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Ren C.,Landmark Center West | Baccarelli A.,University of Milan | Wilker E.,Harvard University | Suh H.,Landmark Center West | And 4 more authors.
Journal of Epidemiology and Community Health | Year: 2010

Background: Many studies have shown that exposures to air pollution are associated with cardiovascular events, although the mechanism remains to be clarified. To identify whether exposures to ambient particles act on autonomic function via the lipid/endothelial metabolism pathway, whether effects of particulate matter <2.5 mm in aerodynamic diameter (PM2.5) on heart rate variability (HRV) were modified by gene polymorphisms related to those pathways were evaluated. Methods: HRV and gene data from the Normative Aging Study and PM2.5 from a monitor located a kilometre from the examination site were used. A mixed model was fitted to investigate the associations between PM2.5 and repeated measurements of HRV by gene polymorphisms of apolipoprotein E (APOE), lipoprotein lipase (LPL) and vascular endothelial growth factor (VEGF) adjusting for potential confounders chosen a priori. Results: A 10 μg/m3 increase in PM2.5 in the 2 days before the examination was associated with 3.8% (95% CI 0.2% to 7.4%), 7.8% (95 CI 0.4% to 15.3%) and 10.6% (95% CI 1.8% to 19.4%) decreases of the standard deviation of normal-to-normal intervals, the low frequency and the high frequency, respectively. Overall, carriers of wild-type APOE, LPL and VEGF genes had stronger effects of particles on HRV than those with hetero- or homozygous types. Variations of LPL-N291S, LPL-D9N and APOE-G113C significantly modified effects of PM2.5 on HRV. Conclusion: Associations between PM2.5 and HRV were modified by gene polymorphisms of APOE, LPL and VEGF; the biological metabolism remains to be identified.

Ko Y.-A.,University of Michigan | Saha-Chaudhuri P.,Duke University | Park S.K.,University of Michigan | Vokonas P.S.,VA Normative Aging Study | And 2 more authors.
Genetic Epidemiology | Year: 2013

There has been extensive literature on modeling gene-gene interaction (GGI) and gene-environment interaction (GEI) in case-control studies with limited literature on statistical methods for GGI and GEI in longitudinahe issue of robust modeling of interactions in repeated-measures studies. While classical interaction models proposed by Tukey and Mandel have interaction strucures as a function of main effects, a newer class of models, additive main effects and multiplicative interaction (AMMI) models, do not have similar restrictive assumptions on the interaction structure. AMMI entails a singular value decomposition of the cell residual matrix after fitting the additive main effects and has been shown to perform well across various interaction structures. We consider these models for testing GGI and GEI from two perspectives: likelihood ratio test based on cell means and a regression-based approach using individual observations. Simulation results indicate that both approaches for AMMI models lead to valid tests in terms of maintaining the type I error rate, with the regression approach having better power properties. The performance of these models was evaluated across different interaction structures and 12 common epistasis patterns. In summary, AMMI model is robust with respect to misspecified interaction structure and is a useful screening tool for interaction even in the absence of main effects. We use the proposed methods to examine the interplay between the hemochromatosis gene and cumulative lead exposure on pulse pressure in the Normative Aging Study. © 2013 WILEY PERIODICALS, INC.

Fang S.C.,Harvard University | Mehta A.J.,Harvard University | Mehta A.J.,Swiss Tropical and Public Health Institute | Mehta A.J.,University of Basel | And 8 more authors.
Environmental Health Perspectives | Year: 2012

Background: Traffic-related particles (TRPs) are associated with adverse cardiovascular events. The exact mechanisms are unclear, but systemic inflammatory responses likely play a role. Objectives: We conducted a repeated measures study among male participants of the Normative Aging Study in the greater Boston, Massachusetts, area to determine whether individual-level residential black carbon (BC), a marker of TRPs, is associated with systemic inflammation and whether coronary heart disease (CHD), diabetes, and obesity modify associations. Methods: We quantified markers of inflammation in 1,163 serum samples from 580 men. Exposure to BC up to 4 weeks prior was predicted from a validated spatiotemporal land-use regression model. Linear mixed effects models estimated the effects of BC on each marker while adjusting for potential confounders. Results: Associations between BC and blood markers were not observed in main effects models or when stratified by obesity status. However, BC was positively associated with markers of inflammation in men with CHD (particularly vascular endothelial growth factor) and in men with diabetes (particularly interleukin-1β and tumor necrosis factor-α). Significant exposure time windows varied by marker, although in general the strongest associations were observed with moving averages of 2-7 days after a lag of several days. Conclusions: In an elderly male population, estimated BC exposures were positively associated with markers of systemic inflammation but only in men with CHD or diabetes.

Lambrou A.,Harvard University | Baccarelli A.,Harvard University | Wright R.O.,Harvard University | Weisskopf M.,Harvard University | And 5 more authors.
Epidemiology | Year: 2012

BACKGROUND:: Arsenic exposure has been linked to epigenetic modifications such as DNA methylation in in-vitro and animal studies. This association has also been explored in highly exposed human populations, but studies among populations environmentally exposed to low arsenic levels are lacking. METHODS:: We evaluated the association between exposure to arsenic, measured in toenails, and blood DNA methylation in Alu and Long Interspersed Nucleotide Element-1 (LINE-1) repetitive elements in elderly men environmentally exposed to low levels of arsenic. We also explored potential effect modification by plasma folate, cobalamin (vitamin B12), and pyridoxine (vitamin B6). The study population was 581 participants from the Normative Aging Study in Boston, of whom 434, 140, and 7 had 1, 2, and 3 visits, respectively, between 1999-2002 and 2006-2007. We used mixed-effects models and included interaction terms to assess potential effect modification by nutritional factors. RESULTS:: There was a trend of increasing Alu and decreasing LINE-1 DNA methylation as arsenic exposure increased. In subjects with plasma folate below the median (<14.1 ng/mL), arsenic was positively associated with Alu DNA methylation (β = 0.08 [95% confidence interval = 0.03 to 0.13] for one interquartile range [0.06 μg/g] increase in arsenic), whereas a negative association was observed in subjects with plasma folate above the median (β =-0.08 [-0.17 to 0.01]). CONCLUSIONS:: We found an association between arsenic exposure and DNA methylation in Alu repetitive elements that varied by folate level. This suggests a potential role for nutritional factors in arsenic toxicity. © 2012 by Lippincott Williams & Wilkins.

Ikeda A.,Harvard University | Schwartz J.,Harvard University | Peters J.L.,Harvard University | Fang S.,Harvard University | And 4 more authors.
Psychosomatic Medicine | Year: 2011

Background: Recent research suggests that optimism may reduce the risk of incident cardiovascular disease, but the mechanisms have not been determined. This study examines the association of optimism with change in inflammation and endothelial function over time in men. Methods: Longitudinal data were obtained from the Normative Aging Study excluding men with preexisting coronary heart disease or active infection at the time optimism was assessed (n = 340; mean [standard deviation] age = 70.9 [6.7] years). The Life Orientation Test was used to measure optimism, and serum markers were used to measure inflammation and endothelial dysfunction and were obtained repeatedly during the course of the study (1999Y2008). These markers included high-sensitivity C-reactive protein, interleukin 6, soluble intercellular adhesion molecule 1, soluble vascular cell adhesion molecule 1, and soluble tumor necrosis factor receptor II.Within this sample, 243 men (71%) had two or more repeated measures of each outcome, resulting in a total of 746 observations for analysis. Linear mixed-effects models with a random subject intercept were used to estimate associations. Results: Higher overall optimism scores were associated with lower levels of interleukin 6 and soluble intercellular adhesion molecule 1 pooled across multiple time points in multivariable models but were not associated with rate of change in these markers over time. Analyses considering separate effects of optimism and pessimism subscales with each outcome indicated stronger effects of a pessimistic orientation versus an optimistic orientation. Conclusions: Higher overall optimism scores were associated with lower levels of inflammation and endothelial dysfunction in older men free of coronary heart disease. © 2011 by the American Psychosomatic Society.

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