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Determinants of airflow obstruction in severe alpha-1-antitrypsin deficiency
  1. Dawn L DeMeo1,
  2. Robert A Sandhaus2,
  3. Alan F Barker3,
  4. Mark L Brantly4,
  5. Edward Eden5,
  6. N Gerard McElvaney6,
  7. Stephen Rennard7,
  8. Esteban Burchard8,
  9. James M Stocks9,
  10. James K Stoller10,
  11. Charlie Strange11,
  12. Gerard M Turino5,
  13. Edward J Campbell12,
  14. Edwin K Silverman1
  1. 1Channing Laboratory, Brigham and Women’s Hospital, Boston, Massachusetts, USA
  2. 2National Jewish Medical and Research Center, Denver, Colorado, USA
  3. 3Oregon Health and Science University, Portland, Oregon, USA
  4. 4University of Florida, Gainesville, Florida, USA
  5. 5St. Luke’s/Roosevelt Hospital, New York, New York, USA
  6. 6Beaumont Hospital, Dublin, Ireland
  7. 7University of Nebraska, Omaha, Nebraska, USA
  8. 8University of California, San Francisco, California, USA
  9. 9University of Texas at Tyler, Tyler, Texas, USA
  10. 10Cleveland Clinic, Cleveland, Ohio, USA
  11. 11Medical University of South Carolina, Charlottesville, South Carolina, USA
  12. 12University of Utah, Salt Lake City, Utah, USA
  1. Correspondence to:
    Dr Dawn L DeMeo
    Channing Laboratory, 181 Longwood Avenue, Boston, Massachusetts 02115, USA; dawn.demeo{at}


Background: Severe α1-antitrypsin (AAT) deficiency is an autosomal recessive genetic condition associated with an increased but variable risk for chronic obstructive pulmonary disease (COPD). A study was undertaken to assess the impact of chronic bronchitis, pneumonia, asthma and sex on the development of COPD in individuals with severe AAT deficiency.

Methods: The AAT Genetic Modifier Study is a multicentre family-based cohort study designed to study the genetic and epidemiological determinants of COPD in AAT deficiency. 378 individuals (age range 33–80 years), confirmed to be homozygous for the SERPINA1 Z mutation, were included in the analyses. The primary outcomes of interest were a quantitative outcome, forced expiratory volume in 1 s (FEV1) percentage predicted, and a qualitative outcome, severe airflow obstruction (FEV1 <50% predicted).

Results: In multivariate analysis of the overall cohort, cigarette smoking, sex, asthma, chronic bronchitis and pneumonia were risk factors for reduced FEV1 percentage predicted and severe airflow obstruction (p<0.01). Index cases had lower FEV1 values, higher smoking histories and more reports of adult asthma, pneumonia and asthma before age 16 than non-index cases (p<0.01). Men had lower pre- and post-bronchodilator FEV1 percentage predicted than women (p<0.0001); the lowest FEV1 values were observed in men reporting a history of childhood asthma (26.9%). This trend for more severe obstruction in men remained when index and non-index groups were examined separately, with men representing the majority of non-index individuals with airflow obstruction (71%). Chronic bronchitis (OR 3.8, CI 1.8 to 12.0) and a physician’s report of asthma (OR 4.2, CI 1.4 to 13.1) were predictors of severe airflow obstruction in multivariate analysis of non-index men but not women.

Conclusion: In individuals with severe AAT deficiency, sex, asthma, chronic bronchitis and pneumonia are risk factors for severe COPD, in addition to cigarette smoking. These results suggest that, in subjects severely deficient in AAT, men, individuals with symptoms of chronic bronchitis and/or a past diagnosis of asthma or pneumonia may benefit from closer monitoring and potentially earlier treatment.

  • AAT, α1-antitrypsin
  • COPD, chronic obstructive pulmonary disease
  • FEV1, forced expiratory volume in 1 s
  • FVC, forced vital capacity

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  • Published Online First 27 March 2007

  • Funding: K08 HL072918 (DLD), ALA Research Grant (DLD), R01 HL68926 (EKS) and an ALA Career Investigator Award (EKS).

  • Competing interests: None.

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