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1.  Genome-Wide Study of Percent Emphysema on Computed Tomography in the General Population. The Multi-Ethnic Study of Atherosclerosis Lung/SNP Health Association Resource Study 
Rationale: Pulmonary emphysema overlaps partially with spirometrically defined chronic obstructive pulmonary disease and is heritable, with moderately high familial clustering.
Objectives: To complete a genome-wide association study (GWAS) for the percentage of emphysema-like lung on computed tomography in the Multi-Ethnic Study of Atherosclerosis (MESA) Lung/SNP Health Association Resource (SHARe) Study, a large, population-based cohort in the United States.
Methods: We determined percent emphysema and upper-lower lobe ratio in emphysema defined by lung regions less than −950 HU on cardiac scans. Genetic analyses were reported combined across four race/ethnic groups: non-Hispanic white (n = 2,587), African American (n = 2,510), Hispanic (n = 2,113), and Chinese (n = 704) and stratified by race and ethnicity.
Measurements and Main Results: Among 7,914 participants, we identified regions at genome-wide significance for percent emphysema in or near SNRPF (rs7957346; P = 2.2 × 10−8) and PPT2 (rs10947233; P = 3.2 × 10−8), both of which replicated in an additional 6,023 individuals of European ancestry. Both single-nucleotide polymorphisms were previously implicated as genes influencing lung function, and analyses including lung function revealed independent associations for percent emphysema. Among Hispanics, we identified a genetic locus for upper-lower lobe ratio near the α-mannosidase–related gene MAN2B1 (rs10411619; P = 1.1 × 10−9; minor allele frequency [MAF], 4.4%). Among Chinese, we identified single-nucleotide polymorphisms associated with upper-lower lobe ratio near DHX15 (rs7698250; P = 1.8 × 10−10; MAF, 2.7%) and MGAT5B (rs7221059; P = 2.7 × 10−8; MAF, 2.6%), which acts on α-linked mannose. Among African Americans, a locus near a third α-mannosidase–related gene, MAN1C1 (rs12130495; P = 9.9 × 10−6; MAF, 13.3%) was associated with percent emphysema.
Conclusions: Our results suggest that some genes previously identified as influencing lung function are independently associated with emphysema rather than lung function, and that genes related to α-mannosidase may influence risk of emphysema.
doi:10.1164/rccm.201306-1061OC
PMCID: PMC3977717  PMID: 24383474
emphysema; computed tomography; multiethnic; cohort study; genetic association
2.  Pulmonary Emphysema Subtypes on Computed Tomography in Smokers 
The American journal of medicine  2013;127(1):10.1016/j.amjmed.2013.09.020.
Background
Pulmonary emphysema is divided into three major subtypes at autopsy: centrilobular, paraseptal and panlobular emphysema. These subtypes can be defined by visual assessment on computed tomography (CT); however, clinical characteristics of emphysema subtypes on CT are not well-defined. We developed a reliable approach to visual assessment of emphysema subtypes on CT and examined if emphysema subtypes have distinct characteristics.
Methods
The Multi-Ethnic Study of Atherosclerosis COPD Study recruited smokers with COPD and controls age 50–79 years with ≥10 pack-years. Participants underwent CT following a standardized protocol. Definitions of centrilobular, paraseptal and panlobular emphysema were obtained by literature review. Six-minute walk distance and pulmonary function were performed following guidelines.
Results
Twenty-seven percent of 318 smokers had emphysema on CT. Inter-rater reliability of emphysema subtype was substantial (K:0.70). Compared to participants without emphysema, individuals with centrilobular or panlobular emphysema had greater dyspnea, reduced walk distance, greater hyperinflation, and lower diffusing capacity. In contrast, individuals with PSE were similar to controls, except for male predominance. Centrilobular but not panlobular or paraseptal emphysema was associated with greater smoking history (+21 pack-years P<0.001). Panlobular but not other types of emphysema was associated with reduced body mass index (−5 kg/m2;P=0.01). Other than for dyspnea, these findings were independent of the forced expiratory volume in one second. Seventeen percent of smokers without COPD on spirometry had emphysema, which was independently associated with reduced walk distance.
Conclusions
Emphysema subtypes on CT are common in smokers with and without COPD. Centrilobular and panlobular emphysema but not paraseptal emphysema have considerable symptomatic and physiological consequences.
doi:10.1016/j.amjmed.2013.09.020
PMCID: PMC3882898  PMID: 24384106
Emphysema; computed tomography; centrilobular; paraseptal; panlobular
3.  Establishing normal reference values in quantitative computed tomography of emphysema 
Journal of thoracic imaging  2013;28(5):280-283.
Summary
Quantitative computed tomography (QCT) can provide reliable and valid measures of lung structure and volumes. Similar to lung function and volumes measured by spirometry, lung measures obtained by QCT vary by demographic and anthropomorphic factors including sex, race/ethnicity and height in asymptomatic non-smokers. Hence, some accounting for these factors is necessary to define abnormal from normal QCT values and disease severity. Similar to spirometry and cardiac volumes, prediction equations for QCT may be derived from a sample of asymptomatic individuals to estimate reference values.
This paper describes the methodology of reference equation development using, as an example, quantitative densitometry to detect pulmonary emphysema. The process described is generalizable to other QCT measures, including lung volumes, airway dimensions and gas-trapping. Pulmonary emphysema is defined morphologically by airspace enlargement with alveolar wall destruction and has been shown to correlate with low lung attenuation estimated by QCT. Deriving reference values for a normal quantity of low lung attenuation requires three steps: First, criteria that define normal must be established. Second, variables for inclusion must be selected based on an understanding of subject, scanner and protocol specific factors that influence lung attenuation. Finally, a reference sample of normal individuals must be selected that is representative of the population in which QCT will be used to detect pulmonary emphysema. Sources of bias and confounding inherent to reference values are also discussed.
Reference equation development is a multistep process that can define normal values for QCT measures such as lung attenuation. Normative reference values will increase the utility of QCT in both research and clinical practice.
doi:10.1097/RTI.0b013e3182a0d805
PMCID: PMC3786591  PMID: 23966092
quantitative; computed tomography; emphysema; reference equation; prediction
4.  Plasma sphingomyelin and longitudinal change in emphysema on computed tomography. The MESA Lung study 
Context
Ceramide causes endothelial apoptosis and emphysema-like changes in animal models.
Objectives
Test if plasma sphingomyelin, a major precursor of ceramide, would predict longitudinal increase in the percentage of emphysema-like lung on computed tomography (CT).
Materials and methods
3,840 participants had their plasma sphingomyelin measured at baseline examination and their pulmonary emphysema measured on cardiac CT scans at baseline and on follow-up visits. Mixed effects models were used to adjust for potential confounders.
Results
one standard deviation increase in sphingomyelin predicted a 0.12 % per year (95% CI: 0.02 to 0.22; p = 0.019) greater increase of percent emphysema.
Discussion and conclusion
Higher plasma levels of sphingomyelin predicted greater annual increase in quantitatively measured percent emphysema.
doi:10.3109/1354750X.2014.896414
PMCID: PMC4088962  PMID: 24649875
Sphingomyelin; Ceramide; Emphysema; Computed Tomography
5.  Ethnicity and Sex Modify the Association of Serum C-Reactive Protein with Microalbuminuria 
Ethnicity & disease  2008;18(3):324-329.
Objectives
To study the association between serum C-reactive protein (CRP) and urinary albumin excretion in the Multi-Ethnic Study of Atherosclerosis and to assess whether the association is modified by ethnicity, sex, or systolic blood pressure.
Methods
This was a cross-sectional study of 6675 participants who were free from macro albuminuria and clinical cardiovascular disease (mean age 62.1 years, 53% female; 39% White, 27% African American, 22% Hispanic, and 12% Chinese). Urinary albumin excretion was measured by spot urine albumin-to-creatinine ratio (ACR). Effect modifications were tested after adjusting for age, diabetes, body mass index, smoking, use of angiotensin-converting enzyme inhibitor or angiotensin-receptor blocker, other antihypertensive drugs, estrogens, statins, and high-density lipoprotein cholesterol and triglyceride levels.
Results
The association between CRP and ACR was modified by ethnicity (P=.01) and sex (P<.001), but not by systolic blood pressure. After multivariate adjustment, the association remained in Chinese, African American, and Hispanic men and African American women (P<.02 for African American men, and P<.04 for the other subgroups).
Conclusions
The association between CRP and ACR was modified by ethnicity and sex; it was stronger in non-White men and African American women. These interactions have not been reported before, and future studies should consider them.
PMCID: PMC4089959  PMID: 18785447
Albuminuria; C-Reactive Protein; Ethnicity; Gender
6.  Genetic Ancestry and the Relationship of Cigarette Smoking to Lung Function and Percent Emphysema in Four Race/Ethnic Groups: a Cross-sectional Study 
Thorax  2013;68(7):634-642.
Background
Cigarette smoking is the major cause of chronic obstructive pulmonary disease and emphysema. Recent studies suggest that susceptibility to cigarette smoke may vary by race/ethnicity; however, they were generally small and relied on self-reported race/ethnicity.
Objective
To test the hypothesis that relationships of smoking to lung function and percent emphysema differ by genetic ancestry and self-reported race/ethnicity among Whites, African-Americans, Hispanics and Chinese-Americans.
Design
Cross-sectional population-based study of adults age 45-84 years in the United States
Measurements
Principal components of genetic ancestry and continental ancestry estimated from one-million genome-wide single nucleotide polymorphisms. Pack-years calculated as years smoking cigarettes-per-day/20. Spirometry measured for 3,344 and percent emphysema on computed tomography for 8,224 participants.
Results
The prevalence of ever-smoking was: Whites, 57.6%; African-Americans, 56.4%; Hispanics, 46.7%; and Chinese-Americans, 26.8%. Every 10 pack-years was associated with −0.73% (95% CI −0.90%, −0.56%) decrement in the forced expiratory volume in one second to forced vital capacity (FEV1/FVC) and a 0.23% (95% CI 0.08%, 0.38%) increase in percent emphysema. There was no evidence that relationships of pack-years to the FEV1/FVC, airflow obstruction and percent emphysema varied by genetic ancestry (all p>0.10), self-reported race/ethnicity (all p>0.10) or, among African-Americans, African ancestry. There were small differences in relationships of pack-years to the FEV1 among male Chinese-Americans and to the FEV1/FVC with African and Native American ancestry among male Hispanics only.
Conclusions
In this large cohort, there was little-to-no evidence that the associations of smoking to lung function and percent emphysema differed by genetic ancestry or self-reported race/ethnicity.
doi:10.1136/thoraxjnl-2012-202116
PMCID: PMC4020409  PMID: 23585509
cigarette smoke; genetic ancestry; lung function; chronic obstructive pulmonary disease; COPD; emphysema; FVC; Forced Vital Capacity; FEV1; Forced Expiratory Volume in 1 second
7.  Endothelial Microparticles in Mild Chronic Obstructive Pulmonary Disease and Emphysema. The Multi-Ethnic Study of Atherosclerosis Chronic Obstructive Pulmonary Disease Study 
Rationale: Basic research implicates alveolar endothelial cell apoptosis in the pathogenesis of chronic obstructive pulmonary disease (COPD) and emphysema. However, information on endothelial microparticles (EMPs) in mild COPD and emphysema is lacking.
Objectives: We hypothesized that levels of CD31+ EMPs phenotypic for endothelial cell apoptosis would be elevated in COPD and associated with percent emphysema on computed tomography (CT). Associations with pulmonary microvascular blood flow (PMBF), diffusing capacity, and hyperinflation were also examined.
Methods: The Multi-Ethnic Study of Atherosclerosis COPD Study recruited participants with COPD and control subjects age 50–79 years with greater than or equal to 10 pack-years without clinical cardiovascular disease. CD31+ EMPs were measured using flow cytometry in 180 participants who also underwent CTs and spirometry. CD62E+ EMPs phenotypic for endothelial cell activation were also measured. COPD was defined by standard criteria. Percent emphysema was defined as regions less than −950 Hounsfield units on full-lung scans. PMBF was assessed on gadolinium-enhanced magnetic resonance imaging. Hyperinflation was defined as residual volume/total lung capacity. Linear regression was used to adjust for potential confounding factors.
Measurements and Main Results: CD31+ EMPs were elevated in COPD compared with control subjects (P = 0.03) and were notably increased in mild COPD (P = 0.03). CD31+ EMPs were positively related to percent emphysema (P = 0.045) and were inversely associated with PMBF (P = 0.047) and diffusing capacity (P = 0.01). In contrast, CD62E+ EMPs were elevated in severe COPD (P = 0.003) and hyperinflation (P = 0.001).
Conclusions: CD31+ EMPs, suggestive of endothelial cell apoptosis, were elevated in mild COPD and emphysema. In contrast, CD62E+ EMPs indicative of endothelial activation were elevated in severe COPD and hyperinflation.
doi:10.1164/rccm.201209-1697OC
PMCID: PMC3735242  PMID: 23600492
chronic obstructive pulmonary disease; emphysema; antigens, CD31; endothelium; pulmonary disease
8.  APOM and High-Density Lipoprotein are associated with Lung Function and Percent Emphysema 
The European respiratory journal  2013;43(4):1003-1017.
Chronic obstructive pulmonary disease (COPD) is linked to cardiovascular disease; however, there are few studies on the associations of cardiovascular genes with COPD.
We assessed the association of lung function with 2,100 genes selected for cardiovascular diseases among 20,077 European-Americans and 6,900 African-Americans. We performed replication of significant loci in the other racial group and an independent consortium of Europeans, tested the associations of significant loci with percent emphysema, and examined gene expression in an independent sample. We then tested the association of a related lipid biomarker with FEV1/FVC and percent emphysema.
We identified one new polymorphism for FEV1/FVC (rs805301) in European-Americans (p=1.3×10−6) and a second (rs707974) in the combined European-American and African-American analysis (p=1.38×10−7). Both SNPs flank the gene for apolipoprotein M (apoM), a component of HDL. Both replicated in an independent cohort. SNPs in a second gene related to apoM and HDL, PCSK9, were associated with FEV1/FVC among African-Americans. rs707974 was associated with percent emphysema among European-Americans and African-Americans, and APOM expression was related to FEV1/FVC and percent emphysema. Higher HDL levels were associated with lower FEV1/FVC and greater percent emphysema.
These findings suggest a novel role for the APOM/HDL pathway in the pathogenesis of COPD and emphysema.
doi:10.1183/09031936.00147612
PMCID: PMC4041087  PMID: 23900982
Apolipoproteins; Cholesterol; Percent Emphysema; Polymorphism, Single Nucleotide; Pulmonary Disease, Chronic Obstructive
9.  Pulmonary Hyperinflation and Left Ventricular Mass 
Circulation  2013;127(14):1503-1511e6.
Background
Left ventricular (LV) mass is an important predictor of heart failure and cardiovascular mortality, yet determinants of LV mass are incompletely understood. Pulmonary hyperinflation in chronic obstructive pulmonary disease (COPD) may contribute to changes in intrathoracic pressure that increase LV wall stress. We therefore hypothesized that residual lung volume in COPD would be associated with greater LV mass.
Methods and results
The Multi-Ethnic Study of Atherosclerosis (MESA) COPD Study recruited smokers aged 50–79 years who were free of clinical cardiovascular disease. LV mass was measured by cardiac magnetic resonance. Pulmonary function testing was performed according to guidelines. Regression models were used to adjust for age, sex, body size, blood pressure and other cardiac risk factors.
Among 119 MESA COPD Study participants, mean age was 69±6 years, 55% were male and 65% had COPD, mostly of mild or moderate severity. Mean LV mass was 128±34 grams. Residual lung volume was independently associated with greater LV mass (7.2 grams per standard deviation increase in residual volume; 95% CI 2.2 to 12; P=0.004), and was similar in magnitude to that of systolic blood pressure (7.6 grams per standard deviation increase in systolic blood pressure, 95% CI 4.3 to 11 grams; p<0.001). Similar results were observed for LV mass to end-diastolic volume ratio (p=0.02) and with hyperinflation measured as residual volume to total lung capacity ratio (P=0.009).
Conclusions
Pulmonary hyperinflation, as measured by residual lung volume or residual lung volume to total lung capacity ratio, is associated with greater LV mass.
doi:10.1161/CIRCULATIONAHA.113.001653
PMCID: PMC4018203  PMID: 23493320
Left ventricular mass; hyperinflation; chronic obstructive pulmonary disease
10.  Asthma and lung structure on CT: The MESA Lung Study 
Background
The potential consequences of asthma in childhood and young adulthood on lung structure in older adults have not been studied in a large, population-based cohort.
Objective
The authors hypothesized that a history of asthma onset in childhood (age 18 or before) or young adulthood (age 19 to 45) was associated with altered lung structure on computed tomography (CT) in later life.
Methods
The Multi-Ethnic Study of Atherosclerosis Lung Study recruited 3,965 participants and assessed asthma history using standardized questionnaires, spirometry following guidelines, and segmental airway dimensions and percent low attenuation areas on CT scans.
Results
Asthma with onset in childhood and young adulthood was associated with large decrements in the forced expiratory volume in one second among participants with a mean age of 66 years (−365 ml and −343 ml, respectively; P<0.001). Asthma with onset in childhood and young adulthood was associated with increased mean airway wall thickness standardized to an internal perimeter of 10 mm (Pi10) (0.1 mm, P<0.001 for both), predominantly from narrower segmental airway lumens (−0.39 mm and −0.34 mm, respectively; P<0.001). Asthma with onset in childhood and young adulthood also was associated with a greater percentage of low attenuation areas (1.69% and 4.30%, respectively; P<0.001). Findings were similar among never smokers except that differential percentage of low attenuation areas in child-onset asthma was not seen in them.
Conclusion
Asthma with onset in childhood or young adulthood, was associated with reduced lung function, narrower airways and, among asthmatics who smoked, greater percentage of low attenuation areas in later life.
doi:10.1016/j.jaci.2012.11.036
PMCID: PMC3564253  PMID: 23374265
airway remodeling; airway structure; asthma; emphysema; epidemiology
11.  Cigarette smoking and airway wall thickness on CT scan in a multi-ethnic cohort: The MESA Lung Study 
Respiratory medicine  2012;106(12):1655-1664.
Background
Autopsy studies show that smoking contributes to airway wall hyperplasia and narrowing of the airway lumen. Studies of smoking and airway measures on computed tomography (CT) scan are limited to case-control studies of measures that combine airway lumen and wall thickness.
Objectives
We hypothesized that cumulative cigarette smoking would be associated with increased airway wall thickness in a large, population-based cohort.
Methods
The Multi-Ethnic Study of Atherosclerosis enrolled participants age 45-84 years from the general population. Smoking history was assessed via standardized questionnaire items; current smoking was confirmed in half the cohort with cotinine. Airway lumen and wall thickness were measured in two dimensions in posterior basal segmental bronchi on cardiac-gated CT scans. Analyses were adjusted for age, gender, genetic ancestry, education, height, weight, asthma history, particulate matter, scanner type, and scanner current.
Results
Half of the 7,898 participants had smoked and 14% were current smokers. Pack-years of smoking were associated with thicker airway walls (mean increase 0.002 mm per ten pack-years [95% CI: 0.00002, 0.004] p=0.03). Current smoking was associated with narrower airway lumens (mean decrease −0.11 mm [95% CI: −0.2, −0.02] p=0.02). There was no evidence that either association was modified by genetic ancestry, and findings persisted among participants without clinical disease.
Conclusions
Long-term cigarette smoking was associated with subclinical increases in wall thickness of sub-segmental airways whereas current smoking was associated with narrower airway lumen diameters. Smoking may contribute to airway wall thickening prior to the development of overt chronic obstructive pulmonary disease.
doi:10.1016/j.rmed.2012.08.006
PMCID: PMC3549633  PMID: 22974831
smoking; airway remodeling; Pi10; wall thickness; lumen; chronic obstructive pulmonary disease
12.  Does the relationship between asthma and obesity differ by neighborhood? 
Respiratory medicine  2008;102(12):1797-1804.
doi:10.1016/j.rmed.2008.06.018
PMCID: PMC3695444  PMID: 18707858
epidemiology; survey; urban health
13.  Pulmonary Function is Associated with Distal Aortic Calcium, not Proximal Aortic Distensibility. MESA Lung Study 
COPD  2011;8(2):71-78.
Forced expiratory volume in one second strongly predicts mortality from cardiovascular disease. FEV1 has been associated with aortic stiffness a strong independent predictor of cardiovascular mortality. However, the anatomical site and possible mechanisms linking aortic stiffness and lung function are unknown. We therefore examined if FEV1 and CT percent emphysema were associated with calcification of the abdominal aorta or reduced distensibility of the proximal thoracic aorta.
The Multi-Ethnic Study of Atherosclerosis (MESA) measured aortic calcification on cardiac and abdominal CT scans and proximal aortic distensibility using magnetic resonance among participants aged 45–84 years without clinical cardiovascular disease. Spirometry was measured following ATS/ERS guidelines and percent emphysema was measured in the lung fields of cardiac CT scans. Multivariate analyses adjusted for age, sex, race/ethnicity and cardiovascular risk factors.
Of 1,917 participants with aortic distensibility measures, 13% were current and 38% were former smokers. Eighteen percent had airflow limitation without asthma. FEV1 was associated with the extent of distal aortic calcification (0.76; 95%CI 0.60–0.97, p=0.02) but not proximal aortic calcification or proximal aortic distensibility (−0.04 mmHg−1; 95%CI −0.16–0.09 mmHg−1, p=0.60). Percent emphysema was associated with neither measure.
FEV1 was associated with severity of distal aortic calcification where it was present independently of smoking and other cardiovascular risk factors but not with distensibility or calcification of the proximal aorta.
doi:10.3109/15412555.2011.558543
PMCID: PMC3629728  PMID: 21495835
forced expiratory volume; pulmonary emphysema; aorta; calcification; compliance
14.  Performance of Maximal Inspiratory Pressure Tests and MIP Reference Equations for Four Ethnic Groups 
Respiratory care  2009;54(10):1321-1328.
Background
Maximal inspiratory pressure (MIP) is an important and non-invasive index of diaphragm strength and an independent predictor of all-cause mortality. The ability of adults over a wide age range and multiple ethnicities to perform MIP tests has previously not been evaluated.
Methods
The Multi-Ethnic Study of Atherosclerosis (MESA) recruited white, African-American, Hispanic and Chinese-American participants ages 45–84 years and free of clinical cardiovascular disease in six US cities. MIP was measured using standard techniques among 3849 MESA participants. The MIP quality goal was 5 maneuvers, with the two largest values matching within 10 cmH2O. Correlates of MIP quality and values were assessed in logistic and linear regression models.
Results
The 3849 MESA-Lung participants with MIP measures were 51% female, 35% white, 26% African-American, 23% Hispanic, and 16% Chinese-American. Mean MIP±SD was 73±26 cmH2O for women and 97±29 cmH2O for men. The quality goal was achieved by 83% of the cohort and was associated with female gender, older age, race/ethnicity, study site, low FEV1/FVC ratio, and wheeze with dyspnea. The multivariate correlates of MIP were male gender, younger age, higher BMI, shorter height, higher FVC, higher systolic blood pressure (in women) and health status (in men). There were no clinically important race/ethnic differences in MIP values.
Conclusion
Race-specific reference equations for MIP are unnecessary in the United States. More than 80% of adults can be successfully coached for 5 maneuvers with repeatability within 10 cmH2O.
PMCID: PMC3616895  PMID: 19796411
diaphragm strength; respiratory muscle strength; maximal inspiratory pressure; quality control; pulmonary function testing
15.  Subclinical Atherosclerosis, Airflow Obstruction and Emphysema: the MESA Lung Study 
Airflow obstruction is independent risk factor for cardiovascular events in the general population. The affected vascular bed and contribution of emphysema to cardiovascular risk are unclear. We examined if an obstructive pattern of spirometry and quantitatively defined emphysema were associated with subclinical atherosclerosis in the carotid, peripheral and coronary circulations.
The Multi-Ethnic Study of Atherosclerosis recruited participants age 45–84 years without clinical cardiovascular disease. Spirometry, carotid intima-media thickness, ankle-brachial index and coronary artery calcium were measured using standard protocols. Percent of emphysema-like lung was measured in the lung windows of cardiac computed tomography scans among 3,642 participants. Multiple linear regression was used to adjust for cardiac risk factors including C-reactive protein.
Decrements in the FEV1 and FEV1/FVC were associated with greater internal carotid intima-media thickness among smokers (P=0.03 and P<0.001, respectively) whereas percent emphysema was associated with reduced ankle-brachial index regardless of smoking history (P=0.004). Coronary artery calcium was associated with neither lung function (prevalence ratio for severe airflow obstruction: 0.99; 95% CI, 0.91 to 1.07) nor percent emphysema.
An obstructive pattern of spirometry and emphysema are associated distinctly and independently with subclinical atherosclerosis in the carotid arteries and peripheral circulation, respectively, and were not independently related to coronary artery calcium.
doi:10.1183/09031936.00165410
PMCID: PMC3616898  PMID: 22034646
16.  Reproducibility and Validity of a Handheld Spirometer 
Respiratory care  2008;53(4):433-441.
Background
Handheld spirometers have several advantages over desktop spirometers but worries persist regarding their reproducibility and validity. We undertook an independent examination of an ultrasonic flow-sensing handheld spirometer.
Methods
Laboratory methods included reproducibility and validity testing using a waveform generator with standard American Thoracic Society (ATS) waveforms, in-line testing, calibration adaptor testing, and compression of the mouthpiece. Clinical testing involved repeated testing of 24 spirometry-naive volunteers and comparison to a volume-sensing dry rolling seal spirometer.
Results
The EasyOne Diagnostic spirometer exceeded standard thresholds of acceptability for ATS waveforms. In-line testing yielded valid results with relative differences (mean ± SD) between the EasyOne and the reference spirometer for the forced vital capacity (FVC) of 0.03±0.23 L and the forced expiratory volume in one second (FEV1) of −0.06±0.09 L. The calibration adaptor showed no appreciable problems, but extreme compression of the mouthpiece reduced measures. In clinical testing, coefficients of variation and limits of agreement were, respectively: 3.3% and 0.24 L for the FVC; 2.6% and 0.18 L for the FEV1; and 1.9% and 0.05 for the FEV1/FVC ratio. The EasyOne yielded lower values than the reference spirometry (FVC: −0.12 L; FEV1: −0.17 L; FEV1/FVC ratio: −0.02). Limits of agreement were within criteria for FVC but not for the FEV1, possibly due to a training effect.
Conclusion
The EasyOne spirometer yielded generally reproducible results that were generally valid compared to laboratory-based spirometry. The use of this handheld spirometer in clinical, occupational and research settings seems justified.
PMCID: PMC3595551  PMID: 18364054
17.  Racial Differences in CT Phenotypes in COPD 
COPD  2013;10(1):20-27.
Background
Whether African Americans (AA) are more susceptible to COPD than non-Hispanic Whites (NHW) and whether racial differences in disease phenotype exist is controversial. The objective is to determine racial differences in the extent of emphysema and airway remodeling in COPD.
Methods
First, 2,500 subjects enrolled in the COPDGene study were used to evaluate racial differences in quantitative CT (QCT) parameters of % emphysema, air trapping and airway wall thickness. Independent variables studied included race, age, gender, education, BMI, pack-years, smoking status, age at smoking initiation, asthma, previous work in dusty job, CT scanner and center of recruitment.
Results
Of the 1,063 subjects with GOLD Stage II-IV COPD, 200 self-reported as AA. AAs had a lower mean % emphysema (13.1 % vs. 16.1%, p = 0.005) than NHW and proportionately less emphysema in the lower lung zones. After adjustment for covariates, there was no statistical difference by race in air trapping or airway wall thickness. Measured QCT parameters were more predictive of poor functional status in NHWs compared to AAs.
Conclusions
AAs have less emphysema than NHWs but the same degree of airway disease. Additional factors not easily assessed by current QCT techniques may account for the poor functional status in AAs.
doi:10.3109/15412555.2012.727921
PMCID: PMC4321889  PMID: 23413893
Airway wall thickness; Air trapping; Chronic obstructive pulmonary disease; Emphysema; Quantitative CT; Race
18.  Air Pollution and Percent Emphysema Identified by Computed Tomography in the Multi-Ethnic Study of Atherosclerosis 
Environmental Health Perspectives  2014;123(2):144-151.
Background: Air pollution is linked to low lung function and to respiratory events, yet little is known of associations with lung structure.
Objectives: We examined associations of particulate matter (PM2.5, PM10) and nitrogen oxides (NOx) with percent emphysema-like lung on computed tomography (CT).
Methods: The Multi-Ethnic Study of Atherosclerosis (MESA) recruited participants (45–84 years of age) in six U.S. states. Percent emphysema was defined as lung regions < –910 Hounsfield Units on cardiac CT scans acquired following a highly standardized protocol. Spirometry was also conducted on a subset. Individual-level 1- and 20-year average air pollution exposures were estimated using spatiotemporal models that included cohort-specific measurements. Multivariable regression was conducted to adjust for traditional risk factors and study location.
Results: Among 6,515 participants, we found evidence of an association between percent emphysema and long-term pollution concentrations in an analysis leveraging between-city exposure contrasts. Higher concentrations of PM2.5 (5 μg/m3) and NOx (25 ppb) over the previous year were associated with 0.6 (95% CI: 0.1, 1.2%) and 0.5 (95% CI: 0.1, 0.9%) higher average percent emphysema, respectively. However, after adjustment for study site the associations were –0.6% (95% CI: –1.5, 0.3%) for PM2.5 and –0.5% (95% CI: –1.1, 0.02%) for NOx. Lower lung function measures (FEV1 and FVC) were associated with higher PM2.5 and NOx levels in 3,791 participants before and after adjustment for study site, though most associations were not statistically significant.
Conclusions: Associations between ambient air pollution and percentage of emphysema-like lung were inconclusive in this cross-sectional study, thus longitudinal analyses may better clarify these associations with percent emphysema.
Citation: Adar SD, Kaufman JD, Diez-Roux AV, Hoffman EA, D’Souza J, Stukovsky KH, Rich SS, Rotter JI, Guo X, Raffel LJ, Sampson PD, Oron AP, Raghunathan T, Barr RG. 2015. Air pollution and percent emphysema identified by computed tomography in the Multi-Ethnic Study of Atherosclerosis. Environ Health Perspect 123:144–151; http://dx.doi.org/10.1289/ehp.1307951
doi:10.1289/ehp.1307951
PMCID: PMC4314244  PMID: 25302408
19.  The Epidemiology of Vascular Dysfunction Relating to Chronic Obstructive Pulmonary Disease and Emphysema 
Cor pulmonale has long been described in very severe chronic obstructive pulmonary disease (COPD) and emphysema. Cross-sectional results from population-based studies show that left ventricular filling and a variety of vascular measures in the systemic circulation are abnormal in preclinical COPD and emphysema and that a predominant vascular change in COPD and emphysema is endothelial and microvascular dysfunction. These findings suggest that pulmonary vascular changes may occur early in COPD and emphysema and might contribute to pathogenesis. However, longitudinal epidemiologic studies with direct measures of the pulmonary vasculature are lacking; therefore, inferences are limited at present. New imaging-based approaches to the assessment of the pulmonary vasculature are applicable to epidemiologic studies and may help in defining the relationship of pulmonary vascular damage to progression of COPD and emphysema. These measures may also provide imaging-based surrogate markers, and novel therapeutics targeted to the pulmonary vasculature might reduce symptoms and improve function in these common diseases.
doi:10.1513/pats.201101-008MW
PMCID: PMC3359073  PMID: 22052931
chronic obstructive pulmonary disease; pulmonary emphysema; pulmonary hypertension; vascular disease; pulmonary vasculature
20.  Genome-wide association analysis identifies six new loci associated with forced vital capacity 
Loth, Daan W. | Artigas, María Soler | Gharib, Sina A. | Wain, Louise V. | Franceschini, Nora | Koch, Beate | Pottinger, Tess | Smith, Albert Vernon | Duan, Qing | Oldmeadow, Chris | Lee, Mi Kyeong | Strachan, David P. | James, Alan L. | Huffman, Jennifer E. | Vitart, Veronique | Ramasamy, Adaikalavan | Wareham, Nicholas J. | Kaprio, Jaakko | Wang, Xin-Qun | Trochet, Holly | Kähönen, Mika | Flexeder, Claudia | Albrecht, Eva | Lopez, Lorna M. | de Jong, Kim | Thyagarajan, Bharat | Alves, Alexessander Couto | Enroth, Stefan | Omenaas, Ernst | Joshi, Peter K. | Fall, Tove | Viňuela, Ana | Launer, Lenore J. | Loehr, Laura R. | Fornage, Myriam | Li, Guo | Wilk, Jemma B. | Tang, Wenbo | Manichaikul, Ani | Lahousse, Lies | Harris, Tamara B. | North, Kari E. | Rudnicka, Alicja R. | Hui, Jennie | Gu, Xiangjun | Lumley, Thomas | Wright, Alan F. | Hastie, Nicholas D. | Campbell, Susan | Kumar, Rajesh | Pin, Isabelle | Scott, Robert A. | Pietiläinen, Kirsi H. | Surakka, Ida | Liu, Yongmei | Holliday, Elizabeth G. | Schulz, Holger | Heinrich, Joachim | Davies, Gail | Vonk, Judith M. | Wojczynski, Mary | Pouta, Anneli | Johansson, Åsa | Wild, Sarah H. | Ingelsson, Erik | Rivadeneira, Fernando | Völzke, Henry | Hysi, Pirro G. | Eiriksdottir, Gudny | Morrison, Alanna C. | Rotter, Jerome I. | Gao, Wei | Postma, Dirkje S. | White, Wendy B. | Rich, Stephen S. | Hofman, Albert | Aspelund, Thor | Couper, David | Smith, Lewis J. | Psaty, Bruce M. | Lohman, Kurt | Burchard, Esteban G. | Uitterlinden, André G. | Garcia, Melissa | Joubert, Bonnie R. | McArdle, Wendy L. | Musk, A. Bill | Hansel, Nadia | Heckbert, Susan R. | Zgaga, Lina | van Meurs, Joyce B.J. | Navarro, Pau | Rudan, Igor | Oh, Yeon-Mok | Redline, Susan | Jarvis, Deborah | Zhao, Jing Hua | Rantanen, Taina | O’Connor, George T. | Ripatti, Samuli | Scott, Rodney J. | Karrasch, Stefan | Grallert, Harald | Gaddis, Nathan C. | Starr, John M. | Wijmenga, Cisca | Minster, Ryan L. | Lederer, David J. | Pekkanen, Juha | Gyllensten, Ulf | Campbell, Harry | Morris, Andrew P. | Gläser, Sven | Hammond, Christopher J. | Burkart, Kristin M. | Beilby, John | Kritchevsky, Stephen B. | Gudnason, Vilmundur | Hancock, Dana B. | Williams, O. Dale | Polasek, Ozren | Zemunik, Tatijana | Kolcic, Ivana | Petrini, Marcy F. | Wjst, Matthias | Kim, Woo Jin | Porteous, David J. | Scotland, Generation | Smith, Blair H. | Viljanen, Anne | Heliövaara, Markku | Attia, John R. | Sayers, Ian | Hampel, Regina | Gieger, Christian | Deary, Ian J. | Boezen, H. Marike | Newman, Anne | Jarvelin, Marjo-Riitta | Wilson, James F. | Lind, Lars | Stricker, Bruno H. | Teumer, Alexander | Spector, Timothy D. | Melén, Erik | Peters, Marjolein J. | Lange, Leslie A. | Barr, R. Graham | Bracke, Ken R. | Verhamme, Fien M. | Sung, Joohon | Hiemstra, Pieter S. | Cassano, Patricia A. | Sood, Akshay | Hayward, Caroline | Dupuis, Josée | Hall, Ian P. | Brusselle, Guy G. | Tobin, Martin D. | London, Stephanie J.
Nature genetics  2014;46(7):669-677.
Forced vital capacity (FVC), a spirometric measure of pulmonary function, reflects lung volume and is used to diagnose and monitor lung diseases. We performed genome-wide association study meta-analysis of FVC in 52,253 individuals from 26 studies and followed up the top associations in 32,917 additional individuals of European ancestry. We found six new regions associated at genome-wide significance (P < 5 × 10−8) with FVC in or near EFEMP1, BMP6, MIR-129-2/HSD17B12, PRDM11, WWOX, and KCNJ2. Two (GSTCD and PTCH1) loci previously associated with spirometric measures were related to FVC. Newly implicated regions were followed-up in samples of African American, Korean, Chinese, and Hispanic individuals. We detected transcripts for all six newly implicated genes in human lung tissue. The new loci may inform mechanisms involved in lung development and pathogenesis of restrictive lung disease.
doi:10.1038/ng.3011
PMCID: PMC4140093  PMID: 24929828
21.  A Simplified Score to Quantify Comorbidity in COPD 
PLoS ONE  2014;9(12):e114438.
Importance
Comorbidities are common in COPD, but quantifying their burden is difficult. Currently there is a COPD-specific comorbidity index to predict mortality and another to predict general quality of life. We sought to develop and validate a COPD-specific comorbidity score that reflects comorbidity burden on patient-centered outcomes.
Materials and Methods
Using the COPDGene study (GOLD II-IV COPD), we developed comorbidity scores to describe patient-centered outcomes employing three techniques: 1) simple count, 2) weighted score, and 3) weighted score based upon statistical selection procedure. We tested associations, area under the Curve (AUC) and calibration statistics to validate scores internally with outcomes of respiratory disease-specific quality of life (St. George's Respiratory Questionnaire, SGRQ), six minute walk distance (6MWD), modified Medical Research Council (mMRC) dyspnea score and exacerbation risk, ultimately choosing one score for external validation in SPIROMICS.
Results
Associations between comorbidities and all outcomes were comparable across the three scores. All scores added predictive ability to models including age, gender, race, current smoking status, pack-years smoked and FEV1 (p<0.001 for all comparisons). Area under the curve (AUC) was similar between all three scores across outcomes: SGRQ (range 0·7624–0·7676), MMRC (0·7590–0·7644), 6MWD (0·7531–0·7560) and exacerbation risk (0·6831–0·6919). Because of similar performance, the comorbidity count was used for external validation. In the SPIROMICS cohort, the comorbidity count performed well to predict SGRQ (AUC 0·7891), MMRC (AUC 0·7611), 6MWD (AUC 0·7086), and exacerbation risk (AUC 0·7341).
Conclusions
Quantifying comorbidity provides a more thorough understanding of the risk for patient-centered outcomes in COPD. A comorbidity count performs well to quantify comorbidity in a diverse population with COPD.
doi:10.1371/journal.pone.0114438
PMCID: PMC4267736  PMID: 25514500
22.  Methylomics of gene expression in human monocytes 
Human Molecular Genetics  2013;22(24):5065-5074.
DNA methylation is one of several epigenetic mechanisms that contribute to the regulation of gene expression; however, the extent to which methylation of CpG dinucleotides correlates with gene expression at the genome-wide level is still largely unknown. Using purified primary monocytes from subjects in a large community-based cohort (n = 1264), we characterized methylation (>485 000 CpG sites) and mRNA expression (>48K transcripts) and carried out genome-wide association analyses of 8370 expression phenotypes. We identified 11 203 potential cis-acting CpG loci whose degree of methylation was associated with gene expression (eMS) at a false discovery rate threshold of 0.001. Most of the associations were consistent in effect size and direction of effect across sex and three ethnicities. Contrary to expectation, these eMS were not predominately enriched in promoter regions, or CpG islands, but rather in the 3′ UTR, gene bodies, CpG shores or ‘offshore’ sites, and both positive and negative correlations between methylation and expression were observed across all locations. eMS were enriched for regions predicted to be regulatory by ENCODE (Encyclopedia of DNA Elements) data in multiple cell types, particularly enhancers. One of the strongest association signals detected (P < 2.2 × 10−308) was a methylation probe (cg17005068) in the promoter/enhancer region of the glutathione S-transferase theta 1 gene (GSTT1, encoding the detoxification enzyme) with GSTT1 mRNA expression. Our study provides a detailed description of the epigenetic architecture in human monocytes and its relationship to gene expression. These data may help prioritize interrogation of biologically relevant methylation loci and provide new insights into the epigenetic basis of human health and diseases.
doi:10.1093/hmg/ddt356
PMCID: PMC3836482  PMID: 23900078
23.  Similar Relation of Age and Height to Lung Function Among Whites, African Americans, and Hispanics 
American Journal of Epidemiology  2011;173(4):376-387.
Current guidelines recommend separate spirometry reference equations for whites, African Americans, and Mexican Americans, but the justification for this recommendation is controversial. The authors examined the statistical justification for race/ethnic-specific reference equations in adults in the Third National Health and Nutrition Examination Survey (1988–1994) and the Multi-Ethnic Study of Atherosclerosis Lung Study (2000–2006). Spirometry was measured following American Thoracic Society guidelines. “Statistical justification” was defined as the presence of effect modification by race/ethnicity among never-smoking participants without respiratory disease or symptoms and was tested with interaction terms for race/ethnicity (× age and height) in regression models. There was no evidence of effect modification by race/ethnicity for forced expiratory volume in 1 second, forced vital capacity, or the forced expiratory volume in 1 second/forced vital capacity ratio among white, African-American, and Mexican-American men or women on an additive scale or a log scale. Interaction terms for race/ethnicity explained less than 1% of variability in lung function. The mean lung function for a given age, gender, and height was the same for whites and Mexican Americans but was lower for African Americans. Findings were similar in the Multi-Ethnic Study of Atherosclerosis Lung Study. The associations of age and height with lung function are similar across the 3 major US race/ethnic groups. Multiethnic rather than race/ethnic-specific spirometry reference equations are applicable for the US population.
doi:10.1093/aje/kwq417
PMCID: PMC3032806  PMID: 21242304
African Americans; age groups; body height; European continental ancestry group; Hispanic Americans; respiratory function tests; spirometry
24.  Common genes underlying asthma and COPD? Genome-wide analysis on the Dutch hypothesis 
The European respiratory journal  2014;44(4):860-872.
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 NFκβ pathway) and GNG5P5, respectively. SNP rs9534578 in GNG5P5 reached genome-wide significance after first stage replication (p=9.96·*10−9). The second stage replication in seven independent cohorts provided no significant replication. eQTL analysis in blood and lung on the top 20 associated SNPs identified two SNPs in COMMD10 influencing gene expression.
Inflammatory processes differ in asthma and COPD and are mediated by NFκβ, 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 of two COMMD10 SNPs, since they influence gene expression in both blood cells and lung tissue. Our findings either suggest that there is no common genetic component in asthma and COPD or, alternatively, different environmental factors, like lifestyle and occupation in different countries and continents may have obscured the genetic common contribution.
doi:10.1183/09031936.00001914
PMCID: PMC4217133  PMID: 24993907
25.  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) 
Thorax  2014;69(11):987-996.
Background
COPD is characterized 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 computed tomography (CT) in COPD and controls using spatially matched airways, thereby avoiding selection bias of airways in the lung.
Methods
The MESA COPD Study and 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 standardized paths into the lungs. Case-control airway comparisons were spatially matched by generation and adjusted for demographics, body size, smoking, CT dose, percent emphysema, airway length, and lung volume.
Results
Among 311 MESA COPD participants, airway wall areas at generations 3–6 were smaller in COPD compared to 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.
doi:10.1136/thoraxjnl-2014-205160
PMCID: PMC4198462  PMID: 24928812
Chronic obstructive pulmonary disease; computed tomography; airways; walls

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