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1.
Nat Genet ; 51(3): 494-505, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30804561

RESUMO

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.


Assuntos
Predisposição Genética para Doença/genética , Doença Pulmonar Obstrutiva Crônica/genética , Adulto , Idoso , Asma/genética , Estudos de Casos e Controles , Feminino , Expressão Gênica/genética , Loci Gênicos/genética , Estudo de Associação Genômica Ampla/métodos , Humanos , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Fibrose Pulmonar/genética , Fumar/genética
2.
Environ Res ; 168: 222-229, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30317107

RESUMO

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.


Assuntos
Osso e Ossos/metabolismo , Doença das Coronárias/epidemiologia , Dieta/estatística & dados numéricos , Chumbo/metabolismo , Idoso , Ingestão de Energia , Exposição Ambiental/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Verduras
3.
Artigo em Inglês | MEDLINE | ID: mdl-30482937

RESUMO

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.

4.
Environ Health Perspect ; 126(8): 087002, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-30102601

RESUMO

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.

5.
Environ Int ; 119: 527-535, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30059941

RESUMO

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.

6.
Am J Respir Crit Care Med ; 198(8): 1033-1042, 2018 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-29671603

RESUMO

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.

7.
Environ Res ; 165: 110-117, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29684737

RESUMO

While the effects of weather variability on cardio-respiratory mortality are well described, research examining the effects on morbidity, especially for vulnerable populations, is warranted. We investigated the associations between lung function and outdoor temperature (T in Celsius degrees (°C)) and relative humidity (RH), in a cohort of elderly men, the Normative Aging Study. Our study included 1103 participants whose forced vital capacity (FVC), forced expiratory volume in one second (FEV1), and weather exposures were assessed one to five times during the period 1995-2011 (i.e. 3162 observations). Temperature and relative humidity were measured at one location 4 h to 7 days before lung function tests. We used linear mixed-effects models to examine the associations with outdoor T and RH. A 5-degree increase in the 3-day moving average T was associated with a significant 0.7% decrease (95%CI: -1.24, -0.20) in FVC and a 5% increase in the 7-day moving average RH was associated with a significant 0.2% decrease (95%CI: -0.40, -0.02) in FVC and FEV1. The associations with T were greater when combined with higher exposures of black carbon with a 1.6% decrease (95%CI -2.2; -0.9) in FVC and a 1% decrease (95%CI -1.7; -0.4) in FEV1. The relationships between T and RH and lung function were linear. No synergistic effect of T and RH was found. Heat and lung function are two predictors of mortality. Our findings suggest that increases in temperature and relative humidity are related to decreases in lung function, and such observations might be amplified by high black carbon levels.

8.
J Am Heart Assoc ; 7(21): e010014, 2018 11 06.
Artigo em Inglês | MEDLINE | ID: mdl-30608198

RESUMO

Background Bone lead offers a better method over blood lead measurement to discern long-term lead exposure and accumulation. We examined the risk of resistant hypertension based on bone lead levels in a prospective cohort study of NAS (Normative Aging Study). Methods and Results Participants had clinic data on hypertension (systolic blood pressure, diastolic blood pressure, and antihypertension medication), lead (blood, bone-patella, bone-tibia), and demographic and confounding variables. Cases of resistant hypertension were identified by meeting criteria for: (1) inadequate systolic blood pressure (>140 mm Hg) or diastolic blood pressure (>90 mm Hg) while taking 3 medications or (2) requiring >4 medications for blood pressure control. A modified Poisson regression was used for model analysis. Of the 475 participants, 97 cases of resistant hypertension (20.4%) were identified. Among the cases of resistant hypertension, the median tibia and patella lead levels were 20 µg/g and 25 µg/g, respectively, while median tibia and patella lead levels were 20 µg/g and 27.5 µg/g, respectively, in participants without resistant hypertension. Tibia lead demonstrated a significant association with resistant hypertension (relative risk, 1.19; 95% confidence interval, 1.01-1.41 [ P=0.04]) per interquartile range increase in tibia lead (13-28.5 µg/g). Patella lead was not associated with resistant hypertension (relative risk, 1.10; 95% confidence interval, 0.92-1.31 [ P=0.31]) per interquartile range increase in patella lead (18-40 µg/g). Blood lead levels were not significantly associated with resistant hypertension (relative risk, 1.11; 95% confidence interval, 0.88-1.40 [ P=0.38]). Conclusions Tibia lead represents a novel risk factor for resistant hypertension. Our study demonstrates an increased association between tibia lead and resistant hypertension status, with an increased risk of 19% per 1 interquartile range increase in tibia lead.

9.
J Nutr ; 147(7): 1374-1383, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28592514

RESUMO

Background: Little is known about the effects of overall dietary pattern on lead concentration.Objective: We examined the association of overall dietary patterns, derived from a semiquantitative food frequency questionnaire, with bone and blood lead concentrations.Methods: These longitudinal analyses included mostly non-Hispanic white, middle-aged-to-elderly men from the Veterans Affairs Normative Aging Study. Long-term lead exposures were measured as tibia and patella lead concentrations by using K-shell-X-ray fluorescence. Short-term lead exposures were measured as blood lead concentrations by using graphite furnace atomic absorption spectroscopy. Dietary pattern scores were derived by using factor analysis. Linear mixed-effects models were utilized to predict blood lead concentrations among 983 men, aged 44-92 y at baseline, with a total of 3273 observations (during 1987-2008). We constructed linear regression models to determine the relations between dietary patterns and bone lead concentrations among 649 participants with an age range of 49-93 y.Results: Two major dietary patterns were identified: a prudent dietary pattern, characterized by high intakes of fruit, legumes, vegetables, whole grains, poultry, and seafood; and a Western dietary pattern, characterized by high intakes of processed meat, red meat, refined grains, high-fat dairy products, French fries, butter, and eggs. After adjusting for age, smoking status, body mass index, total energy intake, education, occupation, neighborhood-based education and income level, men in the highest tertile of the Western pattern score (compared with the lowest) had 0.91 µg/dL (95% CI: 0.41, 1.42 µg/dL) higher blood lead, 5.96 µg/g (95% CI: 1.76, 10.16 µg/g) higher patella lead, and 3.83 µg/g (95% CI: 0.97, 6.70 µg/g) higher tibia lead. No significant association was detected with the prudent dietary pattern in the adjusted model.Conclusions: These findings suggest that the Western diet is associated with a greater lead body burden among the middle-aged-to-elderly men. More studies are needed to examine the underlying mechanisms by which dietary patterns are associated with lead concentrations.


Assuntos
Dieta , Contaminação de Alimentos , Chumbo/sangue , Chumbo/química , Idoso , Idoso de 80 Anos ou mais , Humanos , Masculino , Pessoa de Meia-Idade
10.
Am J Respir Cell Mol Biol ; 57(3): 367-375, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28441029

RESUMO

Chronic obstructive pulmonary disease (COPD) is caused by a complex interaction of environmental exposures, most commonly cigarette smoke, and genetic factors. Chronic cigarette smoke exposure in the mouse is a commonly used animal model of COPD. We aimed to expand our knowledge about the variable susceptibility of inbred strains to this model and test for genetic variants associated with this trait. To that end, we sought to measure differential susceptibility to cigarette smoke-induced emphysema in the mouse, identify genetic loci associated with this quantitative trait, and find homologous human genes associated with COPD. Alveolar chord length (CL) in 34 inbred strains of mice was measured after 6 months of exposure to cigarette smoke. After testing for association, we connected a murine candidate locus to a published meta-analysis of moderate-to-severe COPD. We identified deleterious mutations in a candidate gene in silico and measured gene expression in extreme strains. A/J was the most susceptible strain in our survey (Δ CL 7.0 ± 2.2 µm) and CBA/J was the least susceptible (Δ CL -0.3 ± 1.2 µm). By integrating mouse and human genome-wide scans, we identified the candidate gene Abi3bp. CBA/J mice harbor predicted deleterious variants in Abi3bp, and expression of the gene differs significantly between CBA/J and A/J mice. This is the first report of susceptibility to cigarette smoke-induced emphysema in 34 inbred strains of mice, and Abi3bp is identified as a potential contributor to this phenotype.


Assuntos
Proteínas de Transporte/metabolismo , Enfisema Pulmonar/metabolismo , Fumar/efeitos adversos , Animais , Proteínas de Transporte/genética , Simulação por Computador , Suscetibilidade a Doenças , Perfilação da Expressão Gênica , Genoma Humano , Estudo de Associação Genômica Ampla , Humanos , Camundongos Endogâmicos , Mutação/genética , Alvéolos Pulmonares/metabolismo , Alvéolos Pulmonares/patologia , Enfisema Pulmonar/patologia
11.
Hum Mol Genet ; 26(8): 1584-1596, 2017 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-28334838

RESUMO

The Asp358Ala variant in the interleukin-6 receptor (IL-6R) gene has been implicated in asthma, autoimmune and cardiovascular disorders, but its role in other respiratory conditions such as chronic obstructive pulmonary disease (COPD) has not been investigated. The aims of this study were to evaluate whether there is an association between Asp358Ala and COPD or asthma risk, and to explore the role of the Asp358Ala variant in sIL-6R shedding from neutrophils and its pro-inflammatory effects in the lung. We undertook logistic regression using data from the UK Biobank and the ECLIPSE COPD cohort. Results were meta-analyzed with summary data from a further three COPD cohorts (7,519 total cases and 35,653 total controls), showing no association between Asp358Ala and COPD (OR = 1.02 [95% CI: 0.96, 1.07]). Data from the UK Biobank showed a positive association between the Asp358Ala variant and atopic asthma (OR = 1.07 [1.01, 1.13]). In a series of in vitro studies using blood samples from 37 participants, we found that shedding of sIL-6R from neutrophils was greater in carriers of the Asp358Ala minor allele than in non-carriers. Human pulmonary artery endothelial cells cultured with serum from homozygous carriers showed an increase in MCP-1 release in carriers of the minor allele, with the difference eliminated upon addition of tocilizumab. In conclusion, there is evidence that neutrophils may be an important source of sIL-6R in the lungs, and the Asp358Ala variant may have pro-inflammatory effects in lung cells. However, we were unable to identify evidence for an association between Asp358Ala and COPD.


Assuntos
Asma/genética , Estudos de Associação Genética , Doença Pulmonar Obstrutiva Crônica/genética , Receptores de Interleucina-6/genética , Asma/sangue , Asma/patologia , Feminino , Humanos , Pulmão/metabolismo , Pulmão/patologia , Masculino , Neutrófilos/metabolismo , Neutrófilos/patologia , Doença Pulmonar Obstrutiva Crônica/sangue , Doença Pulmonar Obstrutiva Crônica/patologia
12.
Nat Genet ; 49(3): 426-432, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28166215

RESUMO

Chronic obstructive pulmonary disease (COPD) is a leading cause of mortality worldwide. We performed a genetic association study in 15,256 cases and 47,936 controls, with replication of select top results (P < 5 × 10-6) in 9,498 cases and 9,748 controls. In the combined meta-analysis, we identified 22 loci associated at genome-wide significance, including 13 new associations with COPD. Nine of these 13 loci have been associated with lung function in general population samples, while 4 (EEFSEC, DSP, MTCL1, and SFTPD) are new. We noted two loci shared with pulmonary fibrosis (FAM13A and DSP) but that had opposite risk alleles for COPD. None of our loci overlapped with genome-wide associations for asthma, although one locus has been implicated in joint susceptibility to asthma and obesity. We also identified genetic correlation between COPD and asthma. Our findings highlight new loci associated with COPD, demonstrate the importance of specific loci associated with lung function to COPD, and identify potential regions of genetic overlap between COPD and other respiratory diseases.


Assuntos
Loci Gênicos/genética , Predisposição Genética para Doença/genética , Pulmão/fisiologia , Doença Pulmonar Obstrutiva Crônica/genética , Fibrose Pulmonar/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Asma/genética , Feminino , Estudo de Associação Genômica Ampla/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Fatores de Risco , Fumar/genética
13.
Am J Respir Cell Mol Biol ; 57(1): 35-46, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28170284

RESUMO

The heritability of chronic obstructive pulmonary disease (COPD) cannot be fully explained by recognized genetic risk factors identified as achieving genome-wide significance. In addition, the combined contribution of genetic variation to COPD risk has not been fully explored. We sought to determine: (1) whether studies of variants from previous studies of COPD or lung function in a larger sample could identify additional associated variants, particularly for severe COPD; and (2) the impact of genetic risk scores on COPD. We genotyped 3,346 single-nucleotide polymorphisms (SNPs) in 2,588 cases (1,803 severe COPD) and 1,782 control subjects from four cohorts, and performed association testing with COPD, combining these results with existing genotyping data from 6,633 cases (3,497 severe COPD) and 5,704 control subjects. In addition, we developed genetic risk scores from SNPs associated with lung function and COPD and tested their discriminatory power for COPD-related measures. We identified significant associations between SNPs near PPIC (P = 1.28 × 10-8) and PPP4R4/SERPINA1 (P = 1.01 × 10-8) and severe COPD; the latter association may be driven by recognized variants in SERPINA1. Genetic risk scores based on SNPs previously associated with COPD and lung function had a modest ability to discriminate COPD (area under the curve, ∼0.6), and accounted for a mean 0.9-1.9% lower forced expiratory volume in 1 second percent predicted for each additional risk allele. In a large genetic association analysis, we identified associations with severe COPD near PPIC and SERPINA1. A risk score based on combining genetic variants had modest, but significant, effects on risk of COPD and lung function.


Assuntos
Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Doença Pulmonar Obstrutiva Crônica/genética , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Testes de Função Respiratória , Fatores de Risco
14.
J Air Waste Manag Assoc ; 67(1): 96-104, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-28001123

RESUMO

Many studies have demonstrated that cold and hot temperatures are associated with increased deaths and hospitalization rates; new findings indicate also an association with more specific cardiac risk factors. Most of these existing studies have relied on few weather stations to characterize exposures; few have used residence-specific estimates of temperature, or examined the exposure-response function. We investigated the association of arrhythmia episodes with spatial and temporal variation in temperature. We also evaluated the association btween monitored ambient temperature (central) and the same outcome. This longitudinal analysis included 701 older men participating in the VA Normative Aging Study. Arrhythmia episodes were measured as ventricular ectopy (VE) (bigeminy, trigeminy, or couplets episodes) by 4-min electrocardiogram (ECG) monitoring in repeated visits during 2000-2010. The outcome was defined as having or not VE episodes during a study visit. We applied a mixed-effect logistic regression model with a random intercept for subject, controlling for seasonality, weekday, medication use, smoking, diabetes status, body mass index, and age. We also examined effect modification by personal characteristics, confounding by air pollution, and the exposure-response function. For 1°C increase in the same day residence-specific temperature, the odds of having VE episodes was 1.10 (95% confidence interval [CI]: 1.04-1.17). The odds associated with 1°C increase in central temperature was 1.05 (95% CI: 1.02-1.09). The exposure-response function was nonlinear for averages of temperature, presenting a J-shaped pattern, suggesting greater risk at lower and higher temperatures. Increased warm temperature and decreased cold temperature may increase the risk of ventricular arrhythmias. IMPLICATIONS: This is the first study to provide evidence that residence-specific temperature exposure is associated with increased risk of ventricular arrhythmias in cohort of elderly subjects without known chronic medical conditions; that the delayed effect of temperature has a nonlinear relationship; and therefore that both warm and cold temperature increase the risk of having ventricular arrhythmias. Moreover, we show that the use of residence-specific temperature data reduces downward bias due to exposure error, by comparing the estimated health effect based on our spatiotemporal exposure prediction model to those based on a single local weather monitor.


Assuntos
Poluentes Atmosféricos/efeitos adversos , Poluentes Atmosféricos/química , Poluição do Ar/efeitos adversos , Arritmias Cardíacas/etiologia , Idoso , Envelhecimento , Poluição do Ar/análise , Temperatura Baixa , Temperatura Alta , Habitação , Humanos , Masculino , Pessoa de Meia-Idade , Material Particulado , Fatores de Risco , Temperatura Ambiente , Estados Unidos , United States Department of Veterans Affairs
15.
Epigenetics ; 12(2): 139-148, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27982729

RESUMO

Although there is growing evidence that exposure to ambient particulate matter is associated with global DNA methylation and gene-specific methylation, little is known regarding epigenome-wide changes in DNA methylation in relation to particles and, especially, particle components. Using the Illumina Infinium HumanMethylation450 BeadChip, we examined the relationship between one-year moving averages of PM2.5 species (Al, Ca, Cu, Fe, K, Na, Ni, S, Si, V, and Zn) and DNA methylation at 484,613 CpG probes in a longitudinal cohort that included 646 subjects. Bonferroni correction was applied to adjust for multiple comparisons. Bioinformatics analysis of the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment was also performed. We observed 20 Bonferroni significant (P-value < 9.4× 10-9) CpGs for Fe, 8 for Ni, and 1 for V. Particularly, methylation at Schlafen Family Member 11 (SLFN11) cg10911913 was positively associated with measured levels of all 3 species. The SLFN11 gene codes for an interferon-induced protein that inhibits retroviruses and sensitizes cancer cells to DNA-damaging agents. Bioinformatics analysis suggests that gene targets may be relevant to pathways including cancers, signal transduction, and cell growth and death. Ours is the first study to examine the epigenome-wide association between ambient particles species and DNA methylation. We found that long-term exposures to specific components of ambient particle pollution, especially particles emitted during oil combustion, were associated with methylation changes in genes relevant to immune responses. Our findings provide insight into potential biologic mechanisms on an epigenetic level.


Assuntos
Metilação de DNA , Epigênese Genética , Material Particulado/toxicidade , Idoso , Idoso de 80 Anos ou mais , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Metais/análise , Proteínas Nucleares/genética , Material Particulado/química
16.
Environ Res ; 152: 102-108, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27770710

RESUMO

BACKGROUND: Lead (Pb) exposure has been associated with poorer cognitive function cross-sectionally in aging adults, however the association between cumulative Pb exposure and longitudinal changes in cognition is little characterized. METHODS: In a 1993-2007 subcohort of the VA Normative Aging Study (Mini-mental status exam (MMSE) n=741; global cognition summary score n=715), we used linear mixed effects models to test associations between cumulative Pb exposure (patella or tibia bone Pb) and repeated measures of cognition (MMSE, individual cognitive tests, and global cognition summary). Cox proportional hazard modeling assessed the risk of an MMSE score falling below 25. RESULTS: Among men 51-98 at baseline, higher patella Pb concentration (IQR: 21µg/g) was associated with -0.13 lower baseline MMSE (95% CI: -0.25, -0.004) and faster longitudinal MMSE decline (-0.016 units/year, 95% CI: -0.032, -0.0004) over 15 years. Each IQR increase in patella Pb was associated with increased risk of a MMSE score below 25 (HR=1.21, 95% CI: 0.99, 1.49; p=0.07). There were no significant associations between Pb and global cognition (both baseline and longitudinal change). Patella Pb was associated with faster longitudinal decline in Word List Total Recall in the language domain (0.014 units/year, 95% CI: -0.026, -0.001) and Word List Delayed Recall in the memory domain (0.014 units/year, 95% CI: -0.027, -0.002). We found weaker associations with tibia Pb. CONCLUSIONS: Cumulative Pb exposure is associated with faster declines in MMSE and Word List Total and Delayed Recall tests. These findings support the hypothesis that Pb exposure accelerates cognitive aging.


Assuntos
Transtornos Cognitivos/epidemiologia , Cognição/efeitos dos fármacos , Exposição Ambiental , Poluentes Ambientais/metabolismo , Poluentes Ambientais/toxicidade , Chumbo/metabolismo , Chumbo/toxicidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Envelhecimento , Transtornos Cognitivos/induzido quimicamente , Humanos , Estudos Longitudinais , Masculino , Massachusetts/epidemiologia , Pessoa de Meia-Idade , Testes Neuropsicológicos , Patela/química , Modelos de Riscos Proporcionais , Tíbia/química , Adulto Jovem
17.
PLoS One ; 11(9): e0161472, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27584680

RESUMO

BACKGROUND: 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. OBJECTIVES: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.


Assuntos
Envelhecimento/fisiologia , Doença das Coronárias/induzido quimicamente , Exposição Ambiental , Chumbo/toxicidade , Idoso , Osso e Ossos/química , Doença das Coronárias/genética , Feminino , Predisposição Genética para Doença , Humanos , Chumbo/análise , Chumbo/farmacocinética , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético
18.
Environ Res ; 150: 446-51, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27391696

RESUMO

Few studies have examined the association between ambient temperature and cognitive function, or used exposure to temperature at a given address instead of a single stationary monitor. The existing literature on the temperature-cognition relationship has mostly consisted of experimental studies that involve a small sample size and a few specific temperature values. In the current study, we examined the association between residential air temperature and Mini-Mental State Examination (MMSE) scores, a quantitative measurement of cognitive function, in a longitudinal cohort of elderly men. Residential air temperature was estimated by a novel spatiotemporal approach that incorporates satellite remote sensing, land use regression, meteorological variables and spatial smoothing in the Northeastern USA. We then applied logistic regression generalized estimating equations to examine the relationship between residential temperature (range: -5.8-25.7°C), and the risk of low MMSE scores (MMSE scores ≤25) among 594 elderly men (1085 visits in total) from the Veterans Affairs Normative Aging Study, 2000-2008. Sensitivity analysis on visits wherein subjects lived within 30km of the clinic center in Massachusetts or aged ≥70 years was also evaluated. A statistically significant, U-shaped association between residential air temperature and low MMSE score (p-value=0.036) was observed. Sensitivity analysis suggested that the estimated effect remains among individuals aged ≥70 years. In conclusion, the data suggest that risk of low MMSE scores is highest when temperature is either high or low, and lowest when ambient temperature is approximately within 10-15°C in a cohort of elderly men. Further research is needed to confirm our findings and assess generalizability to other populations.


Assuntos
Cognição , Temperatura Ambiente , Idoso , Habitação , Humanos , Estudos Longitudinais , Masculino , Testes Neuropsicológicos , Análise Espaço-Temporal
19.
Environ Health Perspect ; 124(9): 1353-60, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-26955062

RESUMO

BACKGROUND: It is unknown if ambient fine particulate matter (PM2.5) is associated with lower renal function, a cardiovascular risk factor. OBJECTIVE: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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. CITATION: 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; http://dx.doi.org/10.1289/ehp.1510269.


Assuntos
Poluentes Atmosféricos/toxicidade , Exposição Ambiental , Taxa de Filtração Glomerular/efeitos dos fármacos , Material Particulado/toxicidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Pressão Sanguínea , Boston , Estudos de Coortes , Creatinina/sangue , Humanos , Testes de Função Renal , Modelos Lineares , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Tamanho da Partícula , Veteranos/estatística & dados numéricos , Adulto Jovem
20.
Parkinsonism Relat Disord ; 23: 57-61, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26725141

RESUMO

INTRODUCTION: The literature on the effect of head injuries on the risk of PD is inconclusive. Some researchers have hypothesized that studies that have seen an effect are simply capturing injury related to pre-clinical PD. However in animal models brain inflammation, which can be initiated by head trauma, has been shown to produce PD-like effects. Furthermore, animal studies have found that early life inflammation in particular is of relevance for PD pathology. METHODS: We conducted an unmatched case-control study of 379 neurologist confirmed PD patients and 230 controls from the greater Boston, Massachusetts area with questionnaire data on history of head injury and other covariates. We used multivariable logistic regression to estimate adjusted odds ratios (OR) and their corresponding 95% confidence intervals (CI) for PD. RESULTS: When we excluded injuries that occurred less than 10 years prior to the diagnosis of PD (in order to avoid reverse causation), we found an increased risk of PD associated with a head injury that resulted in a loss of consciousness, but it did not reach statistical significance (OR = 1.57; 95% CI = 0.89-2.80). We found a significant (p = 0.04) effect of age at first head injury. For every 5 year earlier age at first head injury with loss of consciousness the OR for PD was 1.37 (95% CI: 1.01-1.86). CONCLUSION: Our results suggest that head injury in early life increases the risk of PD.


Assuntos
Traumatismos Craniocerebrais/complicações , Traumatismos Craniocerebrais/epidemiologia , Doença de Parkinson/etiologia , Adolescente , Idoso , Estudos de Casos e Controles , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Fatores de Risco , Inquéritos e Questionários
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