Clarification of the risk of chronic obstructive pulmonary disease in α1-antitrypsin deficiency PiMZ heterozygotes

Am J Respir Crit Care Med. 2014 Feb 15;189(4):419-27. doi: 10.1164/rccm.201311-1984OC.


Rationale: Severe α1-antitrypsin deficiency (typically PiZZ homozygosity) is associated with a significantly increased risk of airflow obstruction and emphysema but the risk of chronic obstructive pulmonary disease (COPD) in PiMZ heterozygotes remains uncertain.

Objectives: This was a family-based study to determine the risk of COPD in PiMZ individuals.

Methods: We compared 99 PiMM and 89 PiMZ nonindex subjects recruited from 51 index probands who were confirmed PiMZ heterozygotes and also had a diagnosis of COPD Global Initiative for Chronic Obstructive Lung Disease stage II-IV. The primary outcome measures of interest were quantitative variables of pre- and post-bronchodilator FEV1/FVC ratio, FEV1 (liters), FEV1 (% predicted), forced expiratory flow midexpiratory phase (FEF25-75; liters per second), FEF25-75 (% predicted), and a categorical outcome of COPD.

Measurements and main results: PiMZ heterozygotes compared with PiMM individuals had a reduced median (interquartile range) post-bronchodilator FEV1 (% predicted) (92.0 [75.6-105.4] vs. 98.6 [85.5-109.7]; P = 0.04), FEV1/FVC ratio (0.75 [0.66-0.79] vs. 0.78 [0.73-0.83]; P = 0.004), and FEF25-75 (% predicted) (63.84 [38.45-84.35] vs. 72.8 [55.5-97.7]; P = 0.0013) compared with PiMM individuals. This effect was abrogated in never-smoking and accentuated in ever-smoking PiMZ individuals. PiMZ heterozygosity was associated with an adjusted odds ratio for COPD of 5.18 (95% confidence interval, 1.27-21.15; P = 0.02) and this was higher (odds ratio, 10.65; 95% confidence interval, 2.17-52.29; P = 0.004) in ever-smoking individuals.

Conclusions: These results indicate that PiMZ heterozygotes have significantly more airflow obstruction and COPD than PiMM individuals and cigarette smoke exposure exerts a significant modifier effect.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Female
  • Forced Expiratory Volume
  • Gene-Environment Interaction
  • Genetic Markers
  • Heterozygote*
  • Humans
  • Male
  • Middle Aged
  • Odds Ratio
  • Phenotype*
  • Pulmonary Disease, Chronic Obstructive / diagnosis
  • Pulmonary Disease, Chronic Obstructive / etiology*
  • Pulmonary Disease, Chronic Obstructive / physiopathology
  • Risk Factors
  • Smoking / adverse effects
  • Spirometry
  • Surveys and Questionnaires
  • Vital Capacity
  • alpha 1-Antitrypsin / genetics*
  • alpha 1-Antitrypsin Deficiency / complications
  • alpha 1-Antitrypsin Deficiency / genetics*


  • Genetic Markers
  • SERPINA1 protein, human
  • alpha 1-Antitrypsin