α₁-Antitrypsin protease inhibitor MZ heterozygosity is associated with airflow obstruction in two large cohorts.

Channing Laboratory, Brigham and Women's Hospital and Harvard Medical School, 181 Longwood Ave, Boston, MA 02115, USA.
Chest (Impact Factor: 5.85). 11/2010; 138(5):1125-32. DOI:10.1378/chest.10-0746
Source: PubMed

ABSTRACT 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.
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.
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.
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.

0 0
  • [show abstract] [hide abstract]
    ABSTRACT: Rationale: Severe alpha-1 antitrypsin deficiency (typically PiZZ homozygosity) is associated with a significantly increased risk of airflow obstruction and emphysema but the risk of 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 non-index subjects recruited from 51 index probands who were confirmed PiMZ heterozygotes and also had a diagnosis of COPD GOLD Stage II-IV. The primary outcome measures of interest were quantitative variables of pre- and post-bronchodilator (BD) FEV1/FVC ratio, FEV1 (L/s), FEV1 (% predicted), FEF25-75 (L/s), FEF25-75 (% predicted) and a categorical outcome of COPD. Results: PiMZ heterozygotes compared to PiMM individuals had a reduced median (IQR) 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 FEF¬25-75 (% 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 (CI) = 1.27 - 21.15, p = 0.02] and this was higher [OR = 10.65, (95% CI = 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.
    American Journal of Respiratory and Critical Care Medicine 01/2014; · 11.04 Impact Factor
  • [show abstract] [hide abstract]
    ABSTRACT: The recognition of α-1-antitrypsin deficiency, its function, and its role in predisposition to the development of severe emphysema was a watershed in our understanding of the pathophysiology of the condition. This led to the concept and development of intravenous replacement therapy used worldwide to protect against lung damage induced by neutrophil elastase. Nevertheless, much remained unknown about the deficiency and its impact, although in recent years the genetic and clinical variations in manifestation have provided new insights into assessing impact, efficacy of therapy, and development of new therapeutic strategies, including gene therapy, and outcome measures, such as biomarkers and computed tomography. The current article reviews this progress over the preceding 50 years.
    Trends in Molecular Medicine 12/2013; · 9.57 Impact Factor
  • [show abstract] [hide abstract]
    ABSTRACT: Alpha1-antitrypsin (AAT) deficiency was first described in 1963 together with its associations with severe early-onset basal panacinar emphysema. The genetic defects leading to deficiency have been elucidated and the pathophysiologic processes, clinical variation in phenotype, and the role of genetic modifiers have been recognized. Strategies to increase plasma (and hence tissue) concentrations of AAT have been developed. The only recognized specific therapeutic strategy is regular infusions of the purified plasma protein, and evidence confirms its efficacy in protecting the lung (at least partially). Early detection and modification of lifestyle remains crucial to the management of AAT deficiency.
    Clinics in chest medicine 03/2014; 35(1):39-50. · 2.51 Impact Factor

Full-text (2 Sources)

Available from
Mar 6, 2014