Change in Lung Function and Morbidity from Chronic Obstructive Pulmonary Disease in α1-Antitrypsin MZ Heterozygotes: A Longitudinal Study of the General Population

Change in Lung Function and Morbidity from Chronic Obstructive Pulmonary Disease in α₁-Antitrypsin MZ Heterozygotes: A Longitudinal Study of the General Population

Morten Dahl, MD;
Anne Tybjærg-Hansen, MD, DMSc;
Peter Lange, MD, DMSc;
Jørgen Vestbo, MD, DMSc; and
Børge G. Nordestgaard, MD, DMSc

From Herlev University Hospital, Herlev; Copenhagen University Hospital and Bispebjerg University Hospital, Copenhagen; and Hvidovre University Hospital, Hvidovre, Denmark.

Abstract

Background: A deteriorating effect of severe α₁-antitrypsin deficiency (ZZ genotype) on lung function is well known, whereas the role of intermediate deficiency (MZ genotype) remains uncertain.

Objective: To test the hypothesis that MZ intermediate α₁-antitrypsin deficiency affects pulmonary function and disease.

Design: Population-based cohort study with 21-year follow-up.

Setting: Copenhagen, Denmark.

Participants: 9187 adults randomly selected from the Danish general population.

Measurements: Plasma α₁-antitrypsin levels, annual decrease in FEV₁, airway obstruction, and hospitalization and mortality from chronic obstructive pulmonary disease (COPD).

Results: 451 participants (4.9%) carried the MZ genotype. Plasma α₁-antitrypsin levels were 31% lower in MZ heterozygotes than in persons with the MM genotype (Student t-test, P < 0.001). Annual decrease in FEV₁ was 25 mL in MZ heterozygotes and 21 mL in persons with the MM genotype (t-test, P = 0.048). Airway obstruction was found in 19% of MZ heterozygotes compared with 15% of MM carriers (chi-square test, P = 0.023); in a logistic regression analysis adjusted for age, sex, and tobacco consumption, the corresponding odds ratio was 1.3 (CI, 1.0 to 1.7). The incidence of hospitalization and mortality from COPD was 32 cases per 10 000 person-years in persons with the MZ genotype and 22 cases per 10 000 person-years in those with the MM genotype (log-rank test, P = 0.063). In a Cox regression model adjusted for age, sex, tobacco use, and FEV₁ at study entry, relative risk for COPD outcomes in persons with the MZ genotype versus persons with the MM genotype was 1.5 (CI, 1.0 to 2.3). All these results were independent of the S and E alleles in this gene and were not affected by cystic fibrosis ΔF508 heterozygosity.

Conclusions: MZ heterozygotes had a slightly greater rate of decrease in FEV₁ and were modestly over-represented among persons with airway obstruction and COPD. In the population at large, MZ heterozygosity may account for a fraction of COPD cases—on the order of 2%, similar to the percentage of persons with COPD who have the severe but rare ZZ genotype.

Article and Author Information

Acknowledgments: The authors thank Anne-Merete Bengtsen, Charlotte Worm, and Hanne Damm for technical assistance and the participants of the Copenhagen City Heart Study for their willingness to participate.
Grant Support: By the Danish Lung Association, the Danish Heart Foundation, the Danish Medical Research Council, Løvens Kemiske Fabrik's Forskningsfond, and the Beckett Fund.
Requests for Single Reprints: Børge G. Nordestgaard, MD, DMSc, Department of Clinical Biochemistry, Herlev University Hospital, DK-2730 Herlev, Denmark; e-mail, brno{at}herlevhosp.kbhamt.dk.
Current Author Addresses: Drs. Dahl and Nordestgaard: Department of Clinical Biochemistry 54M1, Herlev University Hospital, Herlev Ringvej 75, DK-2730 Herlev, Denmark.
Dr. Tybjærg-Hansen: Department of Clinical Biochemistry KB3011, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, DK-2100, Copenhagen Ø, Denmark.
Drs. Lange and Vestbo: Department of Respiratory Medicine 121, Hvidovre University Hospital, Kettegård Allé 30, DK-2650 Hvidovre, Denmark.
Author Contributions: Conception and design: M. Dahl, A. Tybjærg-Hansen, P. Lange, J. Vestbo, B.G. Nordestgaard.
Analysis and interpretation of the data: M. Dahl, A. Tybjærg-Hansen, P. Lange, J. Vestbo, B.G. Nordestgaard.
Drafting of the article: M. Dahl.
Critical revision of the article for important intellectual content: M. Dahl, A. Tybjærg-Hansen, P. Lange, J. Vestbo, B.G. Nordestgaard.
Final approval of the article: M. Dahl, A. Tybjærg-Hansen, P. Lange, J. Vestbo, B.G. Nordestgaard.
Statistical expertise: M. Dahl, A. Tybjærg-Hansen, P. Lange, J. Vestbo, B.G. Nordestgaard.
Obtaining of funding: A. Tybjærg-Hansen, B.G. Nordestgaard.
Collection and assembly of data: M. Dahl, A. Tybjærg-Hansen, B.G. Nordestgaard.