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Chronic lower respiratory disease (CLRD) overtook stroke as the third leading cause of death in the United States in 2008. The Centers for Disease Control defines chronic lower respiratory disease (CLRD) as chronic obstructive pulmonary disease (COPD), emphysema, chronic bronchitis, asthma and the interstitial lung diseases and more rare entities. COPD has been defined by airflow obstruction on physiologic testing, emphysema by anatomical lung destruction and chronic bronchitis by symptoms since the 1960's.

Columbia Respiratory Epidemiology Program (C-REP) aims to arrive at a better definition and understanding of CLRD by applying advanced imaging married to physiology, genetic and genomic approaches in the general population and to develop diagnostic and therapeutic strategies for these diseases.

R.Graham Barr, MD, DrPH
Associate Professor of Medicine
Associate Professor of Epidemiology

 

Research Overview:

Lung Function and Structure (COPD and Emphysema)



Lung function has been measured in studies totaling hundreds of thousands of participants since Hutchinson invented the spirometer in 1846. Major risk factors for low lung function include smoking, asthma history, air pollution and occupational exposures.

Few population-based cohorts have, to date, assessed COPD itself, which is defined by spirometric measurements following a bronchodilator. A focus of the Multi-Ethnic Study of Atherosclerosis (MESA) Lung Study and the Hispanic Community Health Study is definition of risk factors for COPD, distinct from low lung function.

Emphysema was previously assessed on autopsy or pathology specimens but now can be assessed by CT scan. A second major focus of the MESA Lung Study is to define the significance of emphysema on CT scan in the general population and to define risk factors for emphysema, as distinct from COPD.

Endothelial Hypothesis of Emphysema

Liebow observed more than 50 years ago that capillary obliteration occurred in COPD. Although long considered a sequelae of severe COPD and emphysema, we have demonstrated that endothelial dysfunction and perturbation occurs in mild, early and particularly emphysematous COPD. Emerging evidence suggests that this perturbation is may not be a bystander and that endothelial and microvascular damage may contribute to CLRD pathogenesis potentially via changes in lipid biology. This hypothesis may have direct therapeutic applications, one strategy for which we are testing in a clinical trial.

Cardiopulmonary Function



Cardiac and pulmonary structure and function are tightly linked, to the point that Cournand and Richards, in performing their seminal work at Columbia, envisaged the lungs and the heart as one organ. C-REP is using innovative MRI-based approaches to evaluate how pulmonary function and structure may affect cardiac function, with particular relevance to heart failure with preserved function. The MESA COPD Study is investigating cardiopulmonary interactions at epigenetic, cellular, functional and structural levels.


Genetics and Genomics

C-REP is motivated to use ‘omic approaches perhaps less for discovery than for testing of ongoing hypothesis. Activities include the MESA Lung/SHARe Study, a large genome-wide association study (GWAS) for emphysema on CT scan, the Lung Working Group for the Candidate Association Resource (CARe), and ongoing gene expression work.


Cohorts:

The MESA Lung Study, part of the larger MESA Study, was the first population-based cohort to incorporate both lung function measured by spirometry and lung structure assessed on CT scans in the general population. It provides a population laboratory for understanding CLRD.

The MESA Lung/SHARe Study is a genome-wide association study (GWAS) of emphysema on CT scan among more than 8,200 MESA participants.

The MESA COPD Study is a nested case-control study of COPD of 325 participants to examine cardiopulmonary interactions in COPD. Measures include cardiopulmonary MRI, full-lung CT scan, pulmonary function testing, cellular and blood biomarkers, and gene expression.

The EMphysema and Cancer Action Program (EMCAP) is a cohort of older smokers who were followed longitudinally for lung function decline and progression of emphysema to test nutritional hypotheses in COPD and emphysema.

C-REP is also a clinical site for:

The Subpopulations and Intermediate Outcome Measures In COPD Study (SPIROMICS), a 3,200 patient study with aims to subphenotype and develop intermediate outcome measures for COPD.

The COPD Gene Study, a 10,000 person study of COPD genetics and subphenotypes.

C-REP also houses:

The Spirometry Reading Center for the Hispanic Community Health Study, a 16,000 person community based study of the health of Hispanics.

The Lung Working Group for the Candidate gene Association Resource (CARe). CARe included IBC chip of the seven NHBLI cohorts with spirometry, in addition to genome-wide genotyping of African Americans.


Recent Publications:

  1. Barr RG, Ahmed FS, Carr JJ, Hoffman EA, Jiang R, Kawut SM, Watson KE. Subclinical atherosclerosis, airflow obstruction and emphysema: the MESA Lung Study. Eur Respir J 2012;39:846-54. PMID 22034646.
  2. Kiefer EM, Hankinson JL, Barr RG. Similar relation of age and height to lung function among whites, African Americans, and Hispanics. Am J Epidemiol 2011;173:376-87. PMID: 21242304.
  3. Soler Artigas M, Loth DW, Wain LV et al. Genome-wide association and large-scale follow up identifies 16 new loci influencing lung function. Nat Genet 2011;43:1082-90. PMID: 21946350.
  4. Rodriguez J, Jiang R, Johnson WC, MacKenzie BA, Smith LJ, Barr RG. The association of pipe and cigar use with cotinine levels, lung function and airflow obstruction: a cross-sectional study. Ann Intern Med 2010;152:201-10. PMID: 20157134.
  5. Hancock DB, Eijgelsheim M, Wilk JB, Gharib SA, Loehr LR, Marciante KD, Franceschini N, van Durme YMTA, Chen T, Barr RG, Schabath MB, Couper DJ, Brusselle GG, Psaty BM,  van Duijn CM, Uitterlinden UG, Hofman A, Punjabi NM, Rivadeneira F, Morrison AC, Enright PL, North KE, Heckbert SR, Lumley T, Stricker BHC, O'Connor GT, London SJ. Meta-analyses of genome-wide association studies identify multiple loci associated with pulmonary function. Nature Genetics 2010;42;45-52. PMID: 20010835.
  6. Lovasi GS, Diez Roux AV, Hoffman EA, Kawut SM, Jacobs DR Jr, Barr RG. Environmental tobacco smoke exposure in childhood is associated with early emphysema in adulthood: The MESA Lung Study. Am J Epidemiol 2010;171:43-62. PMID: 19942575.
  7. Barr RG, Bluemke DA, Ahmed FS, Carr JJ, Enright PL, Hoffman EA, Jiang R, Kawut SM, Kronmal RA, Lima JA, Shahar E, Smith LJ, Watson KE.  Percent emphysema, airflow obstruction and impaired left ventricular filling. New Engl J Med 2010;362:217-27. PMID: 20089972.
  8. Barr RG, Mesia Vela S, Austin JHM, Keller B, Reeves AP, Shimbo D, Stevenson L. Impaired flow-mediated dilatation of the brachial artery is associated with low pulmonary function & emphysema in ex-smokers. The EMCAP Study. Am J Respir Crit Care Med , 2007;176:1200-7. PMID: 17761614.


Program Members:

Faculty: K. Burkart, K. Donohue, G. Lovasi

Post-doctoral Fellows: E. Oelsner, R. Powell, R. Shridharan, B. Smith, F. Ahmed, J. Madrigano

Statistical Analysts: M. Parikh, T. Pottinger


Open Positions:

Applications for post-doctoral positions are always welcome from qualified candidates in epidemiology and imaging-related disciplines. (We currently collaborate broadly with faculty in Radiology, Physics, Biomedical Engineering, and Statistics, among others). Please email a description of your research interests as they relate to the C-REP along with your CV here.

 

MESA Lung Study
MESA Lung SHARe Study
MESA COPD Study
Study Participation