKGROUND: Most absorbed lead ends up in the bone, where it can be measured as a biomarker of cumulative exposure, elevations of which have been shown to predict a higher risk of coronary heart disease (CHD). Knowledge about the role of dietary patterns is critical to the development of effective interventions for the cardiovascular toxicity of cumulative lead exposure. METHODS: 594 men, free of CHD at baseline, were followed from August 1991 to June 2011 in the Normative Aging Study. Bone lead concentrations were measured by K-shell-X-ray fluorescence. Dietary patterns were identified using principal components analysis. Two dietary patterns were identified: a 'prudent' pattern characterized by high intake of fruit, vegetables, legumes, tomatoes, poultry, and seafood; and a 'Western' pattern, with high intake of red meat, processed meat, refined grains, high-fat dairy products, high-energy drinks, fries, butter and eggs. Cox proportional hazard models were used to compute hazard ratios (HRs) and 95% confidence intervals (CIs) for incident CHD. Effect modification on the multiplicative scale was examined through cross-product interaction terms. RESULTS: 137 men developed incident CHD events during 5071 person-years of follow-up. After adjusting for age, body mass index, total energy intake, smoking status, total cholesterol to high-density lipoprotein ratio, education and occupation, an HR of incident CHD was 1.64 (95% CI: 1.27-2.11) with each doubling in patella lead concentration in the low prudent diet group (< median prudent score); and the HR decreased to 1.07 (95% CI: 0.86-1.34) in the high prudent diet (≥ median prudent score) (p-for-interaction = 0.01), suggesting protective effects of prudent diet against lead-related CHD. By contrast, the association between tibia lead and CHD was non-significantly larger in the low Western diet group (HR = 1.43, 95% CI: 1.14-1.80) compared with the high Western diet group (HR = 1.08, 95% CI: 0.86-1.34) (p-for-interaction = 0.06). No significant effect modifications were detected by Western diet in the patella lead-CHD association and by prudent diet in the tibia lead-CHD association. CONCLUSIONS: Prudent diet may reduce the risk of development of CHD in relation to patella lead. However, these findings need to be interpreted with caution, given the modest sample size.

Correlation over time of toenail metals among participants in the VA normative aging study from 1992 to 2014.

BACKGROUND: Scientists use biomarkers to evaluate metal exposures. One biomarker, toenails, is easily obtained and minimally invasive, but less commonly used as a biomarker of exposure. Their utility will depend on understanding characteristics of their variation in a population over time. The objective of our study is to describe the correlation of toenail metal levels many years apart among participants in the VA Normative Aging Study (NAS). METHODS: Toenail clippings from 825 participants of the NAS from year 1992 to 2014 were analyzed for lead (Pb), Arsenic (As), Cadmium (Cd), Manganese (Mn), and Mercury (Hg). We utilized linear mixed models to assess correlation between toenail metal concentrations in multiple toenail samples from the same subject collected years apart and identified the optimal covariance pattern by likelihood ratio tests and Akaike's information criterion (AIC). Correlations among different metals were described using Spearman correlations. RESULTS: The average number of times toenail samples were collected from each subject ranged from 1.63 (Hg) to 2.04 (As). The average number of years between toenails collected per subject ranged from 4.73 (SD = 2.44) (Mn) to 5.35 (SD = 2.69) (Hg). Metal concentrations had slightly different correlation patterns over time, although for all metals correlations decreased with increasing time between samples. Estimated correlations over a 3-year span were highest for toenail Pb (0.68) and Hg (0.67), while As, Cd, and Mn had lower correlations of 0.49, 0.44, and 0.47, respectively. Even across a 6-year span, the lowest correlation was 0.35 (Cd). CONCLUSIONS: Our results suggest that Pb, As, Cd, Mn, and Hg levels from toenail clippings can reasonably reflect exposures over several years in elderly men in the NAS. Even across 6 years, toenail metal levels were generally well correlated among NAS participants. As such, they may be useful as biomarkers of exposure in epidemiological studies of similar populations.

Bone Lead Levels and Risk of Incident Primary Open-Angle Glaucoma: The VA Normative Aging Study.

BACKGROUND: Oxidative stress may play an important role in the etiology of primary open-angle glaucoma (POAG). The association between risk of POAG and lead exposure, which is an environmental source of oxidative stress, has not been fully investigated yet. OBJECTIVE: Our objective was to determine the association between bone lead­a biomarker of cumulative lead dose (tibia lead) or an endogenous source of stored lead (patella lead)­and incident POAG. METHODS: We examined a prospective cohort of 634 POAG-free men [mean baseline age=66.8 y of age (SD=6.7)] from the Normative Aging Study (NAS) who had tibia and patella K X-ray fluorescence lead measurements between 1 January 1991 and 31 December 1999. They also had standard ocular evaluations by NAS optometrists until 31 December 2014. POAG cases were identified by consistent reports of enlarged or asymmetric cup-to-disc ratio together with visual field defect or existence of disc hemorrhage. We used Cox proportional hazards regressions to estimate hazard ratios (HRs) of incident POAG and adjusted survival curves to examine changes in the risk of POAG during follow-up according to bone lead quartiles. RESULTS: We identified 44 incident cases of POAG by the end of follow-up (incidence rate=74 per 10,000 person-years; median follow-up=10.6 y). In fully adjusted models, 10-fold increases in patella lead and tibia lead were associated with HRs of 5.06 (95% CI: 1.61, 15.88, p=0.005) and 3.07 (95% CI: 0.94, 10.0, p=0.06), respectively. The HRs comparing participants in the third and fourth quartiles with the lowest quartile were 3.41 (95% CI: 1.34, 8.66) and 3.24 (95% CI: 1.22, 8.62) for patella lead (p-for-trend=0.01), and 3.84 (95% CI: 1.54, 9.55) and 2.61 (95% CI: 0.95, 7.21) for tibia lead (p-for-trend=0.02). CONCLUSIONS: Our study provides longitudinal evidence that bone lead may be an important risk factor for POAG in the U.S. population. https://doi.org/10.1289/EHP3442.

Iron-processing genotypes, nutrient intakes, and cadmium levels in the Normative Aging Study: Evidence of sensitive subpopulations in cadmium risk assessment.

BACKGROUND: Because iron and cadmium share common transport mechanisms, iron-processing protein variants such as HFE C282Y, HFE H63D, and Transferrin P570S may influence cadmium metabolism. Our aim was to evaluate associations between common HFE and Transferrin polymorphisms and toenail cadmium levels among older men. METHODS: In a longitudinal cohort of men age 51-97, the Normative Aging Study (NAS), we evaluated toenail cadmium concentrations and missense single nucleotide polymorphisms (SNPs) in the HFE and Transferrin genes. We fit age-adjusted models to estimate associations between genotypes and toenail cadmium concentrations. We then considered potential interactions with smoking status, hemoglobin, and nutritional intakes known to modulate cadmium absorption. For the significant interactions, we also evaluated genotype specific effect estimates. RESULTS: HFE and Transferrin genotypes were not associated with toenail cadmium concentrations in the main effect analyses, but there were significant interactions between HFE H63D and hemoglobin (pinteraction = 0.021), as well as HFE H63D and vitamin C intake (pinteraction = 0.048). Genotype specific effect estimates suggested: 1) an inverse relationship between hemoglobin and cadmium levels among HFE H63D homozygotes, and 2) an inverse relationship between vitamin C intake and cadmium levels that strengthens with the number of HFE H63D variant alleles a subject carries. CONCLUSIONS: These findings suggest that sensitive subpopulations defined by diet, hemoglobin level, and genotype may absorb more cadmium from their environment and thus should be considered in cadmium risk analyses. These findings are particularly relevant given the high prevalence of the H63D variant worldwide.

Longitudinal Modeling of Lung Function Trajectories in Smokers with and without Chronic Obstructive Pulmonary Disease.

RATIONALE: The relationship between longitudinal lung function trajectories, chest computed tomography (CT) imaging, and genetic predisposition to chronic obstructive pulmonary disease (COPD) has not been explored. OBJECTIVES: 1) To model trajectories using a data-driven approach applied to longitudinal data spanning adulthood in the Normative Aging Study (NAS), and 2) to apply these models to demographically similar subjects in the COPDGene (Genetic Epidemiology of COPD) Study with detailed phenotypic characterization including chest CT. METHODS: We modeled lung function trajectories in 1,060 subjects in NAS with a median follow-up time of 29 years. We assigned 3,546 non-Hispanic white males in COPDGene to these trajectories for further analysis. We assessed phenotypic and genetic differences between trajectories and across age strata. MEASUREMENTS AND MAIN RESULTS: We identified four trajectories in NAS with differing levels of maximum lung function and rate of decline. In COPDGene, 617 subjects (17%) were assigned to the lowest trajectory and had the greatest radiologic burden of disease (P < 0.01); 1,283 subjects (36%) were assigned to a low trajectory with evidence of airway disease preceding emphysema on CT; 1,411 subjects (40%) and 237 subjects (7%) were assigned to the remaining two trajectories and tended to have preserved lung function and negligible emphysema. The genetic contribution to these trajectories was as high as 83% (P = 0.02), and membership in lower lung function trajectories was associated with greater parental histories of COPD, decreased exercise capacity, greater dyspnea, and more frequent COPD exacerbations. CONCLUSIONS: Data-driven analysis identifies four lung function trajectories. Trajectory membership has a genetic basis and is associated with distinct lung structural abnormalities.