title: Alpha-1 Antitrypsin PiMZ Genotype Is Associated with Chronic Obstructive Pulmonary Disease in Two Racial Groups.
abstract: BACKGROUND
  Alpha-1 antitrypsin deficiency, caused primarily by homozygosity for the Z allele of the SERPINA1 gene, is a well-established genetic cause of chronic obstructive pulmonary disease (COPD). Whether the heterozygous PiMZ genotype for alpha-1 antitrypsin confers increased risk for COPD has been debated.
  
  
  OBJECTIVE
  We analyzed 8,271 subjects in the Genetic Epidemiology of COPD (COPDGene) Study, hypothesizing that PiMZ would independently associate with COPD and COPD-related phenotypes.
  
  
  METHODS
  The COPDGene Study comprises a multiethnic, cross-sectional, observational cohort of non-Hispanic white and African American current and former smokers with at least 10 pack-years of smoking who were enrolled for detailed clinical and genetic studies of COPD and COPD-related traits. We performed multivariate logistic regression analysis for moderate to severe COPD and assessed Pi genotype with other relevant covariates in models stratified by race. We analyzed quantitative characteristics on the basis of volumetric computed tomography with generalized linear models controlling for genotype, scanner type, and similar covariates.
  
  
  RESULTS
  White PiMZ COPDGene subjects had significantly lower lung function, FEV1percent predicted (68 ± 28 vs. 75 ± 27; P = 0.0005), and FEV1/FVC ratio (0.59 ± 0.18 vs. 0.63 ± 0.17; P = 0.0008), as well as more radiographic emphysema (P = 0.001), than subjects without alpha-1 antitrypsin Z risk alleles. Similarly, African American PiMZ subjects had lower lung function, FEV1percent predicted (65 ± 33 vs. 84 ± 25; P = 0.009) and FEV1/FVC (0.61 ± 0.21 vs. 0.71 ± 0.15; P = 0.03).
  
  
  CONCLUSIONS
  In the COPDGene Study, we demonstrate that PiMZ heterozygous individuals who smoke are at increased risk for COPD and obstructive lung function impairment compared with Z-allele noncarriers, regardless of race. Although severe alpha-1 antitrypsin deficiency is uncommon in African Americans, our study adds further support for initial targeted detection of all subjects with COPD for alpha-1 antitrypsin deficiency, including African Americans. Clinical trial registered with www.clinicaltrials.gov (NCT00608784).
authors.affiliation: 1 Morehouse School of Medicine, Atlanta, Georgia.
authors.forename: Marilyn G
authors.initials: MG
authors.lastname: Foreman
authors.affiliation: 2 National Jewish Health, Denver, Colorado.
authors.forename: Carla
authors.initials: C
authors.lastname: Wilson
authors.affiliation: 3 Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Dawn L
authors.initials: DL
authors.lastname: DeMeo
authors.affiliation: 3 Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Craig P
authors.initials: CP
authors.lastname: Hersh
authors.affiliation: 4 Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Terri H
authors.initials: TH
authors.lastname: Beaty
authors.affiliation: 3 Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Michael H
authors.initials: MH
authors.lastname: Cho
authors.affiliation: 3 Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: John
authors.initials: J
authors.lastname: Ziniti
authors.affiliation: 2 National Jewish Health, Denver, Colorado.|5 School of Public Health, University of Colorado, Denver, Colorado.
authors.forename: Douglas
authors.initials: D
authors.lastname: Curran-Everett
authors.affiliation: 6 School of Medicine, Temple University, Philadelphia, Pennsylvania; and.
authors.forename: Gerard
authors.initials: G
authors.lastname: Criner
authors.affiliation: 5 School of Public Health, University of Colorado, Denver, Colorado.
authors.forename: John E
authors.initials: JE
authors.lastname: Hokanson
authors.affiliation: 7 College of Medicine, University of Florida, Gainesville, Florida.
authors.forename: Mark
authors.initials: M
authors.lastname: Brantly
authors.affiliation: 7 College of Medicine, University of Florida, Gainesville, Florida.
authors.forename: Farshid N
authors.initials: FN
authors.lastname: Rouhani
authors.affiliation: 2 National Jewish Health, Denver, Colorado.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Sandhaus
authors.affiliation: 2 National Jewish Health, Denver, Colorado.
authors.forename: James D
authors.initials: JD
authors.lastname: Crapo
authors.affiliation: 3 Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Edwin K
authors.initials: EK
authors.lastname: Silverman
mesh_terms: D001741:Black or African American / Q000235:genetics; D000368:Aged; D015331:Cohort Studies; D003430:Cross-Sectional Studies; D005260:Female; D005541:Forced Expiratory Volume; D006801:Humans; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D010641:Phenotype; D029424:Pulmonary Disease, Chronic Obstructive / Q000208:ethnology* / Q000235:genetics*; D018570:Risk Assessment; D014481:United States; D014797:Vital Capacity; D044465:White People / Q000235:genetics; D000515:alpha 1-Antitrypsin / Q000235:genetics*; D019896:alpha 1-Antitrypsin Deficiency / Q000175:diagnosis* / Q000235:genetics
chemical_list: C043392:SERPINA1 protein, human; D000515:alpha 1-Antitrypsin
keywords: African Americans; alpha-1 antitrypsin deficiency; chronic obstructive pulmonary disease; emphysema; genetics