a1-Antitrypsin protease inhibitor MZ heterozygosity is associated with airflow obstruction in two large cohorts.

ABSTRACT BACKGROUND: Severe alpha-1 antitrypsin deficiency is a known genetic risk factor for chronic obstructive pulmonary disease (COPD). Heterozygous (PI MZ) individuals have moderately reduced serum levels of alpha-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=1669) and a multicenter family-based study from Europe and North America (n=2707). We sought to determine whether PI MZ was associated with the specific COPD-related phenotypes of lung function and quantitative CT measurements of emphysema and airway disease. RESULTS: PI MZ was associated with 3.5% lower FEV(1)/FVC ratio in the case-control study (p=0.035), and 3.9% lower FEV(1)/VC ratio in the family study (p=0.009). In the case-control study, PI MZ was also associated with 3.7% more emphysema on quantitative analysis of chest CT scans (p=0.003). 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 individuals 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 to 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 development of airflow obstruction than PI MM individuals.