Associations between long-term exposure to air pollution and kidney function utilizing electronic healthcare records: a cross-sectional study.

BACKGROUND: Chronic kidney disease (CKD) affects more than 38 million people in the United States, predominantly those over 65 years of age. While CKD etiology is complex, recent research suggests associations with environmental exposures. METHODS: Our primary objective is to examine creatinine-based estimated glomerular filtration rate (eGFRcr) and diagnosis of CKD and potential associations with fine particulate matter (PM2.5), ozone (O3), and nitrogen dioxide (NO2) using a random sample of North Carolina electronic healthcare records (EHRs) from 2004 to 2016. We estimated eGFRcr using the serum creatinine-based 2021 CKD-EPI equation. PM2.5 and NO2 data come from a hybrid model using 1 km2 grids and O3 data from 12 km2 CMAQ grids. Exposure concentrations were 1-year averages. We used linear mixed models to estimate eGFRcr per IQR increase of pollutants. We used multiple logistic regression to estimate associations between pollutants and first appearance of CKD. We adjusted for patient sex, race, age, comorbidities, temporality, and 2010 census block group variables. RESULTS: We found 44,872 serum creatinine measurements among 7,722 patients. An IQR increase in PM2.5 was associated with a 1.63 mL/min/1.73m2 (95% CI: -1.96, -1.31) reduction in eGFRcr, with O3 and NO2 showing positive associations. There were 1,015 patients identified with CKD through e-phenotyping and ICD codes. None of the environmental exposures were positively associated with a first-time measure of eGFRcr < 60 mL/min/1.73m2. NO2 was inversely associated with a first-time diagnosis of CKD with aOR of 0.77 (95% CI: 0.66, 0.90). CONCLUSIONS: One-year average PM2.5 was associated with reduced eGFRcr, while O3 and NO2 were inversely associated. Neither PM2.5 or O3 were associated with a first-time identification of CKD, NO2 was inversely associated. We recommend future research examining the relationship between air pollution and impaired renal function.

Associations between source-apportioned PM2.5 and 30-day readmissions in heart failure patients.

BACKGROUND: Air pollution exposure is a significant risk factor for morbidity and mortality, especially for those with pre-existing chronic disease. Previous studies highlighted the risks that long-term particulate matter exposure has for readmissions. However, few studies have evaluated source and component specific associations particularly among vulnerable patient populations. OBJECTIVES: Use electronic health records from 5556 heart failure (HF) patients diagnosed between July 5, 2004 and December 31, 2010 that were part of the EPA CARES resource in conjunction with modeled source-specific fine particulate matter (PM2.5) to estimate the association between exposure to source and component apportioned PM2.5 at the time of HF diagnosis and 30-day readmissions. METHODS: We used zero-inflated mixed effects Poisson models with a random intercept for zip code to model associations while adjusting for age at diagnosis, year of diagnosis, race, sex, smoking status, and neighborhood socioeconomic status. We undertook several sensitivity analyses to explore the impact of geocoding precision and other factors on associations and expressed associations per interquartile range increase in exposures. RESULTS: We observed associations between 30-day readmissions and an interquartile range increase in gasoline- (16.9% increase; 95% confidence interval = 4.8%, 30.4%) and diesel-derived PM2.5 (9.9% increase; 95% confidence interval = 1.7%, 18.7%), and the secondary organic carbon component of PM2.5 (SOC; 20.4% increase; 95% confidence interval = 8.3%, 33.9%). Associations were stable in sensitivity analyses, and most consistently observed among Black study participants, those in lower income areas, and those diagnosed with HF at an earlier age. Concentration-response curves indicated a linear association for diesel and SOC. While there was some non-linearity in the gasoline concentration-response curve, only the linear component was associated with 30-day readmissions. DISCUSSION: There appear to be source specific associations between PM2.5 and 30-day readmissions particularly for traffic-related sources, potentially indicating unique toxicity of some sources for readmission risks that should be further explored.

Serum lead, mercury, manganese, and copper and DNA methylation age among adults in Detroit, Michigan.

Although the effects of lead, mercury, manganese, and copper on individual disease processes are well understood, estimating the health effects of long-term exposure to these metals at the low concentrations often observed in the general population is difficult. In addition, the health effects of joint exposure to multiple metals are difficult to estimate. Biological aging refers to the integrative progression of multiple physiologic and molecular changes that make individuals more at risk of disease. Biomarkers of biological aging may be useful to estimate the population-level effects of metal exposure prior to the development of disease in the population. We used data from 290 participants in the Detroit Neighborhood Health Study to estimate the effect of serum lead, mercury, manganese, and copper on three DNA methylation-based biomarkers of biological aging (Horvath Age, PhenoAge, and GrimAge). We used mixed models and Bayesian kernel machine regression and controlled for participant sex, race, ethnicity, cigarette use, income, educational attainment, and block group poverty. We observed consistently positive estimates of the effects between lead and GrimAge acceleration and mercury and PhenoAge acceleration. In contrast, we observed consistently negative associations between manganese and PhenoAge acceleration and mercury and Horvath Age acceleration. We also observed curvilinear relationships between copper and both PhenoAge and GrimAge acceleration. Increasing total exposure to the observed mixture of metals was associated with increased PhenoAge and GrimAge acceleration and decreased Horvath Age acceleration. These findings indicate that an increase in serum lead or mercury from the 25th to 75th percentile is associated with a ∼0.25-year increase in two epigenetic markers of all-cause mortality in a population of adults in Detroit, Michigan. While few of the findings were statistically significant, their consistency and novelty warrant interest.

Associations between PFAS occurrence and multimorbidity as observed in an electronic health record cohort.

Per and polyfluoroalkyl substances (PFAS) are associated with health outcomes ranging from cancer to high cholesterol. However, there has been little examination of how PFAS exposure might impact the development of multiple chronic diseases, known as multimorbidity. Here, we associated the presence of one or more PFAS in water systems serving the zip code of residence with chronic disease and multimorbidity. Methods: We used data from the unregulated contaminant monitoring rule 3 to estimate exposure to PFAS for a random sample of 10,168 patients from the University of North Carolina Healthcare System. The presence of 16 chronic diseases was determined via. their electronic health records. We used a logistic regression model in a cross-sectional study design to associate the presence of one or more PFAS with multimorbidity. Models were adjusted for age, race, sex, smoking status, socioeconomic status, and 20 county-level confounders. Results: There were four PFAS found in water systems that served at least one zip code represented in our patient data: PFOA, PFHpA, PFOS, and PFHxS. Exposure to any PFAS was associated with a odds ratio of 1.25 for multimorbidity (95% confidence interval = 1.09, 1.45). Among the chronic diseases with at least 300 cases, we observed associations with dyslipidemia, hypertension, ischemic heart disease, and osteoporosis. Conclusion: Exposure to PFAS is associated with a range of chronic diseases as well as multimorbidity. Accounting for the joint impacts of PFAS on multiple chronic conditions may give an increasingly clear picture of the public health impacts of PFAS.

Associations between neighborhood socioeconomic cluster and hypertension, diabetes, myocardial infarction, and coronary artery disease within a cohort of cardiac catheterization patients.

BACKGROUND: Neighborhood-level socioeconomic status (SES) is associated with health outcomes, including cardiovascular disease and diabetes, but these associations are rarely studied across large, diverse populations. METHODS: We used Ward's Hierarchical clustering to define eight neighborhood clusters across North Carolina using 11 census-based indicators of SES, race, housing, and urbanicity and assigned 6992 cardiac catheterization patients at Duke University Hospital from 2001 to 2010 to clusters. We examined associations between clusters and coronary artery disease index > 23 (CAD), history of myocardial infarction, hypertension, and diabetes using logistic regression adjusted for age, race, sex, body mass index, region of North Carolina, distance to Duke University Hospital, and smoking status. RESULTS: Four clusters were urban, three rural, and one suburban higher-middle-SES (referent). We observed greater odds of myocardial infarction in all six clusters with lower or middle-SES. Odds of CAD were elevated in the rural cluster that was low-SES and plurality Black (OR 1.16, 95% CI 0.94-1.43) and in the rural cluster that was majority American Indian (OR 1.31, 95% CI 0.91-1.90). Odds of diabetes and hypertension were elevated in two urban and one rural low- and lower-middle SES clusters with large Black populations. CONCLUSIONS: We observed higher prevalence of cardiovascular disease and diabetes in neighborhoods that were predominantly rural, low-SES, and non-White, highlighting the importance of public health and healthcare system outreach into these communities to promote cardiometabolic health and prevent and manage hypertension, diabetes and coronary artery disease.

Long-Term Exposure to Particulate Air Pollution Is Associated With 30-Day Readmissions and Hospital Visits Among Patients With Heart Failure.

Background Long-term air pollution exposure is a significant risk factor for inpatient hospital admissions in the general population. However, we lack information on whether long-term air pollution exposure is a risk factor for hospital readmissions, particularly in individuals with elevated readmission rates. Methods and Results We determined the number of readmissions and total hospital visits (outpatient visits+emergency room visits+inpatient admissions) for 20 920 individuals with heart failure. We used quasi-Poisson regression models to associate annual average fine particulate matter at the date of heart failure diagnosis with the number of hospital visits and 30-day readmissions. We used inverse probability weights to balance the distribution of confounders and adjust for the competing risk of death. Models were adjusted for age, race, sex, smoking status, urbanicity, year of diagnosis, short-term fine particulate matter exposure, comorbid disease, and socioeconomic status. A 1-µg/m3 increase in fine particulate matter was associated with a 9.31% increase (95% CI, 7.85%-10.8%) in total hospital visits, a 4.35% increase (95% CI, 1.12%-7.68%) in inpatient admissions, and a 14.2% increase (95% CI, 8.41%-20.2%) in 30-day readmissions. Associations were robust to different modeling approaches. Conclusions These results highlight the potential for air pollution to play a role in hospital use, particularly hospital visits and readmissions. Given the elevated frequency of hospitalizations and readmissions among patients with heart failure, these results also represent an important insight into modifiable environmental risk factors that may improve outcomes and reduce hospital use among patients with heart failure.

Controlled human exposures to diesel exhaust: a human epigenome-wide experiment of target bronchial epithelial cells.

Diesel exhaust (DE) is a major contributor to ambient air pollution around the world. It is a known human carcinogen that targets the respiratory system and increases risk for many diseases, but there is limited research on the effects of DE exposure on the epigenome of human bronchial epithelial cells. Understanding the epigenetic impact of this environmental pollutant can elucidate biological mechanisms involved in the pathogenesis of harmful DE-related health effects. To estimate the causal effect of short-term DE exposure on the bronchial epithelial epigenome, we conducted a controlled single-blinded randomized crossover human experiment of exposure to DE and used bronchoscopy and Illumina 450K arrays for data collection and analysis, respectively. Of the 13 participants, 11 (85%) were male and 2 (15%) were female, and 12 (92%) were White and one (8%) was Hispanic; the mean age was 26 years (SD = 3.8 years). Eighty CpGs were differentially methylated, achieving the minimum possible exact P-value of P = 2.44 × 10-4 (i.e. 2/213). In regional analyses, we found two differentially methylated regions (DMRs) annotated to the chromosome 5 open reading frame 63 genes (C5orf63; 7-CpGs) and unc-45 myosin chaperone A gene (UNC45A; 5-CpGs). Both DMRs showed increased DNA methylation after DE exposure. The average causal effects for the DMRs ranged from 1.5% to 6.0% increases in DNA methylation at individual CpGs. In conclusion, we found that short-term DE alters DNA methylation of genes in target bronchial epithelial cells, demonstrating epigenetic level effects of exposure that could be implicated in pulmonary pathologies.

Accelerated epigenetic age as a biomarker of cardiovascular sensitivity to traffic-related air pollution.

BACKGROUND: Accelerated epigenetic age has been proposed as a biomarker of increased aging, which may indicate disruptions in cellular and organ system homeostasis and thus contribute to sensitivity to environmental exposures. METHODS: Using 497 participants from the CATHGEN cohort, we evaluated whether accelerated epigenetic aging increases cardiovascular sensitivity to traffic-related air pollution (TRAP) exposure. We used residential proximity to major roadways and source apportioned air pollution models as measures of TRAP exposure, and chose peripheral arterial disease (PAD) and blood pressure as outcomes based on previous associations with TRAP. We used Horvath epigenetic age acceleration (AAD) and phenotypic age acceleration (PhenoAAD) as measures of age acceleration, and adjusted all models for chronological age, race, sex, smoking, and socioeconomic status. RESULTS: We observed significant interactions between TRAP and both AAD and PhenoAAD. Interactions indicated that increased epigenetic age acceleration elevated associations between proximity to roadways and PAD. Interactions were also observed between AAD and gasoline and diesel source apportioned PM2.5. CONCLUSION: Epigenetic age acceleration may be a biomarker of sensitivity to air pollution, particularly for TRAP in urban cohorts. This presents a novel means by which to understand sensitivity to air pollution and provides a molecular measure of environmental sensitivity.

Exhaled breath condensate biomarkers in critically ill, mechanically ventilated patients.

Pneumonia is a significant risk for critically ill, mechanically ventilated (CIMV) patients. Diagnosis of pneumonia generally requires a combination of clinician-guided diagnoses and clinical scoring systems. Exhaled breath condensate (EBC) can be safely collected non-invasively from CIMV patients. Hundreds of biomarkers in EBC are associated with acute disease states, including pneumonia. We evaluated cytokines in EBC from CIMV patients and hypothesized that these biomarkers would correlate with disease severity in pneumonia, sepsis, and death. EBC IL-2 levels were associated with chest radiograph severity scores (odds ratio = 1.68; 95% confidence interval = 1.09-2.60; P = 0.02). EBC TNF-α levels were also associated with pneumonia (odds ratio = 3.20; 95% confidence interval = 1.19-8.65; P = 0.02). The techniques and results from this study may be useful for all mechanically ventilated patients.

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.

Blood DNA methylation sites predict death risk in a longitudinal study of 12, 300 individuals.

DNA methylation has fundamental roles in gene programming and aging that may help predict mortality. However, no large-scale study has investigated whether site-specific DNA methylation predicts all-cause mortality. We used the Illumina-HumanMethylation450-BeadChip to identify blood DNA methylation sites associated with all-cause mortality for 12, 300 participants in 12 Cohorts of the Heart and Aging Research in Genetic Epidemiology (CHARGE) Consortium. Over an average 10-year follow-up, there were 2,561 deaths across the cohorts. Nine sites mapping to three intergenic and six gene-specific regions were associated with mortality (P < 9.3x10-7) independently of age and other mortality predictors. Six sites (cg14866069, cg23666362, cg20045320, cg07839457, cg07677157, cg09615688)-mapping respectively to BMPR1B, MIR1973, IFITM3, NLRC5, and two intergenic regions-were associated with reduced mortality risk. The remaining three sites (cg17086398, cg12619262, cg18424841)-mapping respectively to SERINC2, CHST12, and an intergenic region-were associated with increased mortality risk. DNA methylation at each site predicted 5%-15% of all deaths. We also assessed the causal association of those sites to age-related chronic diseases by using Mendelian randomization, identifying weak causal relationship between cg18424841 and cg09615688 with coronary heart disease. Of the nine sites, three (cg20045320, cg07839457, cg07677157) were associated with lower incidence of heart disease risk and two (cg20045320, cg07839457) with smoking and inflammation in prior CHARGE analyses. Methylation of cg20045320, cg07839457, and cg17086398 was associated with decreased expression of nearby genes (IFITM3, IRF, NLRC5, MT1, MT2, MARCKSL1) linked to immune responses and cardiometabolic diseases. These sites may serve as useful clinical tools for mortality risk assessment and preventative care.

Epigenetic predictors of all-cause mortality are associated with objective measures of neighborhood disadvantage in an urban population.

BACKGROUND: Neighborhood characteristics are robust predictors of overall health and mortality risk for residents. Though there has been some investigation of the role that molecular indicators may play in mediating neighborhood exposures, there has been little effort to incorporate newly developed epigenetic biomarkers into our understanding of neighborhood characteristics and health outcomes. METHODS: Using 157 participants of the Detroit Neighborhood Health Study with detailed assessments of neighborhood characteristics and genome-wide DNA methylation profiling via the Illumina 450K methylation array, we assessed the relationship between objective neighborhood characteristics and a validated DNA methylation-based epigenetic mortality risk score (eMRS). Associations were adjusted for age, race, sex, ever smoking, ever alcohol usage, education, years spent in neighborhood, and employment. A secondary model additionally adjusted for personal neighborhood perception. We summarized 19 neighborhood quality indicators assessed for participants into 9 principal components which explained over 90% of the variance in the data and served as metrics of objective neighborhood quality exposures. RESULTS: Of the nine principal components utilized for this study, one was strongly associated with the eMRS (ß = 0.15; 95% confidence interval = 0.06-0.24; P = 0.002). This principal component (PC7) was most strongly driven by the presence of abandoned cars, poor streets, and non-art graffiti. Models including both PC7 and individual indicators of neighborhood perception indicated that only PC7 and not neighborhood perception impacted the eMRS. When stratified on neighborhood indicators of greenspace, we observed a potentially protective effect of large mature trees as this feature substantially attenuated the observed association. CONCLUSION: Objective measures of neighborhood disadvantage are significantly associated with an epigenetic predictor of mortality risk, presenting a potential novel avenue by which neighborhood-level exposures may impact health. Associations were independent of an individual's perception of their neighborhood and attenuated by neighborhood greenspace features. More work should be done to determine molecular risk factors associated with neighborhoods, and potentially protective neighborhood features against adverse molecular effects.

Blood Leukocyte DNA Methylation Predicts Risk of Future Myocardial Infarction and Coronary Heart Disease.

BACKGROUND: DNA methylation is implicated in coronary heart disease (CHD), but current evidence is based on small, cross-sectional studies. We examined blood DNA methylation in relation to incident CHD across multiple prospective cohorts. METHODS: Nine population-based cohorts from the United States and Europe profiled epigenome-wide blood leukocyte DNA methylation using the Illumina Infinium 450k microarray, and prospectively ascertained CHD events including coronary insufficiency/unstable angina, recognized myocardial infarction, coronary revascularization, and coronary death. Cohorts conducted race-specific analyses adjusted for age, sex, smoking, education, body mass index, blood cell type proportions, and technical variables. We conducted fixed-effect meta-analyses across cohorts. RESULTS: Among 11 461 individuals (mean age 64 years, 67% women, 35% African American) free of CHD at baseline, 1895 developed CHD during a mean follow-up of 11.2 years. Methylation levels at 52 CpG (cytosine-phosphate-guanine) sites were associated with incident CHD or myocardial infarction (false discovery rate<0.05). These CpGs map to genes with key roles in calcium regulation (ATP2B2, CASR, GUCA1B, HPCAL1), and genes identified in genome- and epigenome-wide studies of serum calcium (CASR), serum calcium-related risk of CHD (CASR), coronary artery calcified plaque (PTPRN2), and kidney function (CDH23, HPCAL1), among others. Mendelian randomization analyses supported a causal effect of DNA methylation on incident CHD; these CpGs map to active regulatory regions proximal to long non-coding RNA transcripts. CONCLUSION: Methylation of blood-derived DNA is associated with risk of future CHD across diverse populations and may serve as an informative tool for gaining further insight on the development of CHD.

Neighborhood sociodemographic effects on the associations between long-term PM2.5 exposure and cardiovascular outcomes and diabetes.

Introduction: Exposure to PM2.5 air pollution and neighborhood-level sociodemographic characteristics are associated with cardiovascular disease and possibly diabetes. However, the joint effect of sociodemographics and PM2.5 on these outcomes is uncertain. Methods: We examined whether clusters of sociodemographic characteristics modified effects of long-term PM2.5 exposure on coronary artery disease (CAD), myocardial infarction (MI), hypertension, and diabetes. We used medical records data from 2192 cardiac catheterization patients residing in North Carolina and assigned to one of six previously-determined clusters. For each participant, we estimated annual PM2.5 exposure at their primary residence using a hybrid model with a 1 km2 resolution. We used logistic regression models adjusted for age, sex, body mass index, and smoking status, to assess cluster-specific associations with PM2.5 and to determine if there were interactions between cluster and PM2.5 on outcomes. Results: Compared to cluster 3 (OR 0.93, 95% CI 0.82-1.07; urban, low proportion of black individuals and high socioeconomic status), we observed greater associations between PM2.5 and hypertension in clusters 1 (OR 1.22, 95% CI 0.99-1.50, pint 0.03) and 2 (OR 1.64, 95% CI 1.16-2.32, pint 0.003), which were urban, high proportion of black individuals, and low socioeconomic status. PM2.5 was associated with MI (OR 1.29, 95% CI 1.16-1.42) but not diabetes, regardless of cluster and was associated with CAD in cluster 3 (OR 1.15, 95% CI 1.00, 1.31) and overall (OR 1.07, 95% CI 0.98, 1.17). Discussion: Areas of relative disadvantage have a stronger association between PM2.5 and hypertension compared to areas of relative advantage.

A genome-wide association study identifies new loci for factor VII and implicates factor VII in ischemic stroke etiology.

Factor VII (FVII) is an important component of the coagulation cascade. Few genetic loci regulating FVII activity and/or levels have been discovered to date. We conducted a meta-analysis of 9 genome-wide association studies of plasma FVII levels (7 FVII activity and 2 FVII antigen) among 27 495 participants of European and African ancestry. Each study performed ancestry-specific association analyses. Inverse variance weighted meta-analysis was performed within each ancestry group and then combined for a trans-ancestry meta-analysis. Our primary analysis included the 7 studies that measured FVII activity, and a secondary analysis included all 9 studies. We provided functional genomic validation for newly identified significant loci by silencing candidate genes in a human liver cell line (HuH7) using small-interfering RNA and then measuring F7 messenger RNA and FVII protein expression. Lastly, we used meta-analysis results to perform Mendelian randomization analysis to estimate the causal effect of FVII activity on coronary artery disease, ischemic stroke (IS), and venous thromboembolism. We identified 2 novel (REEP3 and JAZF1-AS1) and 6 known loci associated with FVII activity, explaining 19.0% of the phenotypic variance. Adding FVII antigen data to the meta-analysis did not result in the discovery of further loci. Silencing REEP3 in HuH7 cells upregulated FVII, whereas silencing JAZF1 downregulated FVII. Mendelian randomization analyses suggest that FVII activity has a positive causal effect on the risk of IS. Variants at REEP3 and JAZF1 contribute to FVII activity by regulating F7 expression levels. FVII activity appears to contribute to the etiology of IS in the general population.

Association of long-term PM2.5 exposure with traditional and novel lipid measures related to cardiovascular disease risk.

BACKGROUND: Fine particulate matter (PM2.5) exposure is associated with increased morbidity and mortality, particularly for cardiovascular disease. The association between long-term exposure to PM2.5 and measures of lipoprotein subfractions remains unclear. Therefore, we examined associations between long-term PM2.5 exposure and traditional and novel lipoprotein measures in a cardiac catheterization cohort in North Carolina. METHODS: This cross-sectional study included 6587 patients who had visited Duke University for a cardiac catheterization between 2001 and 2010 and resided in North Carolina. We used estimates of daily PM2.5 concentrations on a 1 km-grid based on satellite measurements. PM2.5 predictions were matched to the address of each patient and averaged for the year prior to catheterization date. Serum lipids included HDL, LDL, and triglyceride-rich particle, and apolipoprotein B concentrations (HDL-P, LDL-P, TRL-P, and apoB, respectively). Linear and quantile regression models were used to estimate change in lipoprotein levels with each µg/m3 increase in annual average PM2.5. Models were adjusted for age, sex, race/ethnicity, history of smoking, area-level education, urban/rural status, body mass index, and diabetes. RESULTS: For a 1-µg/m3 increment in PM2.5 exposure, we observed increases in total and small LDL-P, LDL-C, TRL-P, apoB, total cholesterol, and triglycerides. The percent change from the mean outcome level was 2.00% (95% CI: 1.38%, 2.64%) for total LDL-P and 2.25% (95% CI: 1.43%, 3.06%) for small LDL-P. CONCLUSION: Among this sample of cardiac catheterization patients residing in North Carolina, long-term PM2.5 exposure was associated with increases in several lipoprotein concentrations. This abstract does not necessarily reflect U.S. EPA policy.

DNA Methylation Age-Environmental Influences, Health Impacts, and Its Role in Environmental Epidemiology.

PURPOSE OF REVIEW: DNA methylation-based aging biomarkers are valuable tools for evaluating the aging process from a molecular perspective. These epigenetic aging biomarkers can be evaluated across the lifespan and are tissue specific. This review examines the literature relating environmental exposures to DNA methylation-based aging biomarkers and also the literature evaluating these biomarkers as predictors of health outcomes. RECENT FINDINGS: Multiple studies evaluated the association between air pollution and DNA methylation age and consistently observed that higher exposures are associated with elevated DNA methylation age. Psychosocial exposures, e.g., traumas and adolescent adversity, and infections are also associated with epigenetic aging. DNA methylation age has been repeatedly associated with mortality, cancer, and cognitive impairment. DNA methylation age is responsive to the environment and predictive of health outcomes. Studies are still needed to evaluate whether DNA methylation age acts as a mediator or modifier of environmental health effects and to understand the impact of factors such as race, gender, and genetics.

Associations Between Residential Proximity to Traffic and Vascular Disease in a Cardiac Catheterization Cohort.

OBJECTIVE: Exposure to mobile source emissions is nearly ubiquitous in developed nations and is associated with multiple adverse health outcomes. There is an ongoing need to understand the specificity of traffic exposure associations with vascular outcomes, particularly in individuals with cardiovascular disease. APPROACH AND RESULTS: We performed a cross-sectional study using 2124 individuals residing in North Carolina, United States, who received a cardiac catheterization at the Duke University Medical Center. Traffic-related exposure was assessed via 2 metrics: (1) the distance between the primary residence and the nearest major roadway; and (2) location of the primary residence in regions defined based on local traffic patterns. We examined 4 cardiovascular disease outcomes: hypertension, peripheral arterial disease, the number of diseased coronary vessels, and recent myocardial infarction. Statistical models were adjusted for race, sex, smoking, type 2 diabetes mellitus, body mass index, hyperlipidemia, and home value. Results are expressed in terms of the odds ratio (OR). A 23% decrease in residential distance to major roadways was associated with higher prevalence of peripheral arterial disease (OR=1.29; 95% confidence interval, 1.08-1.55) and hypertension (OR=1.15; 95% confidence interval, 1.01-1.31). Associations with peripheral arterial disease were strongest in men (OR=1.42; 95% confidence interval, 1.17-1.74) while associations with hypertension were strongest in women (OR=1.21; 95% confidence interval, 0.99-1.49). Neither myocardial infarction nor the number of diseased coronary vessels were associated with traffic exposure. CONCLUSIONS: Traffic-related exposure is associated with peripheral arterial disease and hypertension while no associations are observed for 2 coronary-specific vascular outcomes.

The dynamics of smoking-related disturbed methylation: a two time-point study of methylation change in smokers, non-smokers and former smokers.

BACKGROUND: The evidence for epigenome-wide associations between smoking and DNA methylation continues to grow through cross-sectional studies. However, few large-scale investigations have explored the associations using observations for individuals at multiple time-points. Here, through the use of the Illumina 450K BeadChip and data collected at two time-points separated by approximately 7 years, we investigate changes in methylation over time associated with quitting smoking or remaining a former smoker, and those associated with continued smoking. RESULTS: Our results indicate that after quitting smoking the most rapid reversion of altered methylation occurs within the first two decades, with reversion rates related to the initial differences in methylation. For 52 CpG sites, the change in methylation from baseline to follow-up is significantly different for former smokers relative to the change for never smokers (lowest p-value 3.61 x 10-39 for cg26703534, gene AHRR). Most of these sites' respective regions have been previously implicated in smoking-associated diseases. Despite the early rapid change, dynamism of methylation appears greater in former smokers vs never smokers even four decades after cessation. Furthermore, our study reveals the heterogeneous effect of continued smoking: the methylation levels of some loci further diverge between smokers and non-smokers, while others re-approach. Though intensity of smoking habit appears more significant than duration, results remain inconclusive. CONCLUSIONS: This study improves the understanding of the dynamic link between cigarette smoking and methylation, revealing the continued fluctuation of methylation levels decades after smoking cessation and demonstrating that continuing smoking can have an array of effects. The results can facilitate insights into the molecular mechanisms behind smoking-induced disturbed methylation, improving the possibility for development of biomarkers of past smoking behavior and increasing the understanding of the molecular path from exposure to disease.

Fine particulate matter and cardiovascular disease: Comparison of assessment methods for long-term exposure.

BACKGROUND: Adverse cardiovascular events have been linked with PM2.5 exposure obtained primarily from air quality monitors, which rarely co-locate with participant residences. Modeled PM2.5 predictions at finer resolution may more accurately predict residential exposure; however few studies have compared results across different exposure assessment methods. METHODS: We utilized a cohort of 5679 patients who had undergone a cardiac catheterization between 2002-2009 and resided in NC. Exposure to PM2.5 for the year prior to catheterization was estimated using data from air quality monitors (AQS), Community Multiscale Air Quality (CMAQ) fused models at the census tract and 12km spatial resolutions, and satellite-based models at 10km and 1km resolutions. Case status was either a coronary artery disease (CAD) index >23 or a recent myocardial infarction (MI). Logistic regression was used to model odds of having CAD or an MI with each 1-unit (µg/m3) increase in PM2.5, adjusting for sex, race, smoking status, socioeconomic status, and urban/rural status. RESULTS: We found that the elevated odds for CAD>23 and MI were nearly equivalent for all exposure assessment methods. One difference was that data from AQS and the census tract CMAQ showed a rural/urban difference in relative risk, which was not apparent with the satellite or 12km-CMAQ models. CONCLUSIONS: Long-term air pollution exposure was associated with coronary artery disease for both modeled and monitored data.