Change in lung function and morbidity from chronic obstructive pulmonary disease in alpha1-antitrypsin MZ heterozygotes: A longitudinal study of the general population.
BACKGROUND
A deteriorating effect of severe alpha(1)-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 alpha(1)-antitrypsin deficiency affects pulmonary function and disease.


METHODS
Population-based cohort study with 21-year follow-up.


METHODS
Copenhagen, Denmark.


METHODS
9187 adults randomly selected from the Danish general population.


METHODS
Plasma alpha(1)-antitrypsin levels, annual decrease in FEV(1), airway obstruction, and hospitalization and mortality from chronic obstructive pulmonary disease (COPD).


RESULTS
451 participants (4.9%) carried the MZ genotype. Plasma alpha(1)-antitrypsin levels were 31% lower in MZ heterozygotes than in persons with the MM genotype (Student t -test, P < 0.001). Annual decrease in FEV(1) 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 FEV(1) 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 Delta F508 heterozygosity.


CONCLUSIONS
MZ heterozygotes had a slightly greater rate of decrease in FEV(1) 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.
Dahl
Morten
M
Department of Clinical Biochemistry 54M1, Herlev University Hospital, Herlev Ringvej 75, DK-2730 Herlev, Denmark.
Tybjaerg-Hansen
Anne
A
Lange
Peter
P
Vestbo
Jørgen
J
Nordestgaard
Børge G
BG
D000328:Adult; D001798:Blood Proteins / Q000235:genetics; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D003718:Denmark / Q000453:epidemiology; D005260:Female; D005500:Follow-Up Studies; D005541:Forced Expiratory Volume; D006579:Heterozygote; D006760:Hospitalization / Q000706:statistics & numerical data; D006801:Humans; D008297:Male; D009154:Mutation; D029424:Pulmonary Disease, Chronic Obstructive / Q000201:enzymology / Q000235:genetics* / Q000401:mortality / Q000503:physiopathology*; D012044:Regression Analysis; D012907:Smoking / Q000009:adverse effects; D013147:Spirometry; D011795:Surveys and Questionnaires; D019896:alpha 1-Antitrypsin Deficiency / Q000097:blood / Q000235:genetics*
D001798:Blood Proteins; C505032:CFTR protein, human; D019005:Cystic Fibrosis Transmembrane Conductance Regulator