Kathleen M. Donohue

Prenatal and postnatal bisphenol A exposure and asthma development among inner-city children

BACKGROUND Bisphenol A (BPA) is used widely to manufacture food container linings. Mouse models suggest exposure to BPA might increase allergic inflammation. OBJECTIVES We hypothesized that BPA exposure, as assessed based on urinary BPA concentrations, would be associated with increased odds of wheeze and asthma and increased fraction of exhaled nitric oxide (Feno) values in children. METHODS The Columbia Center for Childrens Environmental Health recruited pregnant women for a prospective birth cohort study (n = 568). Mothers during the third trimester and children at ages 3, 5, and 7 years provided spot urine samples. Total urinary BPA concentrations were measured by using online solid-phase extraction, high-performance liquid chromatography, isotope-dilution tandem mass spectrometry. Wheeze in the last 12 months was measured by using questionnaires at ages 5, 6, and 7 years. Asthma was determined by a physician once between ages 5 and 12 years. Feno values were measured at ages 7 to 11 years. RESULTS Prenatal urinary BPA concentrations were associated inversely with wheeze at age 5 years (odds ratio [OR], 0.7; 95% CI, 0.5-0.9; P = .02). Urinary BPA concentrations at age 3 years were associated positively with wheeze at ages 5 years (OR, 1.4; 95% CI, 1.1-1.8; P = .02) and 6 years (OR, 1.4; 95% CI, 1.0-1.9; P = .03). BPA concentrations at age 7 years were associated with wheeze at age 7 years (OR, 1.4; 95% CI, 1.0-1.9; P = .04) and Feno values (β = 0.1; 95% CI, 0.02-0.2; P = .02). BPA concentrations at ages 3, 5, and 7 years were associated with asthma (OR, 1.5 [95% CI, 1.1-2.0], P = .005; OR, 1.4 [95% CI, 1.0-1.9], P = .03; and OR, 1.5 [95% CI, 1.0-2.1], P = .04, respectively). CONCLUSIONS This is the first report of an association between postnatal urinary BPA concentrations and asthma in children.

Anti-cockroach and anti-mouse IgE are associated with early wheeze and atopy in an inner-city birth cohort

BACKGROUND The relationships between cockroach and mouse allergen exposure, anti-cockroach and anti-mouse IgE, and wheeze, rhinitis, and atopic dermatitis in children as young as age 3 years are of public health importance but have not been thoroughly evaluated. OBJECTIVE We hypothesized that inner-city children might have anti-cockroach and anti-mouse IgE by age 3 years, and their presence would be associated with respiratory and atopic symptoms. METHODS Children were followed prospectively from birth through age 3 years (n = 404). Residential levels of cockroach and mouse allergens, sera levels of anti-cockroach and anti-mouse IgE, and parental report of wheeze, rhinitis, and atopic dermatitis were measured. RESULTS The odds of early wheeze were significantly higher among children who had IgE to cockroach (odds ratio [OR], 3.3; 95% CI, 1.8-6.2), mouse (OR, 4.6; 95% CI, 2.3-9.0), or both (OR, 9.7; 95% CI, 3.4-27.3). The odds of rhinitis or atopic dermatitis were also higher among children with IgE to cockroach, mouse, or both. Higher IgE class to cockroach and mouse was associated with wheeze and atopic dermatitis (tests for trend, P < .002). CONCLUSIONS Children age 2 to 3 years who have anti-cockroach and anti-mouse IgE are at increased risk of wheeze and atopy. Moreover, a dose-response relationship was found between higher IgE class and increased prevalence of wheeze, rhinitis, or atopic dermatitis. These findings indicate the importance of reducing exposure to cockroach and mouse allergens for susceptible children.

Comparison of spatially matched airways reveals thinner airway walls in COPD. The Multi-Ethnic Study of Atherosclerosis (MESA) COPD Study and the Subpopulations and Intermediate Outcomes in COPD Study (SPIROMICS)

Background COPD is characterised by reduced airway lumen dimensions and fewer peripheral airways. Most studies of airway properties sample airways based upon lumen dimension or at random, which may bias comparisons given reduced airway lumen dimensions and number in COPD. We sought to compare central airway wall dimensions on CT in COPD and controls using spatially matched airways, thereby avoiding selection bias of airways in the lung. Methods The Multi-Ethnic Study of Atherosclerosis (MESA) COPD Study and Subpopulations and Intermediate Outcomes in COPD Study (SPIROMICS) recruited smokers with COPD and controls aged 50–79 years and 40–80 years, respectively. COPD was defined by current guidelines. Using CT image data, airway dimensions were measured for all central airway segments (generations 0–6) following 5 standardised paths into the lungs. Case-control airway comparisons were spatially matched by generation and adjusted for demographics, body size, smoking, CT dose, per cent emphysema, airway length and lung volume. Results Among 311 MESA COPD participants, airway wall areas at generations 3–6 were smaller in COPD compared with controls (all p<0.001). Among 1248 SPIROMICS participants, airway wall areas at generations 1–6 were smaller (all p<0.001), and this reduction was monotonic with increasing COPD severity (p<0.001). In both studies, sampling airways by lumen diameter or randomly resulted in a comparison of more proximal airways in COPD to more peripheral airways in controls (p<0.001) resulting in the appearance of thicker walls in COPD (p<0.02). Conclusions Airway walls are thinner in COPD when comparing spatially matched central airways. Other approaches to airway sampling result in comparisons of more proximal to more distal airways and potentially biased assessment of airway properties in COPD.

Asthma Predicts Cardiovascular Disease Events The Multi-Ethnic Study of Atherosclerosis

Objectives—To identify and characterize an association between persistent asthma and cardiovascular disease (CVD) risk in the Multi-Ethnic Study of Atherosclerosis (MESA). Approach and Results—MESA is a longitudinal prospective study of an ethnically diverse cohort of individuals free of known CVD at its inception. The presence and severity of asthma were assessed in the MESA at examination 1. Persistent asthma was defined as asthmatics using controller medications (inhaled corticosteroids, leukotriene inhibitors, and oral corticosteroids) and intermittent asthma as asthmatics not using controller medications. Participants were followed up for a mean (SD) of 9.1 (2.8) years for development of incident CVD (coronary death, myocardial infarction, angina, stroke, and CVD death). Multivariable Cox regression models were used to assess associations of asthma and CVD. The 6792 participants were 62.2 (SD, 10.2) years old: 47% men (28% black, 22% Hispanic, and 12% Chinese). Persistent asthmatics (n=156), compared with intermittent (n=511) and nonasthmatics (n=6125), respectively, had higher C-reactive protein (1.2 [1.2] versus 0.9 [1.2] versus 0.6 [1.2] mg/L) and fibrinogen (379 [88] versus 356 [80] versus 345 [73] mg/dL) levels. Persistent asthmatics had the lowest unadjusted CVD-free survival rate of 84.1%, 95% confidence interval (78.9%–90.3%) compared with intermittent asthmatics 91.1% (88.5%–93.8%) and nonasthmatics 90.2% (89.4%–91%). Persistent asthmatics had greater risk of CVD events than nonasthmatics (hazard ratio [95% confidence interval], 1.6 [1.01–2.5]; P=0.040]), even after adjustment for age, sex, race, CVD risk factors, and antihypertensive and lipid medication use. Conclusions—In this large multiethnic cohort, persistent asthmatics had a higher CVD event rate than nonasthmatics.Objectives— To identify and characterize an association between persistent asthma and cardiovascular disease (CVD) risk in the Multi-Ethnic Study of Atherosclerosis (MESA). Approach and Results— MESA is a longitudinal prospective study of an ethnically diverse cohort of individuals free of known CVD at its inception. The presence and severity of asthma were assessed in the MESA at examination 1. Persistent asthma was defined as asthmatics using controller medications (inhaled corticosteroids, leukotriene inhibitors, and oral corticosteroids) and intermittent asthma as asthmatics not using controller medications. Participants were followed up for a mean (SD) of 9.1 (2.8) years for development of incident CVD (coronary death, myocardial infarction, angina, stroke, and CVD death). Multivariable Cox regression models were used to assess associations of asthma and CVD. The 6792 participants were 62.2 (SD, 10.2) years old: 47% men (28% black, 22% Hispanic, and 12% Chinese). Persistent asthmatics (n=156), compared with intermittent (n=511) and nonasthmatics (n=6125), respectively, had higher C-reactive protein (1.2 [1.2] versus 0.9 [1.2] versus 0.6 [1.2] mg/L) and fibrinogen (379 [88] versus 356 [80] versus 345 [73] mg/dL) levels. Persistent asthmatics had the lowest unadjusted CVD-free survival rate of 84.1%, 95% confidence interval (78.9%–90.3%) compared with intermittent asthmatics 91.1% (88.5%–93.8%) and nonasthmatics 90.2% (89.4%–91%). Persistent asthmatics had greater risk of CVD events than nonasthmatics (hazard ratio [95% confidence interval], 1.6 [1.01–2.5]; P =0.040]), even after adjustment for age, sex, race, CVD risk factors, and antihypertensive and lipid medication use. Conclusions— In this large multiethnic cohort, persistent asthmatics had a higher CVD event rate than nonasthmatics. # Significance {#article-title-31}

Common genes underlying asthma and COPD? Genome-wide analysis on the Dutch hypothesis

Asthma and chronic obstructive pulmonary disease (COPD) are thought to share a genetic background (“Dutch hypothesis”). We investigated whether asthma and COPD have common underlying genetic factors, performing genome-wide association studies for both asthma and COPD and combining the results in meta-analyses. Three loci showed potential involvement in both diseases: chr2p24.3, chr5q23.1 and chr13q14.2, containing DDX1, COMMD10 (both participating in the nuclear factor (NF) &kgr;&bgr; pathway) and GNG5P5, respectively. Single nucleotide polymorphisms (SNPs) rs9534578 in GNG5P5 reached genome-wide significance after first replication phase (p=9.96×10−9). The second replication phase, in seven independent cohorts, provided no significant replication. Expression quantitative trait loci (eQTL) analysis in blood cells and lung tissue on the top 20 associated SNPs identified two SNPs in COMMD10 that influenced gene expression. Inflammatory processes differ in asthma and COPD and are mediated by NF-&kgr;&bgr;, which could be driven by the same underlying genes, COMMD10 and DDX1. None of the SNPs reached genome-wide significance. Our eQTL studies support a functional role for two COMMD10 SNPs, since they influence gene expression in both blood cells and lung tissue. Our findings suggest that there is either no common genetic component in asthma and COPD or, alternatively, different environmental factors, e.g. lifestyle and occupation in different countries and continents, which may have obscured the genetic common contribution. This article provides suggestive evidence, but not firm evidence that there is overlap in genetics of asthma and COPD http://ow.ly/we9yE

Asthma Predicts Cardiovascular Disease Events

Objectives—To identify and characterize an association between persistent asthma and cardiovascular disease (CVD) risk in the Multi-Ethnic Study of Atherosclerosis (MESA). Approach and Results—MESA is a longitudinal prospective study of an ethnically diverse cohort of individuals free of known CVD at its inception. The presence and severity of asthma were assessed in the MESA at examination 1. Persistent asthma was defined as asthmatics using controller medications (inhaled corticosteroids, leukotriene inhibitors, and oral corticosteroids) and intermittent asthma as asthmatics not using controller medications. Participants were followed up for a mean (SD) of 9.1 (2.8) years for development of incident CVD (coronary death, myocardial infarction, angina, stroke, and CVD death). Multivariable Cox regression models were used to assess associations of asthma and CVD. The 6792 participants were 62.2 (SD, 10.2) years old: 47% men (28% black, 22% Hispanic, and 12% Chinese). Persistent asthmatics (n=156), compared with intermittent (n=511) and nonasthmatics (n=6125), respectively, had higher C-reactive protein (1.2 [1.2] versus 0.9 [1.2] versus 0.6 [1.2] mg/L) and fibrinogen (379 [88] versus 356 [80] versus 345 [73] mg/dL) levels. Persistent asthmatics had the lowest unadjusted CVD-free survival rate of 84.1%, 95% confidence interval (78.9%–90.3%) compared with intermittent asthmatics 91.1% (88.5%–93.8%) and nonasthmatics 90.2% (89.4%–91%). Persistent asthmatics had greater risk of CVD events than nonasthmatics (hazard ratio [95% confidence interval], 1.6 [1.01–2.5]; P=0.040]), even after adjustment for age, sex, race, CVD risk factors, and antihypertensive and lipid medication use. Conclusions—In this large multiethnic cohort, persistent asthmatics had a higher CVD event rate than nonasthmatics.Objectives— To identify and characterize an association between persistent asthma and cardiovascular disease (CVD) risk in the Multi-Ethnic Study of Atherosclerosis (MESA). Approach and Results— MESA is a longitudinal prospective study of an ethnically diverse cohort of individuals free of known CVD at its inception. The presence and severity of asthma were assessed in the MESA at examination 1. Persistent asthma was defined as asthmatics using controller medications (inhaled corticosteroids, leukotriene inhibitors, and oral corticosteroids) and intermittent asthma as asthmatics not using controller medications. Participants were followed up for a mean (SD) of 9.1 (2.8) years for development of incident CVD (coronary death, myocardial infarction, angina, stroke, and CVD death). Multivariable Cox regression models were used to assess associations of asthma and CVD. The 6792 participants were 62.2 (SD, 10.2) years old: 47% men (28% black, 22% Hispanic, and 12% Chinese). Persistent asthmatics (n=156), compared with intermittent (n=511) and nonasthmatics (n=6125), respectively, had higher C-reactive protein (1.2 [1.2] versus 0.9 [1.2] versus 0.6 [1.2] mg/L) and fibrinogen (379 [88] versus 356 [80] versus 345 [73] mg/dL) levels. Persistent asthmatics had the lowest unadjusted CVD-free survival rate of 84.1%, 95% confidence interval (78.9%–90.3%) compared with intermittent asthmatics 91.1% (88.5%–93.8%) and nonasthmatics 90.2% (89.4%–91%). Persistent asthmatics had greater risk of CVD events than nonasthmatics (hazard ratio [95% confidence interval], 1.6 [1.01–2.5]; P =0.040]), even after adjustment for age, sex, race, CVD risk factors, and antihypertensive and lipid medication use. Conclusions— In this large multiethnic cohort, persistent asthmatics had a higher CVD event rate than nonasthmatics. # Significance {#article-title-31}

Transcriptomic profiles of aging in purified human immune cells.

BackgroundTranscriptomic studies hold great potential towards understanding the human aging process. Previous transcriptomic studies have identified many genes with age-associated expression levels; however, small samples sizes and mixed cell types often make these results difficult to interpret.ResultsUsing transcriptomic profiles in CD14+ monocytes from 1,264 participants of the Multi-Ethnic Study of Atherosclerosis (aged 55–94 years), we identified 2,704 genes differentially expressed with chronological age (false discovery rate, FDR ≤ 0.001). We further identified six networks of co-expressed genes that included prominent genes from three pathways: protein synthesis (particularly mitochondrial ribosomal genes), oxidative phosphorylation, and autophagy, with expression patterns suggesting these pathways decline with age. Expression of several chromatin remodeler and transcriptional modifier genes strongly correlated with expression of oxidative phosphorylation and ribosomal protein synthesis genes. 17% of genes with age-associated expression harbored CpG sites whose degree of methylation significantly mediated the relationship between age and gene expression (p < 0.05). Lastly, 15 genes with age-associated expression were also associated (FDR ≤ 0.01) with pulse pressure independent of chronological age.Comparing transcriptomic profiles of CD14+ monocytes to CD4+ T cells from a subset (n = 423) of the population, we identified 30 age-associated (FDR < 0.01) genes in common, while larger sets of differentially expressed genes were unique to either T cells (188 genes) or monocytes (383 genes). At the pathway level, a decline in ribosomal protein synthesis machinery gene expression with age was detectable in both cell types.ConclusionsAn overall decline in expression of ribosomal protein synthesis genes with age was detected in CD14+ monocytes and CD4+ T cells, demonstrating that some patterns of aging are likely shared between different cell types. Our findings also support cell-specific effects of age on gene expression, illustrating the importance of using purified cell samples for future transcriptomic studies. Longitudinal work is required to establish the relationship between identified age-associated genes/pathways and aging-related diseases.

Long-term outdoor air pollution and DNA methylation in circulating monocytes: results from the Multi-Ethnic Study of Atherosclerosis (MESA)

BackgroundDNA methylation may mediate effects of air pollution on cardiovascular disease. The association between long-term air pollution exposure and DNA methylation in monocytes, which are central to atherosclerosis, has not been studied. We investigated the association between long-term ambient air pollution exposure and DNA methylation (candidate sites and global) in monocytes of adults (aged ≥55).MethodsOne-year average ambient fine particulate matter (PM2.5) and oxides of nitrogen (NOX) concentrations were predicted at participants’ (n = 1,207) addresses using spatiotemporal models. We assessed DNA methylation in circulating monocytes at 1) 2,713 CpG sites associated with mRNA expression of nearby genes and 2) probes mapping to Alu and LINE-1 repetitive elements (surrogates for global DNA methylation) using Illumina’s Infinium HumanMethylation450 BeadChip. We used linear regression models adjusted for demographics, smoking, physical activity, socioeconomic status, methyl-nutrients, and technical variables. For significant air pollution-associated methylation sites, we also assessed the association between expression of gene transcripts previously associated with these CpG sites and air pollution.ResultsAt a false discovery rate of 0.05, five candidate CpGs (cg20455854, cg07855639, cg07598385, cg17360854, and cg23599683) had methylation significantly associated with PM2.5 and none were associated with NOX. Cg20455854 had the smallest p-value for the association with PM2.5 (p = 2.77 × 10−5). mRNA expression profiles of genes near three of the PM2.5-associated CpGs (ANKHD1, LGALS2, and ANKRD11) were also significantly associated with PM2.5 exposure. Alu and LINE-1 methylation were not associated with long-term air pollution exposure.ConclusionsWe observed novel associations between long-term ambient air pollution exposure and site-specific DNA methylation, but not global DNA methylation, in purified monocytes of a multi-ethnic adult population. Epigenetic markers may provide insights into mechanisms underlying environmental factors in complex diseases like atherosclerosis.

Occupational Risk Factors for COPD Phenotypes in the Multi-Ethnic Study of Atherosclerosis (MESA) Lung Study

Abstract Introduction: The contribution of occupational exposure to the risk of chronic obstructive pulmonary disease COPD in population-based studies is of interest. We compared the performance of self-reported exposure to a newly developed JEM in exposure-response evaluation. Methods: We used cross-sectional data from Multi-Ethnic Study of Atherosclerosis (MESA), a population-based sample of 45–84 year olds free of clinical cardiovascular disease at baseline. MESA ascertained the most recent job and employment, and the MESA Lung Study measured spirometry, and occupational exposures for 3686 participants. Associations between health outcomes (spirometry defined airflow limitation and Medical Research Council-defined chronic bronchitis) and occupational exposure [self-reported occupational exposure to vapor-gas, dust, or fumes (VGDF), severity of exposure, and a job-exposure matrix (JEM)-derived score] were evaluated using logistic regression models adjusted for non-occupational risk factors. Results: The prevalence of airflow limitation was associated with self-reported exposure to vapor-gas (OR 2.6, 95%CI 1.1–2.3), severity of VGDF exposure (P-trend < 0.01), and JEM dust exposure (OR 2.4, 95%CI 1.1–5.0), and with organic dust exposure in females; these associations were generally of greater magnitude among never smokers. The prevalence of chronic bronchitis and wheeze was associated with exposure to VGDF. The association between airflow limitation and the combined effect of smoking and VGDF exposure showed an increasing trend. Self-reported vapor-gas, dust, fumes, years and severity of exposure were associated with increased prevalence of chronic bronchitis and wheeze (P < 0.001). Conclusions: Airflow limitation was associated with self-reported VGDF exposure, its severity, and JEM-ascertained dust exposure in smokers and never-smokers in this multiethnic study.

Prognostic Significance of Large Airway Dimensions on Computed Tomography in the General Population. The Multi-Ethnic Study of Atherosclerosis (MESA) Lung Study

Rationale: Large airway dimensions on computed tomography (CT) have been associated with lung function, symptoms, and exacerbations in chronic obstructive pulmonary disease (COPD), as well as with symptoms in smokers with preserved spirometry. Their prognostic significance in persons without lung disease remains undefined. Objectives: To examine associations between large airway dimensions on CT and respiratory outcomes in a population‐based cohort of adults without prevalent lung disease. Methods: The Multi‐Ethnic Study of Atherosclerosis recruited participants ages 45‐84 years without cardiovascular disease in 2000‐2002; we excluded participants with prevalent chronic lower respiratory disease (CLRD). Spirometry was measured in 2004‐2006 and 2010‐2012. CLRD hospitalizations and deaths were classified by validated criteria through 2014. The average wall thickness for a hypothetical airway of 10‐mm lumen perimeter on CT (Pi10) was calculated using measures of airway wall thickness and lumen diameter. Models were adjusted for age, sex, principal components of ancestry, body mass index, smoking, pack‐years, scanner, percent emphysema, genetic risk score, and initial forced expiratory volume in 1 second (FEV1) percent predicted. Results: Greater Pi10 was associated with 9% faster FEV1 decline (95% confidence interval [CI], 2 to 15%; P = 0.012) and increased incident COPD (odds ratio, 2.22; 95% CI, 1.43‐3.45; P = 0.0004) per standard deviation among 1,830 participants. Over 78,147 person‐years, higher Pi10 was associated with a 57% higher risk of first CLRD hospitalization or mortality (P = 0.0496) per standard deviation. Of Pi10s component measures, both greater airway wall thickness and narrower lumen predicted incident COPD and CLRD clinical events. Conclusions: In adults without CLRD, large airway dimensions on CT were prospectively associated with accelerated lung function decline and increased risks of COPD and CLRD hospitalization and mortality.