title: α₁-Antitrypsin protease inhibitor MZ heterozygosity is associated with airflow obstruction in two large cohorts.
abstract: 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.
authors.affiliation: Channing Laboratory, Brigham and Women's Hospital and Harvard Medical School, 181 Longwood Ave, Boston, MA 02115, USA.
authors.forename: Inga-Cecilie
authors.initials: IC
authors.lastname: Sørheim
authors.forename: Per
authors.initials: P
authors.lastname: Bakke
authors.forename: Amund
authors.initials: A
authors.lastname: Gulsvik
authors.forename: Sreekumar G
authors.initials: SG
authors.lastname: Pillai
authors.forename: Ane
authors.initials: A
authors.lastname: Johannessen
authors.forename: Per I
authors.initials: PI
authors.lastname: Gaarder
authors.forename: Edward J
authors.initials: EJ
authors.lastname: Campbell
authors.forename: Alvar
authors.initials: A
authors.lastname: Agustí
authors.forename: Peter M A
authors.initials: PM
authors.lastname: Calverley
authors.forename: Claudio F
authors.initials: CF
authors.lastname: Donner
authors.forename: Barry J
authors.initials: BJ
authors.lastname: Make
authors.forename: Stephen I
authors.initials: SI
authors.lastname: Rennard
authors.forename: Jørgen
authors.initials: J
authors.lastname: Vestbo
authors.forename: Emiel F M
authors.initials: EF
authors.lastname: Wouters
authors.forename: Peter D
authors.initials: PD
authors.lastname: Paré
authors.forename: Robert D
authors.initials: RD
authors.lastname: Levy
authors.forename: Harvey O
authors.initials: HO
authors.lastname: Coxson
authors.forename: David A
authors.initials: DA
authors.lastname: Lomas
authors.forename: Craig P
authors.initials: CP
authors.lastname: Hersh
authors.forename: Edwin K
authors.initials: EK
authors.lastname: Silverman
mesh_terms: 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
chemical_list: D000515:alpha 1-Antitrypsin