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Original Research: COPD |

α1-Antitrypsin Protease Inhibitor MZ Heterozygosity Is Associated With Airflow Obstruction in Two Large Cohorts

Inga-Cecilie Sørheim, MD; Per Bakke, MD, PhD; Amund Gulsvik, MD, PhD; Sreekumar G. Pillai, PhD; Ane Johannessen, PhD; Per I. Gaarder, MD, PhD; Edward J. Campbell, MD; Alvar Agustí, MD, PhD; Peter M. A. Calverley, MD; Claudio F. Donner, MD, FCCP; Barry J. Make, MD, FCCP; Stephen I. Rennard, MD, FCCP; Jørgen Vestbo, MD, PhD; Emiel F. M. Wouters, MD, PhD, FCCP; Peter D. Paré, MD; Robert D. Levy, MD, FCCP; Harvey O. Coxson, PhD; David A. Lomas, MD, PhD; Craig P. Hersh, MD, MPH; Edwin K. Silverman, MD, PhD
Author and Funding Information

From the Channing Laboratory (Drs Sørheim, Hersh, and Silverman) and Pulmonary and Critical Care Division (Drs Hersh and Silverman), Brigham and Women’s Hospital and Harvard Medical School, Boston, MA; Institute of Medicine (Drs Sørheim, Bakke, and Gulsvik), University of Bergen, Bergen, Norway; Department of Thoracic Medicine (Drs Bakke and Gulsvik), Haukeland University Hospital, Bergen, Norway; GlaxoSmithKline (Dr Pillai), Research Triangle Park, NC; Centre for Clinical Research (Dr Johannessen), Haukeland University Hospital, Bergen, Norway; Department of Immunology and Transfusion Medicine (Dr Gaarder), Ullevaal University Hospital, Oslo, Norway; HerediLab, Inc (Dr Campbell), Salt Lake City, UT; Institut Clinic del Torax (Dr Agustí), Hospital Clinic, Barcelona, Spain; CIBER Enfermedades Respiratorias–Fundación Caubet-Cimera (Dr Agustí), Mallorca, Spain; University of Liverpool (Dr Calverley), Liverpool, England; Division of Pulmonary Disease (Dr Donner), S. Maugeri Foundation, Veruno, Novara, Italy; National Jewish Health (Dr Make), Denver, CO; University of Nebraska (Dr Rennard), Omaha, NE; Department of Cardiology and Respiratory Medicine (Dr Vestbo), Hvidovre Hospital, Copenhagen, Denmark; North West Lung Centre (Dr Vestbo), Wythenshawe Hospital, Manchester, England; Department of Respiratory Medicine (Dr Wouters), University Hospital Maastricht, Maastricht, The Netherlands; Division of Respiratory Medicine (Dr Paré) and the James Hogg iCAPTURE Centre for Cardiovascular and Pulmonary Research (Drs Paré and Coxson), University of British Columbia, St Paul’s Hospital, Vancouver, BC, Canada; Department of Radiology (Drs Levy and Coxson), University of British Columbia and Vancouver General Hospital, Vancouver, BC, Canada; and Department of Medicine (Dr Lomas), University of Cambridge, Cambridge, England.Dr Pillai is currently at Roche Pharmaceuticals (Nutley, NJ).

Correspondence to: Edwin K. Silverman, MD, PhD, Channing Laboratory, 181 Longwood Ave, Boston, MA 02115; e-mail: ed.silverman@channing.harvard.edu


Funding/Support: This work was supported by the National Institutes of Health [Grants HL075478, P01 083069, R01 HL084323 (to Dr Silverman) and HL080242 (to Dr Hersh)] and a grant from the α-1 Foundation (to Dr Hersh). Both studies discussed in this article were supported by GlaxoSmithKline.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (http://www.chestpubs.org/site/misc/reprints.xhtml).


© 2010 American College of Chest Physicians


Chest. 2010;138(5):1125-1132. doi:10.1378/chest.10-0746
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Background:  Severe α1-antitrypsin deficiency is a known genetic risk factor for COPD. Heterozygous (protease inhibitor [PI] MZ) individuals have moderately reduced serum levels of α1-antitrypsin, but whether they have an increased risk of COPD is uncertain.

Methods:  We compared PI MZ and PI MM individuals in two large populations: a case-control study from Norway (n = 1,669) and a multicenter family-based study from Europe and North America (n = 2,707). We sought to determine whether PI MZ was associated with the specific COPD-related phenotypes of lung function and quantitative CT scan measurements of emphysema and airway disease.

Results:  PI MZ was associated with a 3.5% lower FEV1/FVC ratio in the case-control study (P = .035) and 3.9% lower FEV1/vital capacity (VC) ratio in the family study (P = .009). In the case-control study, PI MZ also was associated with 3.7% more emphysema on quantitative analysis of chest CT scans (P = .003). The emphysema result was not replicated in the family study. PI MZ was not associated with airway wall thickness or COPD status in either population. Among subjects with low smoking exposure (< 20 pack-years), PI MZ individuals had more severe emphysema on chest CT scan than PI MM individuals in both studies.

Conclusions:  Compared with PI MM individuals, PI MZ heterozygotes had lower FEV1/(F)VC ratio in two independent studies. Our results suggest that PI MZ individuals may be slightly more susceptible to the development of airflow obstruction than PI MM individuals.

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