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Airway and Parenchymal Disease in Chronic Obstructive Pulmonary Disease Are Distinct Phenotypes

Institute of Public Health and Department of Medicine, University of Cambridge, Cambridge; Cambridge Institute for Medical Research, Cambridge; and The Royal Devon & Exeter NHS Foundation Trust, Exeter, United Kingdom; National Jewish Medical and Research Center, and Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado School of Medicine, Denver, Colorado; Department of Radiology and iCAPTURE Centre, Vancouver General Hospital, Vancouver; Department of Radiology, University of British Columbia, Vancouver, British Columbia, Canada; Translational Medicine and Genetics, GlaxoSmithKline, Raleigh, North Carolina; Channing Laboratory and Pulmonary and Critical Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts

Correspondence and requests for reprints should be addressed to Barry Make, M.D., National Jewish Medical and Research Center, 1400 Jackson Street, Denver, CO 80206. E-mail: makeb{at}njc.org

The relative importance of genetic factors and tobacco smoking intensity in the pathogenesis of the airway disease and emphysematous components of chronic obstructive pulmonary disease (COPD) is unknown. We addressed this question in a family-based study that recruited probands (FEV₁ < 60% predicted, ages 45–65 yr, and > 5 pack-year smoking history) and their current/ex-smoking siblings. The family-based design allowed us to test the relationship between COPD phenotype (emphysema or small airway disease) in a proband and his or her siblings. Subjects completed a questionnaire and underwent spirometry, and a subset of participants underwent chest computed tomography (CT) scans.

Results: The number of pack-years was only weakly correlated with FEV₁ in 634 individuals with emphysema, as assessed by radiologist scoring of chest CT scans (r = –0.09, p = 0.02). The amount of emphysema on CT scan was inversely related to FEV₁ (p < 0.001), but there was no relationship between pack-years and amount of emphysema. Emphysema was more prevalent in the siblings of probands with emphysema (41.7%) than in siblings of nonemphysema probands (23.6%, p < 0.001); this was independent of pack-years smoked (adjusted odds ratio, 2.12; p = 0.03). In 482 individuals without emphysema, FEV₁ was correlated with pack-years smoked (r = –0.38, p < 0.0001). The correlation between pack-years and FEV₁ was particularly strong (r = –0.58, p < 0.0001) in 48 siblings who were from families in which the proband had predominantly small airway disease.

These data suggest that emphysema and airway-related COPD are distinct phenotypes and have different relationships with smoking. Moreover, differences in amount of emphysema are not explained by cumulative smoking, suggesting a complex gene–environment interaction.

FOOTNOTES

Supported by GlaxoSmithKline.

Conflict of Interest Statement: B.P. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. B.M., on behalf of GlaxoSmithKline (GSK), over the last 3 years has served on advisory boards and received $7,500. He spoke at GSK-sponsored programs and received $18,000. He participated in multicenter clinical trials. His institution has received unrestricted educational grants from GSK and has received research grants for participating in GSK multicenter clinical trials. H.O.C. received $11,000 in 2003 for serving on an advisory board for GSK. In addition, he is the coinvestigator on two multicenter studies sponsored by GSK and has received travel expenses to attend meetings related to the project. He has three contract service agreements with GSK to quantify the CT scans in subjects with COPD. A percentage of his salary between 2003 and 2006 ($15,000/yr) derives from contract funds provided to a colleague, Peter D. Pare, by GSK for the development of validated methods to measure emphysema and airway disease using CT. There is no financial relationship between any industry and the current study. N.L.M. has a GSK-sponsored research grant on quantification of emphysema and airway abnormalities of CT scans in patients with COPD. The value of the grant over the last 3 years has been approximately $100,000/year. S.P. is a full-time employee of GSK. W.A. is a full-time employee of GSK and owns stock in GSK. E.S. received grant support, consulting fees, and honoraria from GSK for studies of COPD genetics. He also received a speaker's fee from Wyeth for a talk on COPD genetics. He has received honoraria from Bayer. D.L. has participated as a speaker in scientific meetings organized and financed by GSK. He received £5,000 as a consultant for GSK and £1,500 for serving on an advisory board for GSK. His research group has received £517,000 from GSK to fund the study reported in this paper and they will received approximately £650,000 for the ECLIPSE study, which will assess the natural history of COPD, and to identify novel biomarkers for COPD (2006–2009).

(Received in original form March 20, 2006; accepted in final form March 28, 2006)

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