Denis Bard and Marie-Abele C Bind. 5/2015. “ Percée scientifique ou coup publicitaire ?” Environnement, Risques & Santé, 14, 3, Pp. 188-91.
Marie-Abele C Bind, Brent A Coull, Annette Peters, Andrea A Baccarelli, Letizia Tarantini, Laura Cantone, Pantel S Vokonas, Petros Koutrakis, and Joel D Schwartz. 2015. “Beyond the Mean: Quantile Regression to Explore the Association of Air Pollution with Gene-Specific Methylation in the Normative Aging Study.” Environ Health Perspect, 123, 8, Pp. 759-65.Abstract
BACKGROUND: Air pollution has been related to mean changes in outcomes, including DNA methylation. However, mean regression analyses may not capture associations that occur primarily in the tails of the outcome distribution. OBJECTIVES: In this study, we examined whether the association between particulate air pollution and DNA methylation differs across quantiles of the methylation distribution. We focused on methylation of candidate genes related to coagulation and inflammation: coagulation factor III (F3), intercellular adhesion molecule 1 (ICAM-1), interferon gamma (IFN-γ), interleukin-6 (IL-6), and toll-like receptor 2 (TRL-2). METHODS: We measured gene-specific blood DNA methylation repeatedly in 777 elderly men participating in the Normative Aging Study (1999-2010). We fit quantile regressions for longitudinal data to investigate whether the associations of particle number, PM2.5 (diameter ≤ 2.5 μm)black carbon, and PM2.5 mass concentrations (4-week moving average) with DNA methylation [expressed as the percentage of methylated cytosines over the sum of methylated and unmethylated cytosines at position 5 (%5mC)] varied across deciles of the methylation distribution. We reported the quantile regression coefficients that corresponded to absolute differences in DNA methylation (expressed in %5mC) associated with an interquartile range increase in air pollution concentration. RESULTS: Interquartile range increases in particle number, PM2.5 black carbon, and PM2.5 mass concentrations were associated with significantly lower methylation in the lower tails of the IFN-γ and ICAM-1 methylation distributions. For instance, a 3.4-μg/m3 increase in PM2.5 mass concentration was associated with a 0.18%5mC (95% CI: -0.30, -0.06) decrease on the 20th percentile of ICAM-1 methylation, but was not significantly related to the 80th percentile (estimate: 0.07%5mC, 95% CI: -0.09, 0.24). CONCLUSIONS: In our study population of older men, air pollution exposures were associated with a left shift in the lower tails of the IFN-γ and ICAM-1 methylation distributions.
Jia Zhong, Elena Colicino, Xinyi Lin, Amar Mehta, Itai Kloog, Antonella Zanobetti, Hyang-Min Byun, Marie-Abèle Bind, Laura Cantone, Diddier Prada, Letizia Tarantini, Letizia Trevisi, David Sparrow, Pantel Vokonas, Joel Schwartz, and Andrea A Baccarelli. 2015. “Cardiac autonomic dysfunction: particulate air pollution effects are modulated by epigenetic immunoregulation of Toll-like receptor 2 and dietary flavonoid intake.” J Am Heart Assoc, 4, 1, Pp. e001423.Abstract
BACKGROUND: Short-term fine particles (PM(2.5)) exposure is associated with reduced heart rate variability, a strong predictor of cardiac mortality among older people. Identifying modifiable factors that confer susceptibility is essential for intervention. We evaluated whether Toll-like receptor 2 (TLR2) methylation, a reversible immune-epigenetic process, and its dietary modulation by flavonoids and methyl nutrients, modify susceptibility to heart rate variability effects following PM(2.5) exposure. METHODS AND RESULTS: We measured heart rate variability and PM(2.5) repeatedly over 11 years (1275 total observations) among 573 elderly men from the Normative Aging Study. Blood TLR2 methylation was analyzed using pyrosequencing. Daily flavonoid and methyl nutrients intakes were assessed through the Food Frequency Questionnaire (FFQ). Every 10 μg/m(3) increase in 48-hour PM(2.5) moving average was associated with 7.74% (95% CI: -1.21% to 15.90%; P=0.09), 7.46% (95% CI: 0.99% to 13.50%; P=0.02), 14.18% (95% CI: 1.14% to 25.49%; P=0.03), and 12.94% (95% CI: -2.36% to 25.96%; P=0.09) reductions in root mean square of successive differences, standard deviation of normal-to-normal intervals, low-frequency power, and high-frequency power, respectively. Higher TLR2 methylation exacerbated the root mean square of successive differences, standard deviation of normal-to-normal intervals, low-frequency, and high-frequency reductions associated with heightened PM2.5 (P(interaction)=0.006, 0.03, 0.05, 0.04, respectively). Every interquartile-range increase in flavonoid intake was associated with 5.09% reduction in mean TLR2 methylation (95% CI: 0.12% to 10.06%; P=0.05) and counteracted the effects of PM2.5 on low frequency (P(interaction)=0.05). No significant effect of methyl nutrients on TLR2 methylation was observed. CONCLUSIONS: Higher TLR2 methylation may confer susceptibility to adverse cardiac autonomic effects of PM2.5 exposure in older individuals. Higher flavonoid intake may attenuate these effects, possibly by decreasing TLR2 methylation.
Joel Schwartz, Elena Austin, Marie-Abele Bind, Antonella Zanobetti, and Petros Koutrakis. 2015. “Estimating Causal Associations of Fine Particles With Daily Deaths in Boston.” Am J Epidemiol, 182, 7, Pp. 644-50.Abstract
Many studies have reported associations between daily particles less than 2.5 µm in aerodynamic diameter (PM2.5) and deaths, but they have been associational studies that did not use formal causal modeling approaches. On the basis of a potential outcome approach, we used 2 causal modeling methods with different assumptions and strengths to address whether there was a causal association between daily PM2.5 and deaths in Boston, Massachusetts (2004-2009). We used an instrumental variable approach, including back trajectories as instruments for variations in PM2.5 uncorrelated with other predictors of death. We also used propensity score as an alternative causal modeling analysis. The former protects against confounding by measured and unmeasured confounders and is based on the assumption of a valid instrument. The latter protects against confounding by all measured covariates, provides valid estimates in the case of effect modification, and is based on the assumption of no unmeasured confounders. We found a causal association of PM2.5 with mortality, with a 0.53% (95% confidence interval: 0.09, 0.97) and a 0.50% (95% confidence interval: 0.20, 0.80) increase in daily deaths using the instrumental variable and the propensity score, respectively. We failed to reject the null association with exposure after the deaths (P =0.93). Given these results, prior studies, and extensive toxicological support, the association between PM2.5 and deaths is almost certainly causal.
Marie-Abele Bind, Johanna Lepeule, Antonella Zanobetti, Antonio Gasparrini, Andrea Baccarelli, Brent A Coull, Letizia Tarantini, Pantel S Vokonas, Petros Koutrakis, and Joel Schwartz. 2014. “Air pollution and gene-specific methylation in the Normative Aging Study: association, effect modification, and mediation analysis.” Epigenetics, 9, 3, Pp. 448-58.Abstract
The mechanisms by which air pollution has multiple systemic effects in humans are not fully elucidated, but appear to include inflammation and thrombosis. This study examines whether concentrations of ozone and components of fine particle mass are associated with changes in methylation on tissue factor (F3), interferon gamma (IFN-γ), interleukin 6 (IL-6), toll-like receptor 2 (TLR-2), and intercellular adhesion molecule 1 (ICAM-1). We investigated associations between air pollution exposure and gene-specific methylation in 777 elderly men participating in the Normative Aging Study (1999-2009). We repeatedly measured methylation at multiple CpG sites within each gene's promoter region and calculated the mean of the position-specific measurements. We examined intermediate-term associations between primary and secondary air pollutants and mean methylation and methylation at each position with distributed-lag models. Increase in air pollutants concentrations was significantly associated with F3, ICAM-1, and TLR-2 hypomethylation, and IFN-γ and IL-6 hypermethylation. An interquartile range increase in black carbon concentration averaged over the four weeks prior to assessment was associated with a 12% reduction in F3 methylation (95% CI: -17% to -6%). For some genes, the change in methylation was observed only at specific locations within the promoter region. DNA methylation may reflect biological impact of air pollution. We found some significant mediated effects of black carbon on fibrinogen through a decrease in F3 methylation, and of sulfate and ozone on ICAM-1 protein through a decrease in ICAM-1 methylation.
Marie-Abele Bind, Antonella Zanobetti, Antonio Gasparrini, Annette Peters, Brent Coull, Andrea Baccarelli, Letizia Tarantini, Petros Koutrakis, Pantel Vokonas, and Joel Schwartz. 2014. “Effects of temperature and relative humidity on DNA methylation.” Epidemiology, 25, 4, Pp. 561-9.Abstract
BACKGROUND: Previous studies have found relationships between DNA methylation and various environmental contaminant exposures. Associations with weather have not been examined. Because temperature and humidity are related to mortality even on non-extreme days, we hypothesized that temperature and relative humidity may affect methylation. METHODS: We repeatedly measured methylation on long interspersed nuclear elements (LINE-1), Alu, and 9 candidate genes in blood samples from 777 elderly men participating in the Normative Aging Study (1999-2009). We assessed whether ambient temperature and relative humidity are related to methylation on LINE-1 and Alu, as well as on genes controlling coagulation, inflammation, cortisol, DNA repair, and metabolic pathway. We examined intermediate-term associations of temperature, relative humidity, and their interaction with methylation, using distributed lag models. RESULTS: Temperature or relative humidity levels were associated with methylation on tissue factor (F3), intercellular adhesion molecule 1 (ICAM-1), toll-like receptor 2 (TRL-2), carnitine O-acetyltransferase (CRAT), interferon gamma (IFN-γ), inducible nitric oxide synthase (iNOS), and glucocorticoid receptor, LINE-1, and Alu. For instance, a 5°C increase in 3-week average temperature in ICAM-1 methylation was associated with a 9% increase (95% confidence interval: 3% to 15%), whereas a 10% increase in 3-week average relative humidity was associated with a 5% decrease (-8% to -1%). The relative humidity association with ICAM-1 methylation was stronger on hot days than mild days. CONCLUSIONS: DNA methylation in blood cells may reflect biological effects of temperature and relative humidity. Temperature and relative humidity may also interact to produce stronger effects.
Johanna Lepeule, Marie-Abele Catherine Bind, Andrea A Baccarelli, Petros Koutrakis, Letizia Tarantini, Augusto Litonjua, David Sparrow, Pantel Vokonas, and Joel D Schwartz. 2014. “Epigenetic influences on associations between air pollutants and lung function in elderly men: the normative aging study.” Environ Health Perspect, 122, 6, Pp. 566-72.Abstract
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.
Marie-Abele Bind, Brent Coull, Helen Suh, Robert Wright, Andrea Baccarelli, Pantel Vokonas, and Joel Schwartz. 2014. “A novel genetic score approach using instruments to investigate interactions between pathways and environment: application to air pollution.” PLoS One, 9, 4, Pp. e96000.Abstract
Air pollution has been associated with increased systemic inflammation markers. We developed a new pathway analysis approach to investigate whether gene variants within relevant pathways (oxidative stress, endothelial function, and metal processing) modified the association between particulate air pollution and fibrinogen, C-reactive protein (CRP), intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1). Our study population consisted of 822 elderly participants of the Normative Aging Study (1999-2011). To investigate the role of biological mechanisms and to reduce the number of comparisons in the analysis, we created pathway-specific scores using gene variants related to each pathway. To select the most appropriate gene variants, we used the least absolute shrinkage and selection operator (Lasso) to relate independent outcomes representative of each pathway (8-hydroxydeoxyguanosine for oxidative stress, augmentation index for endothelial function, and patella lead for metal processing) to gene variants. A high genetic score corresponds to a higher allelic risk profile. We fit mixed-effects models to examine modification by the genetic score of the weekly air pollution association with the outcome. Among participants with higher genetic scores within the oxidative stress pathway, we observed significant associations between particle number and fibrinogen, while we did not find any association among participants with lower scores (p(interaction) = 0.04). Compared to individuals with low genetic scores of metal processing gene variants, participants with higher scores had greater effects of particle number on fibrinogen (p(interaction) = 0.12), CRP (p(interaction) = 0.02), and ICAM-1 (pinteraction = 0.08). This two-stage penalization method is easy to implement and can be used for large-scale genetic applications.
Marie-Abele Bind, Andrea Baccarelli, Antonella Zanobetti, Letizia Tarantini, Helen Suh, Pantel Vokonas, and Joel Schwartz. 2012. “Air pollution and markers of coagulation, inflammation, and endothelial function: associations and epigene-environment interactions in an elderly cohort.” Epidemiology, 23, 2, Pp. 332-40.Abstract
BACKGROUND: Previous studies suggest that air pollution is related to thrombosis, inflammation, and endothelial dysfunction. Mechanisms and sources of susceptibility are still unclear. One possibility is that these associations can be modified by DNA methylation states. METHODS: We conducted a cohort study with repeated measurements of fibrinogen, C-reactive protein, intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) in 704 elderly men participating in the Veterans Administration Normative Aging Study (2000-2009). We investigated short- and intermediate-term air pollution effects on these blood markers, and epigene-environment interactions by DNA methylation of Alu, LINE-1, tissue factor (F3), Toll-like receptor 2 (TLR-2), and ICAM-1. RESULTS: We found effects of particle number, black carbon, nitrogen dioxide (NO(2)), and carbon monoxide (CO) on fibrinogen. Ozone was a predictor of C-reactive protein and ICAM-1. Particle number, black carbon, NO(2), CO, PM(2.5), and sulfates were associated with ICAM-1 and VCAM-1. An interquartile range increase in 24-hour exposure for NO(2) was associated with a 1.7% (95% confidence interval = 0.2%-3.3%) increase in fibrinogen for ozone; a 10.8% (2.2%-20.0%) increase in C-reactive protein for particle number; a 5.9% (3.6%-8.3%) increase in ICAM-1; and for PM(2.5), a 3.7% (1.7%-5.8%) increase in VCAM-1. The air pollution effect was stronger among subjects having higher Alu, lower LINE-1, tissue factor, or TLR-2 methylation status. CONCLUSION: We observed associations of traffic-related pollutants on fibrinogen, and both traffic and secondary particles on C-reactive protein, ICAM-1, and VCAM-1. There was effect modification by DNA methylation status, indicating that epigenetic states can convey susceptibility to air pollution.
Antonella Zanobetti, Marie-Abele C Bind, and Joel Schwartz. 2008. “Particulate air pollution and survival in a COPD cohort.” Environ Health, 7, Pp. 48.Abstract
BACKGROUND: Several studies have shown cross-sectional associations between long term exposure to particulate air pollution and survival in general population or convenience cohorts. Less is known about susceptibility, or year to year changes in exposure. We investigated whether particles were associated with survival in a cohort of persons with COPD in 34 US cities, eliminating the usual cross-sectional exposure and treating PM10 as a within city time varying exposure. METHODS: Using hospital discharge data, we constructed a cohort of persons discharged alive with chronic obstructive pulmonary disease using Medicare data between 1985 and 1999. 12-month averages of PM10 were merged to the individual annual follow up in each city. We applied Cox's proportional hazard regression model in each city, with adjustment for individual risk factors. RESULTS: We found significant associations in the survival analyses for single year and multiple lag exposures, with a hazard ratio for mortality for an increase of 10 microg/m(3) PM10 over the previous 4 years of 1.22 (95% CI: 1.17-1.27). CONCLUSION: Persons discharged alive for COPD have substantial mortality risks associated with exposure to particles. The risk is evident for exposure in the previous year, and higher in a 4 year distributed lag model. These risks are significantly greater than seen in time series analyses.