α₁-Antitrypsin protease inhibitor MZ heterozygosity is associated with airflow obstruction in two large cohorts.
BACKGROUND
Severe α₁-antitrypsin deficiency is a known genetic risk factor for COPD. Heterozygous (protease inhibitor [PI] MZ) individuals have moderately reduced serum levels of α₁-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.
Sørheim
Inga-Cecilie
IC
Channing Laboratory, Brigham and Women's Hospital and Harvard Medical School, 181 Longwood Ave, Boston, MA 02115, USA.
Bakke
Per
P
Gulsvik
Amund
A
Pillai
Sreekumar G
SG
Johannessen
Ane
A
Gaarder
Per I
PI
Campbell
Edward J
EJ
Agustí
Alvar
A
Calverley
Peter M A
PM
Donner
Claudio F
CF
Make
Barry J
BJ
Rennard
Stephen I
SI
Vestbo
Jørgen
J
Wouters
Emiel F M
EF
Paré
Peter D
PD
Levy
Robert D
RD
Coxson
Harvey O
HO
Lomas
David A
DA
Hersh
Craig P
CP
Silverman
Edwin K
EK
D000368:Aged; D000402:Airway Obstruction / Q000201:enzymology / Q000209:etiology / Q000235:genetics*; D005060:Europe; D005260:Female; D005541:Forced Expiratory Volume; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D009656:North America; D009664:Norway; D029424:Pulmonary Disease, Chronic Obstructive / Q000150:complications* / Q000235:genetics / Q000503:physiopathology; D012307:Risk Factors; D000515:alpha 1-Antitrypsin / Q000097:blood / Q000235:genetics*; D019896:alpha 1-Antitrypsin Deficiency / Q000150:complications* / Q000235:genetics / Q000503:physiopathology
D000515:alpha 1-Antitrypsin