Chest
Volume 138, Issue 5, November 2010, Pages 1125-1132
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Original Research
COPD
α;1-Antitrypsin Protease Inhibitor MZ Heterozygosity Is Associated With Airflow Obstruction in Two Large Cohorts

https://doi.org/10.1378/chest.10-0746Get rights and content

Background

Severe α;1-antitrypsin deficiency is a known genetic risk factor for COPD. Heterozygous (protease inhibitor [PI] MZ) individuals have moderately reduced serum levels of α;1-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.

Section snippets

Study Populations

The case-control study was performed at Haukeland University Hospital (Bergen, Norway). Case and control subjects were whites aged ≥ 40 years and current or ex-smokers of ≥ 2.5 pack-years. Case subjects had COPD with a post-bronchodilator (BD) FEV1/FVC ratio < 0.7 and FEV1 < 80% predicted.7 Control subjects had normal spirometry (post-BD FEV1/FVC, ≥ 0.7; FEV1, ≥ 80% predicted).

The family-based International COPD Genetics Network (ICGN) study included participants from 10 study centers in Europe

Characteristics of Study Subjects

The characteristics of study subjects in the Norway case-control study are shown in Table 1. A total of 834 cases subjects and 835 control subjects with either PI MM or PI MZ were included. Forty-four (5.3%) case subjects and 34 (4.1%) control subjects were PI MZ (P = .244). Quantitative emphysema data were available for 408 case subjects and 422 control subjects, and data on airway wall thickness were available for 387 cases and 393 control subjects. PI MZ control subjects had smoked more than

Discussion

We examined the associations between AAT PI MZ heterozygosity and COPD-related phenotypes in two large populations: a case-control study from Norway and a multicenter family study from Europe and North America. To our knowledge, this study is the first to examine quantitative CT phenotypes in PI MZ carriers. In both populations, PI MZ was associated with lower FEV1/(F)VC ratio compared with PI MM. In the case-control study, PI MZ also was associated with more-severe emphysema on chest CT scan.

Acknowledgments

Author contributions: Dr Sørheim: contributed to the data analysis and the writing and review of the manuscript.

Dr Bakke: contributed to the data collection and the writing and review of the manuscript.

Dr Gulsvik: contributed to the data collection and the writing and review of the manuscript.

Dr Pillai: contributed to the writing and review of the manuscript.

Dr Johannessen: contributed to the data analysis, statistical support, and the writing and review of the manuscript.

Dr Gaarder:

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    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).

    *

    Dr Pillai is currently at Roche Pharmaceuticals (Nutley, NJ)

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