α1-antitrypsin protease inhibitor MZ heterozygosity is associated with airflow obstruction in two large cohorts

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 FEV 1 /FVC ratio in the case-control study ( P = .035) and 3.9% lower FEV 1 /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 ( Conclusions Compared with PI MM individuals, PI MZ heterozygotes had lower FEV 1 /(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.