Molecular Diagnosis of Intermediate and Severe α1-Antitrypsin Deficiency: MZ Individuals with Chronic Obstructive Pulmonary Disease May Have Lower Lung Function Than MM Individuals

Abstract

We tested whether intermediate (MZ, SZ) and severe (ZZ) alpha(1)-antitrypsin deficiency affects lung function in the population at large. We performed spirometry [forced expiratory volume in 1 s (FEV(1)) and forced vital capacity (FVC)] and genotyping of 9187 individuals from the adult general population of Copenhagen, Denmark. As expected, the frequencies of individuals with MM, MS, SS, MZ, SZ, and ZZ genotypes were 0.891, 0.054, 0.001, 0.052, 0.001, and 0.001, respectively. Genotype interacted with clinically established chronic obstructive pulmonary disease (COPD) on the percentage of the predicted FEV(1) (P = 0. 004): the percentage of the predicted FEV(1) was reduced in MZ compared with MM individuals among those with clinically established COPD, but not among those without COPD. Furthermore, SZ compound heterozygotes had lower FEV(1)/FVC ratios than MM individuals (P <0.05), and ZZ homozygotes had lower percentages of the predicted FEV(1) and FEV(1)/FVC ratios than MM, MS, SS, and MZ individuals (all Ps <0.01). Reduced lung function in SZ and ZZ vs MM individuals could be demonstrated in current and ex-smokers, but not in nonsmokers. Compared with MM individuals in the same groups, FEV(1) was reduced 655 mL in MZ individuals with clinically established COPD, 364 mL in SZ current smokers, and 791 mL in ZZ current smokers. In the population at large, MZ was associated with reduced pulmonary function in individuals with clinically established COPD, whereas SZ and ZZ were associated with reduced pulmonary function in smokers. The presence of the alpha(1)-antitrypsin MZ genotype may in certain circumstances produce marked aggravation of airway obstruction in individuals prone to develop COPD.