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Chronic obstructive pulmonary disease
Chronic obstructive pulmonary disease in α1-antitrypsin PI MZ heterozygotes: a meta-analysis
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  1. C P Hersh1,
  2. M Dahl2,
  3. N P Ly1,
  4. C S Berkey1,
  5. B G Nordestgaard2,
  6. E K Silverman1
  1. 1Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA
  2. 2Department of Clinical Biochemistry, Herlev University Hospital, Copenhagen, Denmark
  1. Correspondence to:
    Dr E K Silverman
    Channing Laboratory, Brigham and Women’s Hospital, 181 Longwood Avenue, Boston, MA 02115, USA; ed.silvermanchanning.harvard.edu

Abstract

Background: Severe α1-antitrypsin deficiency, usually related to homozygosity for the protease inhibitor (PI) Z allele, is a proven genetic risk factor for chronic obstructive pulmonary disease (COPD). The risk of COPD in PI MZ heterozygous individuals is controversial.

Methods: A search of MEDLINE from January 1966 to May 2003 identified studies that examined the risk of COPD in PI MZ individuals and studies that measured forced expiratory volume in 1 second (FEV1) in heterozygotes.

Results: In 16 studies that reported COPD as a categorical outcome, the combined odds ratio (OR) for PI MZ versus PI MM (normal genotype) was 2.31 (95% CI 1.60 to 3.35). The summary OR was higher in case-control studies (OR 2.97; 95% CI 2.08 to 4.26) than in cross sectional studies (OR 1.50; 95% CI 0.97 to 2.31) and was attenuated in studies that adjusted for cigarette smoking (OR 1.61; 95% CI 0.92 to 2.81). In seven studies that reported FEV1 as a continuous outcome there was no difference in mean FEV1 between PI MM and PI MZ individuals.

Conclusions: Case-control studies showed increased odds of COPD in PI MZ individuals, but this finding was not confirmed in cross sectional studies. Variability in study design and quality limits the interpretation. These results are consistent with a small increase in risk of COPD in all PI MZ individuals or a larger risk in a subset. Future studies that adjust for smoking and include other COPD related phenotypes are required to conclusively determine the risk of COPD in PI MZ heterozygotes.

  • α1-antitrypsin
  • chronic obstructive pulmonary disease
  • heterozygote
  • meta-analysis
  • genetics

https://doi.org/10.1136/thx.2004.022541

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    Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death in the United States and a major cause of respiratory disability.1 Exposure to cigarette smoke is a well known environmental risk factor for COPD. Severe deficiency of α1-antitrypsin (AAT) is a proven genetic risk factor, but only 1–3% of all cases of COPD are estimated to be due to severe AAT deficiency.2

    AAT is a serine protease inhibitor that protects the lung from the action of proteases, primarily neutrophil elastase. It is encoded by the polymorphic protease inhibitor (PI) locus on chromosome 14q32.1. The most common alleles are the normal M allele (95% frequency in the US) and the deficient variants S (2–3%) and Z (1–2%).3 Severe AAT deficiency is most commonly due to homozygosity for the Z allele (PI ZZ). Heterozygotes for the Z allele (most commonly PI MZ) have lower serum levels of AAT than normal individuals (PI MM)4 but the risk of lung disease in PI MZ individuals remains uncertain.

    Although the risk of COPD in PI MZ heterozygotes has been analysed in many previous studies, the results have been inconsistent.5–7 In general, case-control studies have found an increased prevalence of PI MZ heterozygosity in COPD patients. However, PI MZ individuals identified from population surveys have not consistently been found to have higher rates of airflow obstruction than PI MM individuals. With an estimated six million PI MZ individuals in the US and over 10 million in Europe, determination of the COPD risk in PI MZ individuals may have broad public health implications.8 We therefore performed a systematic review of the medical literature to examine the risk of COPD in AAT PI MZ heterozygotes.

    METHODS

    Study selection

    A search of MEDLINE was performed to identify all studies that examined the risk of COPD or that measured pulmonary function in AAT PI MZ heterozygotes published between January 1966 and May 2003 using the medical subject headings “α1-antitrypsin”, “α1-antitrypsin deficiency”, “protease inhibitors”, “obstructive lung diseases”, “chronic obstructive pulmonary disease”, “pulmonary emphysema”, “forced expiratory volume”, “respiratory function tests”, and “spirometry”. Bibliographies of pertinent articles and reviews were searched for additional references.

    Two investigators independently evaluated studies for inclusion (CPH, MD). Disagreements were resolved by discussion including a third author (EKS). Included studies were case-control, cohort, and cross sectional studies using the categorical outcome of COPD based on spirometry or a physician’s diagnosis. Studies reporting forced expiratory volume in 1 second (FEV1) as a continuous outcome measure were also included. In the case-control design, comparison with controls from a previously published report was permitted as long as the cases and controls were from the same country and the same method was used for determination of PI type. In all included studies, PI type had to be determined using isoelectric focusing, acid starch gel with crossed immunoelectrophoresis, or a polymerase chain reaction (PCR) based genotyping method.

    Studies defining heterozygotes based on serum AAT levels or functional activity were excluded since PI MZ heterozygotes could not be consistently distinguished from other genotypes. Family studies and studies of children only were also excluded. For the continuous outcome, studies that did not present FEV1 as a percentage of the predicted value were analysed separately. We also attempted to exclude duplicate analyses of the same population of cases.

    Study quality

    A global assessment of the quality of each study was made, based on the following criteria: (1) Was the phenotype of obstructive lung disease defined by objective spirometric indices? (2) Were the cases and controls (in case-control studies) or the PI MZ and PI MM individuals (in population based studies) matched on ethnicity? (3) Did the studies control for cigarette smoking? (4) Did the authors test for Hardy-Weinberg equilibrium in the controls (case-control design) or in the population (cross sectional design)?

    The quality of a study was not a factor in its inclusion, except when the cases and controls were derived from studies in different countries as mentioned above. The quality criteria were used for the subgroup analyses.

    Data analysis

    Two investigators independently extracted data from each study. When studies determined COPD both by spirometric criteria and by physician diagnosis, the spirometric definition was used. Due to the small number of longitudinal studies, only the baseline cross sectional data from cohort studies were used. The effect estimates were combined using the random effects method of DerSimonian and Laird.9 All analyses were performed using STATA release 8 (STATA Corp, College Station, TX, USA). The Q-statistic was used to assess for heterogeneity among studies.

    Funnel plots and weighted regression were used to search for publication bias.10 Subgroup analyses were used to examine three potentially important sources of heterogeneity. The predetermined subgroups were based on study design, use of spirometric criteria to define COPD, and adjustment for cigarette smoking. The stability of the summary risk estimate was evaluated using a sensitivity analysis; each study was individually removed and the odds ratio (OR) was recalculated.

    The studies that reported FEV1 as a continuous outcome were analysed separately. A summary difference in mean FEV1 between PI MM individuals and PI MZ individuals was calculated using the random effects model.

    RESULTS

    Search results and study eligibility

    The initial search yielded 1125 references. From these, 106 studies were retrieved for detailed review and 22 were selected for primary analysis (tables 1 and 2).11–32 Sixteen studies were case-control or cross sectional studies with the binary outcome of COPD or airflow obstruction. Seven cross sectional studies measured FEV1 (% predicted) as a continuous outcome; four additional studies reported FEV1 in litres and were used for confirmatory analysis. One study included both the continuous and categorical outcome measures and was included in both analyses.15

    View this table:
    Table 1

     Studies examining risk of COPD in α1-antitrypsin PI MZ heterozygotes

    View this table:
    Table 2

     Studies reporting FEV1 (% predicted) in α1-antitrypsin PI MZ heterozygotes

    The reasons for exclusion were: determination of PI type by suboptimal methods (n = 14),33–46 reviews, editorials, or conference proceedings (n = 13),5,38,47–57 absence of an adequate control group (n = 11),45,58–67 measured pulmonary function tests other than FEV1 (n = 10),68–77 analysed other PI types but not PI MZ (n = 10),56,57,78–85 recorded FEV1 as an absolute volume and not as percentage of predicted (n = 9, of which four were included in a separate analysis),86–94 did not differentiate PI MZ from other variant genotypes (n = 8),87,90,95–100 used AAT level to define the exposure or the outcome (n = 8),44,47,101–106 COPD defined by self-report or hospital discharge records (n = 3),88,107,108 duplicate studies in the same population of cases (n = 3),109–111 children only (n = 3),97,112,113 and family based study design (n = 2).114,115 Some studies were excluded for more than one reason.

    Study quality

    The quality criteria fulfilled by each study are shown in tables 1 and 2. Nine studies used specific spirometric criteria to define COPD;11,12,15,17,23–25,30,31 these criteria were usually based on a reduced value for the FEV1 and/or the ratio of FEV1 to forced vital capacity (FVC). The other seven studies used clinical diagnoses which may have included pulmonary function testing, but explicit criteria were not stated. By definition, spirometry was recorded in all seven studies that reported mean FEV1 as the outcome measure.

    Most of the case-control studies derived their controls from local sources; only two studies used blood donors as controls. In most of the cross sectional studies the PI MM and PI MZ individuals were derived from the same source population. Four of the North American studies were restricted to Caucasian subjects11,14,26,30 and one matched cases and controls by ethnicity.17 Six studies were conducted in European nations where ethnic homogeneity is likely.13,15,18,20,24,29 Among the studies that examined FEV1 as a continuous outcome, only one of the four North American studies was restricted to Caucasians.28 Three studies measuring FEV1 as a continuous outcome were done in Europe.15,16,19 None of the included studies explicitly addressed population stratification—for example, by testing a panel of unlinked markers.116

    In the categorical analysis of COPD in case-control and cross sectional studies, five studies controlled for cigarette smoking.11,15,23,25,30 Kueppers and coworkers25 matched cases and controls on smoking history categorised into non-smokers, moderate smokers, and heavy smokers based on lifetime pack-years smoked. Two studies stratified by smoking status. Klayton et al23 divided subjects into never versus ever smokers, and Chan-Yeung et al11 into non-smokers, ex-smokers, and current smokers. The study by Dahl et al15 used logistic regression modelling to control for smoking status. One additional study used logistic regression but the resulting OR was not presented;30 for our analysis, the OR was calculated by adding a correction factor of 0.5 to all cells to account for a zero cell. In the analysis of mean FEV1 as a continuous outcome, four studies controlled for cigarette smoking. Hall and colleagues21 restricted the study to non-smokers. Eriksson and coworkers16 performed a stratified analysis, presenting mean FEV1 values for smokers, ex-smokers, and non-smokers. In the studies by Girard et al19 and Horne et al22 PI MZ and PI MM individuals were matched by smoking status.

    In the study by Dahl and colleagues15 a test of Hardy-Weinberg equilibrium was performed; in this population sample the observed genotype frequencies did not differ from those predicted under Hardy-Weinberg equilibrium. In no other study did the authors report testing for Hardy-Weinberg equilibrium. Based on the predetermined criteria, the majority of studies were judged to be of suboptimal quality. The study by Dahl and coworkers15 was the only one that met all four of the predefined quality criteria.

    Odds ratio (OR) for COPD in PI MZ heterozygotes

    Six of the 16 studies examining the categorical outcome of obstructive lung disease found significantly higher ORs for COPD in PI MZ heterozygotes than in PI MM individuals (fig 1). In nine other studies the OR was increased, but not significantly. One study found a reduced OR, but not significantly. The individual study ORs ranged from 0.15 to 16.78. Using the random effects method,9 the summary OR for COPD in PI MZ compared with PI MM individuals was significantly increased at 2.31 (95% CI 1.60 to 3.35).

    Figure 1
    Figure 1

     Case-control and cross sectional studies of COPD in α1-antitrypsin PI MZ heterozygotes. Sizes of boxes represent inverse variance weights (random effects model).9 Lines represent 95% confidence intervals.

    Significant heterogeneity was detected among the studies (Q test: χ215df = 36.1, p = 0.002). Subgroup analyses are shown in fig 2. In a subgroup analysis based on study design, the 11 case-control studies were found to have a larger summary OR than the five cross sectional categorical studies (case-control OR 2.97, 95% CI 2.08 to 4.26; cross sectional OR 1.50, 95% CI 0.97 to 2.31). There was less heterogeneity within each of these subgroups than in the combined analysis (case-control χ210df = 12.3, p = 0.27; cross sectional χ24df = 5.9, p = 0.21).

    Figure 2
    Figure 2

     Subgroup analysis of studies of COPD in α1-antitrypsin PI MZ heterozygotes. Odds ratios with 95% confidence intervals are shown.

    The magnitude of the effect estimate was similar in the nine studies that used spirometric criteria for the definition of obstructive lung disease (OR 2.17, 95% CI 1.22 to 3.87) and the seven studies that relied on clinical diagnoses of COPD (OR 2.52, 95% CI 1.65 to 3.85); heterogeneity was reduced, but still possible, within each of these subgroups as well (spirometric criteria χ28df = 15.4, p = 0.051; no spirometric criteria χ26df = 10.3, p = 0.11).117

    The magnitude of the effect estimate was lower in the five studies that adjusted for cigarette smoking (OR 1.61, 95% CI 0.92 to 2.81) than in the 11 studies that did not (OR 2.73, 95% CI 1.86 to 4.01); in the studies that stratified by smoking status, data were pooled across each stratum for analysis. Again, heterogeneity was reduced within each of these subgroups (adjustment for smoking χ24df = 6.8, p = 0.15; no adjustment for smoking χ210df = 14.7, p = 0.14). Due to the different methods used to control for smoking in the different studies, separate summary ORs for smokers and non-smokers could not be derived.

    In the sensitivity analysis, when the study by Dahl et al15 was removed from the analysis, the summary OR was increased above that obtained using all 16 studies. When each of the other 15 papers was removed individually, the summary OR was unchanged. The funnel plot of OR versus standard error (both log transformed) appeared to be symmetrical, and the regression method of Egger et al10 did not indicate significant evidence for publication bias (p = 0.15).

    Mean FEV1 in PI MZ heterozygotes compared with normal subjects

    The seven cross sectional studies that compared mean FEV1 (% predicted) in PI MM and PI MZ individuals are shown in table 2. One study from the categorical outcome analysis also reported mean values for FEV1 and was included in the continuous outcome analysis.15 For the one study that reported mean FEV1 values stratified by smoking status, data from the individual strata were entered into the analysis.16 In the pooled analysis (fig 3) there was no difference in mean FEV1 (% predicted) between PI MM and PI MZ individuals (summary difference PI MM – PI MZ = 0.62% predicted, 95% CI –2.30 to 3.54). Significant heterogeneity was detected in these studies (χ28df = 24.4, p = 0.002).

    Figure 3
    Figure 3

     Studies reporting FEV1 as percentage predicted in α1-antitrypsin PI MZ heterozygotes. The mean difference is calculated by subtracting the mean FEV1 (% predicted) of PI MZ individuals from that of PI MM individuals. Sizes of boxes represent inverse variance weights (random effects model).9 Lines represent 95% confidence intervals. *Presented mean FEV1 to the nearest percent.

    No asymmetry was detected in the funnel plot of the difference in mean FEV1 versus standard error. Egger’s test did not reveal significant publication bias (p = 0.71). In the sensitivity analysis the mean difference in FEV1 was increased when the study by Dahl et al15 was removed; the mean difference was unaffected when each of the other studies was excluded. Because of the small number of studies, no subgroup analyses were performed for the mean differences in FEV1. A separate analysis of four cross sectional studies that expressed FEV1 in litres (but otherwise met inclusion criteria) was performed.89,91,93,94 There was no difference in mean FEV1 between PI MM and PI MZ individuals (summary difference PI MM – PI MZ  =  −0.01 litres, 95% CI –0.23 to 0.21).

    DISCUSSION

    We have conducted a systematic review of the medical literature to evaluate the risk of COPD in AAT PI MZ heterozygotes. Combining studies reporting a categorical outcome, we found moderately increased odds of obstructive lung disease in PI MZ individuals (OR 2.31). As has been noted in previous narrative reviews, the effect estimate was larger in the case-control studies than in the cross sectional studies.6,7 The magnitude of the OR was attenuated in the studies that adjusted for cigarette smoking, but was not substantially different in the subgroup of studies that used objective spirometric criteria to define COPD. The studies measuring lung function as a continuous outcome did not show a difference in mean FEV1 (% predicted) between PI MM and PI MZ individuals.

    Overall, the study quality was variable. Only one study fulfilled all four of the quality criteria. The differences in study design and quality, including adjustment for cigarette smoking, probably contribute to the significant heterogeneity found among the studies in the analyses of both the categorical and continuous outcome measures. These studies were all observational, so they are all susceptible to a variety of biases. Some of the studies used different sources for the cases and controls (or PI MM and PI MZ individuals), leading to the possibility of selection bias. Only one study tested for Hardy-Weinberg equilibrium; deviations from Hardy-Weinberg equilibrium could be indicative of problems such as genotyping error or population stratification.118

    Confounding by environmental exposures is another potential concern in observational studies. Cigarette smoking is the major environmental risk factor for COPD, but many of the studies did not adjust for smoking as a potential confounder. This is a likely source of heterogeneity between studies. Other potential confounders may also be important, yet control for factors such as age and sex was also inconsistent. In the analysis of lung function as a continuous outcome, the primary analysis included studies that expressed FEV1 as a percentage of predicted since the equations used to calculate the predicted values adjust for important covariates—namely, age, sex, and height. Although different studies used different prediction equations, the same equations were used for both the cases and the controls within an individual study.

    A strict phenotype definition is necessary for genetic epidemiology studies,118 but not all of the studies used objective spirometric criteria for the diagnosis of COPD. This may also be a source of heterogeneity between studies. Although the inclusion criteria allowed for different methods of assessment of PI type, this should not lead to important heterogeneity since the included methods are generally quite reliable.119

    The divergent conclusions reached by the analyses of the categorical and continuous outcomes require further investigation. Overall, the categorical studies—specifically the case-control studies—showed an increased risk of COPD yet no reduction in mean FEV1 was seen in PI MZ individuals in the cross sectional lung function studies. If PI MZ heterozygosity is a risk factor for COPD, one would expect to find both an increased OR in the categorical studies and a reduction in lung function in the studies measuring continuous outcome; reduced FEV1 is a defining feature of COPD.

    If the overall risk increase in PI MZ individuals is uniform but small, then case-control studies may detect this risk more efficiently than cross sectional studies.120 Among the categorical studies, the case-control studies did show an increased OR but the cross sectional categorical studies showed only a trend towards increased risk of COPD in PI MZ individuals.

    Alternatively, these results are consistent with an increased risk of COPD in a subgroup of PI MZ individuals. Cigarette smoking may be an important co-factor, and many of the published population based studies may not be large enough to detect this genotype-by-environment interaction. Other genetic factors are likely to modify the risk of development of lung disease in PI ZZ homozygotes,114,121 and it is possible that genetic modifiers of lung disease in PI MZ individuals also exist.

    The results of a recent cohort study are consistent with a modifier of COPD risk in PI MZ individuals. Among 1551 PI MZ subjects from the Danish Alpha 1-Antitrypsin Deficiency Registry, the relative risk for hospital admission for obstructive lung disease (asthma, emphysema, or chronic bronchitis) was twice that of population controls.107 First degree relatives of PI Z index cases, with the index cases identified based on respiratory symptoms, were the subgroup responsible for this increased risk. This suggests the presence of other genetic and/or environmental factors aggregating in the families of the PI Z index cases.

    Based on this systematic review, the risk of COPD in PI MZ heterozygotes remains uncertain. However, a small increase in risk for all PI MZ individuals or a larger increase in risk in a subgroup of heterozygotes are possible explanations for the apparently discordant results from the analyses of the categorical (especially the case-control studies) and continuous outcome measures. Further studies using rigorous epidemiological methods—including careful control for age, sex, ethnicity, and cigarette smoking—will be required to determine the presence and magnitude of the risk of COPD in PI MZ individuals as a group and in relevant subgroups. It will be important to examine the interaction between PI MZ genotype and cigarette smoking to accurately quantify risk in both smokers and non-smokers. Future studies using other COPD related phenotypes, such as quantitative radiographic measures of emphysema, may also identify clinically relevant subgroups.

    Acknowledgments

    The authors thank Drs Anne Tybjærg-Hansen, Peter Lange, and Jørgen Vestbo for their helpful suggestions and Dr Clare Ramsey for her assistance with translation from French.

    REFERENCES

    1. ↵
      National Heart, Lung, and Blood Institute. Morbidity and mortality: 2002 chart book on cardiovascular, lung, and blood diseases. Bethesda, MD: National Institutes of Health, 2002.
    2. ↵
      Lomas DA, Silverman EK. The genetics of chronic obstructive pulmonary disease. Respir Res2001;2:20–6.
      OpenUrlCrossRefPubMedWeb of Science
    3. ↵
      Blanco I , Bustillo EF, Rodriguez MC. Distribution of alpha 1-antitrypsin PI S and PI Z frequencies in countries outside Europe: a meta-analysis. Clin Genet2001;60:431–41.
      OpenUrlCrossRefPubMedWeb of Science
    4. ↵
      American Thoracic Society. Guidelines for the approach to the patient with severe hereditary alpha-1-antitrypsin deficiency. Am Rev Respir Dis1989;140:1494–7.
      OpenUrlPubMedWeb of Science
    5. ↵
      Mittman C . The PiMZ phenotype: is it a significant risk factor for the development of chronic obstructive lung disease? Am Rev Respir Dis1978;118:649–52.
      OpenUrlPubMedWeb of Science
    6. ↵
      Barker AF, D’Silva RG, Buist AS. Lung function and alpha 1-AT deficiency. In: Crystal RG, ed. Alpha 1-antitrypsin deficiency: biology, pathogenesis, clinical manifestations, therapy. New York: Marcel Dekker, 1996:245–57.
    7. ↵
      Sandford AJ, Weir TD, Pare PD. Genetic risk factors for chronic obstructive pulmonary disease. Eur Respir J1997;10:1380–91.
      OpenUrlAbstract/FREE Full Text
    8. ↵
      de Serres FJ. Worldwide racial and ethnic distribution of alpha 1-antitrypsin deficiency: summary of an analysis of published genetic epidemiologic surveys. Chest2002;122:1818–29.
      OpenUrlCrossRefPubMedWeb of Science
    9. ↵
      DerSimonian R , Laird N. Meta-analysis in clinical trials. Control Clin Trials1986;7:177–88.
      OpenUrlCrossRefPubMedWeb of Science
    10. ↵
      Egger M , Smith GD, Schneider M, et al. Bias in meta-analysis detected by a simple, graphical test. BMJ1997;315:629–34.
      OpenUrlAbstract/FREE Full Text
    11. ↵
      Chan-Yeung M , Ashley MJ, Corey P, et al. Pi phenotypes and the prevalence of chest symptoms and lung function abnormalities in workers employed in dusty industries. Am Rev Respir Dis1978;117:239–45.
      OpenUrlPubMed
    12. ↵
      Abboud RT, Rushton JM, Grzybowski S. Interrelationships between neutrophil elastase, serum alpha1-antitrypsin, lung function and chest radiography in patients with chronic airflow obstruction. Am Rev Respir Dis1979;120:31–40.
      OpenUrlPubMedWeb of Science
    13. ↵
      Bartmann K , Fooke-Achterrath M, Koch G, et al. Heterozygosity in the Pi-system as a pathogenetic cofactor in chronic obstructive pulmonary disease (COPD). Eur J Respir Dis1985;66:284–96.
      OpenUrlPubMedWeb of Science
    14. ↵
      Cox DW, Hoeppner VH, Levison H. Protease inhibitors in patients with chronic obstructive pulmonary disease: the alpha 1-antitrypsin heterozygote controversy. Am Rev Respir Dis1976;113:601–6.
      OpenUrlPubMedWeb of Science
    15. ↵
      Dahl M , Tybjaerg-Hansen A, Lange P, et al. Change in lung function and morbidity from chronic obstructive pulmonary disease in alpha-1-antitrypsin MZ heterozygotes: a longitudinal study of the general population. Ann Intern Med2002;136:270–9.
      OpenUrlPubMedWeb of Science
    16. ↵
      Eriksson S , Lindell SE, Wiberg R. Effects of smoking and intermediate alpha 1-antitrypsin deficiency (PiMZ) on lung function. Eur J Respir Dis1985;67:279–85.
      OpenUrlPubMedWeb of Science
    17. ↵
      Barnett TB, Gottovi D, Johnson AM. Protease inhibitors in chronic obstructive pulmonary disease. Am Rev Respir Dis1975;111:587–93.
      OpenUrlPubMedWeb of Science
    18. ↵
      Fagerhol MK, Hauge HE. Serum Pi types in patients with pulmonary diseases. Acta Allergol1969;24:107–14.
      OpenUrlPubMedWeb of Science
    19. ↵
      Girard F , Aug F, Camara M, et al. Pulmonary abnormality and alpha 1-antitrypsin heterozygote deficiency in a working population. Bull Eur Physiopathol Respir1978;14:11–22.
      OpenUrlPubMedWeb of Science
    20. ↵
      Gulsvik A , Fagerhol MK. Alpha 1-antitrypsin phenotypes and obstructive lung disease in the city of Oslo. Scand J Respir Dis1979;60:267–74.
      OpenUrlPubMedWeb of Science
    21. ↵
      Hall WJ, Hyde RW, Schwartz RH, et al. Pulmonary abnormalities in intermediate alpha-1-antitrypsin deficiency. J Clin Invest1976;58:1069–77.
    22. ↵
      Horne SL, Tennent RK, Cockcroft DW, et al. Pulmonary function in Pi M and MZ grainworkers. Chest1986;89:795–9.
      OpenUrlCrossRefPubMedWeb of Science
    23. ↵
      Klayton R , Fallat R, Cohen AB. Determinants of chronic obstructive pulmonary disease in patients with intermediate levels of alpha1-antitrypsin. Am Rev Respir Dis1975;112:71–5.
      OpenUrlPubMedWeb of Science
    24. ↵
      Kueppers F , Donhardt A. Obstructive lung disease in heterozygotes for alpha-1 antitrypsin deficiency. Ann Intern Med1974;80:209–12.
    25. ↵
      Kueppers F , Miller RD, Gordon H, et al. Familial prevalence of chronic obstructive pulmonary disease in a matched pair study. Am J Med1977;63:336–42.
      OpenUrlCrossRefPubMedWeb of Science
    26. ↵
      Lieberman J , Winter B, Sastre A. Alpha 1-antitrypsin Pi-types in 965 COPD patients. Chest1986;89:370–3.
      OpenUrlCrossRefPubMedWeb of Science
    27. ↵
      Matzen RN, Bader PI, Block WD. α1-Antitrypsin deficiency in clinic patients. Ann Clin Res1977;9:88–92.
      OpenUrlPubMedWeb of Science
    28. ↵
      Morse JO, Lebowitz MD, Knudson RJ, et al. Relation of protease inhibitor phenotypes to obstructive lung diseases in a community. N Engl J Med1977;296:1190–4.
      OpenUrlPubMedWeb of Science
    29. ↵
      Poller W , Meisen C, Olek K. DNA polymorphisms of the alpha 1-antitrypsin gene region in patients with chronic obstructive pulmonary disease. Eur J Clin Invest1990;20:1–7.
      OpenUrlPubMedWeb of Science
    30. ↵
      Sandford AJ, Weir TD, Spinelli JJ, et al. Z and S mutations of the alpha 1-antitrypsin gene and the risk of chronic obstructive pulmonary disease. Am J Respir Cell Mol Biol1999;20:287–91.
      OpenUrlPubMedWeb of Science
    31. ↵
      Talamo RC, Langley CE, Levine BW, et al. Genetic vs. quantitative analysis of serum alpha 1-antitrypsin. N Engl J Med1972;287:1067–9.
    32. ↵
      Webb DR, Hyde RW, Schwartz RH, et al. Serum alpha 1-antitrypsin variants. Prevalence and clinical spirometry. Am Rev Respir Dis1973;108:918–25.
      OpenUrlPubMedWeb of Science
    33. ↵
      Alvarez-Granda L , Cabero-Perez MJ, Bustamante-Ruiz A, et al. PI SZ phenotype in chronic obstructive pulmonary disease. Thorax1997;52:659–61.
      OpenUrlAbstract
    34. Cohen BH, Ball WC, Bias WB, et al. A genetic-epidemiologic study of chronic obstructive pulmonary disease. I. Study design and preliminary observations. Johns Hopkins Med J1975;137:95–104.
      OpenUrlPubMedWeb of Science
    35. Eriksson S , Moestrup T, Hagerstrand I. Liver, lung and malignant disease in heterozygous (Pi MZ) alpha 1-antitrypsin deficiency. Acta Med Scand1975;198:243–7.
      OpenUrlPubMedWeb of Science
    36. Guenter CA, Welch MH, Ferguson S, et al. Alpha-1-antitrypsin deficiency: heterozygosity, intermediate levels, and pulmonary disease. Chest1971;5916S.
    37. Gupta SP, Pande JN, Guleria JS. Pulmonary emphysema and alpha-1 antitrypsin deficiency. Indian J Med Res1977;66:127–32.
      OpenUrlPubMedWeb of Science
    38. ↵
      Janus ED. Alpha 1-antitrypsin Pi types in COPD patients. Chest1988;94:446–7.
      OpenUrlCrossRefPubMedWeb of Science
    39. Kambe M , Morishita K, Tsubokura T, et al. A study on the lung function in alpha 1-antitrypsin-deficient (PiMZ) patients. Hiroshima J Med Sci1993;42:41–5.
      OpenUrlPubMed
    40. Madison R , Mittman C, Afifi AA, et al. Risk factors for obstructive lung disease. Am Rev Respir Dis1981;124:149–53.
      OpenUrlPubMedWeb of Science
    41. Mittman C , Lieberman J, Marasso F, et al. Smoking and chronic obstructive lung disease in alpha-1-antitrypsin deficiency. Chest1971;60:214–21.
      OpenUrlPubMedWeb of Science
    42. Shah AC, Dixit SD, Billimoria FP, et al. Occurrence of alpha 1-antitrypsin deficiency in normal healthy Indians and in patients with various pulmonary diseases. J Indian Med Assoc1983;81:79–82.
      OpenUrlPubMed
    43. Szczeklik A , Stankowska K, Frydecka I. Cardiopulmonary function in α1-antitrypsin heterozygotes exposed to severe air pollution. Am Rev Respir Dis1973;107:289–91.
      OpenUrlPubMedWeb of Science
    44. ↵
      Talamo RC, Allen JD, Kahan MG, et al. Hereditary alpha-1-antitrypsin deficiency. N Engl J Med1968;278:345–51.
    45. ↵
      Varpela E , Salorinne Y. Respiratory disease profile in 22 patients with alpha 1-antitrypsin deficiencies. Scand J Respir Dis Suppl1974;89:251–60.
      OpenUrlPubMed
    46. ↵
      Welch MH, Reinecke ME, Hammarsten JF, et al. Antitrypsin deficiency in pulmonary disease: the significance of intermediate levels. Ann Intern Med1969;71:533–42.
    47. ↵
      Amin M . The role of alpha 1-antitrypsin in generating chronic obstructive pulmonary disorder. Respirology2000;5:S39–S43.
      OpenUrlCrossRef
    48. Berend N . Epidemiological survey of chronic obstructive pulmonary disease and alpha-1-antitrypsin deficiency in Australia. Respirology2001;6 (Suppl) :S21–5.
    49. Camara M , Martin JP. Alpha 1-antitrypsin deficiency and its repercussions in pulmonary pathophysiology. Bull Eur Physiopathol Respir1978;14:91–124.
      OpenUrlPubMedWeb of Science
    50. Haack DG. Interactions of neutrophil elastase, serum trypsin inhibitory activity, and smoking history as risk factors for chronic obstructive pulmonary disease in patients with MM, MZ, and ZZ phenotypes for alpha1-antitrypsin. Am Rev Respir Dis1978;117:812–3.
      OpenUrlPubMedWeb of Science
    51. Hutchison DC. Homozygous and heterozygous alpha-1-antitrypsin deficiency: prevalence in pulmonary emphysema. Proc R Soc Med1976;69:130–1.
      OpenUrlPubMedWeb of Science
    52. Kauffmann F . Genetics of chronic obstructive pulmonary diseases. Searching for their heterogeneity. Bull Eur Physiopathol Respir1984;20:163–210.
      OpenUrlPubMedWeb of Science
    53. Lieberman J , Colp C. A role for intermediate, heterozygous alpha 1-antitrypsin deficiency in obstructive lung disease. Chest1990;98:522–3.
      OpenUrlCrossRefPubMedWeb of Science
    54. Madison R , Zelman R, Mittman C. Inherited risk factors for chronic lung disease. Chest1980;77:255–7.
      OpenUrl
    55. Mittman C , Barbela T, Lieberman J. Alpha 1-antitrypsin deficiency as an indicator of susceptibility to pulmonary disease. J Occup Med1973;15:33–8.
      OpenUrlPubMed
    56. ↵
      Shim YS. Epidemiological survey of chronic obstructive pulmonary disease and alpha-1 antitrypsin deficiency in Korea. Respirology2001;6 (Suppl) :S9–11.
    57. ↵
      Zhu YJ. Epidemiological survey of chronic obstructive pulmonary disease and alpha-1-deficiency in China. Respirology2001;6 (Suppl) :S13–5.
    58. ↵
      Bruun-Petersen K , Bruun-Petersen G, Dahl R, et al. Alpha 1-antitrypsin alleles in patients with pulmonary emphysema, detected by DNA amplification (PCR) and oligonucleotide probes. Eur Respir J1992;5:531–7.
      OpenUrlAbstract/FREE Full Text
    59. Gelb AF, Klein E, Lieberman J. Pulmonary function in nonsmoking subjects with alpha1 antitrypsin deficiency (MZ phenotype). Am J Med1977;62:93–8.
      OpenUrlCrossRefPubMedWeb of Science
    60. Larsson C , Dirksen H, Sundstrom G, et al. Lung function studies in asymptomatic individuals with moderately (Pi SZ) and severely (Pi Z) reduced levels of alpha1-antitrypsin. Scand J Respir Dis1976;57:267–80.
      OpenUrlPubMedWeb of Science
    61. Mittman C , Barbela T, Lieberman J. Antitrypsin deficiency and abnormal protease inhibitor phenotypes. Arch Environ Health1973;27:201–6.
      OpenUrlPubMedWeb of Science
    62. Mittman C , Lieberman J, Rumsfeld J. Prevalence of abnormal protease inhibitor phenotypes in patients with chronic obstructive lung disease. Am Rev Respir Dis1974;109:295–6.
      OpenUrlPubMedWeb of Science
    63. Piitulainen E , Sveger T. Effect of environmental and clinical factors on lung function and respiratory symptoms in adolescents with alpha-1-antitrypsin deficiency. Acta Paediatr1998;87:1120–4.
      OpenUrlCrossRefPubMedWeb of Science
    64. Sandford AJ, Chagani T, Weir TD, et al. Susceptibility genes for rapid decline of lung function in the lung health study. Am J Respir Crit Care Med2001;163:469–73.
      OpenUrlCrossRefPubMedWeb of Science
    65. Seersholm N , Kok-Jensen A. Intermediate alpha 1-antitrypsin deficiency PiSZ: a risk factor for pulmonary emphysema? Respir Med1998;92:241–5.
      OpenUrlCrossRefPubMedWeb of Science
    66. Tarjan E , Magyar P, Vaczi Z, et al. Longitudinal lung function study in heterozygous PiMZ phenotype subjects. Eur Respir J1994;7:2199–204.
      OpenUrlAbstract/FREE Full Text
    67. ↵
      Wencker M , Marx A, Konietzko N, et al. Screening for alpha-1-Pi deficiency in patients with lung diseases. Eur Respir J2002;20:319–24.
      OpenUrlAbstract/FREE Full Text
    68. ↵
      Cooper DM, Hoeppner V, Cox D, et al. Lung function in alpha-1-antitrypsin heterozygotes (Pi type MZ). Am Rev Respir Dis1974;110:708–15.
      OpenUrlPubMedWeb of Science
    69. Hepper NG, Muhm JR, Sheehan WC, et al. Roentgenographic study of chronic obstructive pulmonary disease by alpha1-antitrypsin phenotype. Mayo Clin Proc1978;53:166–72.
      OpenUrlPubMedWeb of Science
    70. Johnson TF, Reisman RE, Arbesman CE, et al. Obstructive airway disease associated with heterozygous alpha-1-antitrypsin deficiency. J Allergy Clin Immunol1976;58:69–75.
      OpenUrlCrossRefPubMedWeb of Science
    71. Kabiraj MU, Simonsson BG, Groth S, et al. Bronchial reactivity, smoking, and alpha1-antitrypsin. A population-based study of middle-aged men. Am Rev Respir Dis1982;126:864–9.
      OpenUrlPubMedWeb of Science
    72. Klasen EC, Biemond I, Laros CD. Alpha 1-antitrypsin deficiency and the flaccid lung syndrome. The heterozygote controversy. Clin Genet1986;29:211–5.
      OpenUrlPubMedWeb of Science
    73. Larsson C , Eriksson S, Dirksen H. Smoking and intermediate alpha1-antitrypsin deficiency and lung function in middle-aged men. BMJ1977;2:922–5.
    74. Lebowitz MD, Knudson RJ, Morse JO, et al. Closing volume and flow volume abnormalities in alpha(1)-antitrypsin phenotype groups in a community population. Am Rev Respir Dis1978;117:179–81.
      OpenUrlPubMedWeb of Science
    75. McDonagh DJ, Nathan SP, Knudson RJ, et al. Assessment of alpha-1-antitrypsin deficiency heterozygosity as a risk factor in the etiology of emphysema. Physiological comparison of adult normal and heterozygous protease inhibitor phenotype subjects from a random population. J Clin Invest1979;63:299–309.
    76. Ostrow DN, Cherniack RM. The mechanical properties of the lungs in intermediate deficiency of alpha 1-antitrypsin. Am Rev Respir Dis1972;106:377–83.
      OpenUrlPubMedWeb of Science
    77. ↵
      Pride NB, Tattersall SF, Pereira RP, et al. Lung distensibility and airway function in intermediate alpha 1-antitrypsin deficiency (PiMZ). Chest1980;77:253–5.
      OpenUrl
    78. ↵
      Ostrow DN, Manfreda J, Dorman T, et al. Alpha1-antitrypsin phenotypes and lung function in a moderately polluted northern Ontario community. Can Med Assoc J1978;118:669–72.
      OpenUrlAbstract
    79. Bencze K , Sabatke L, Fruhmann G. Alpha 1-antitrypsin: the PiMM subtypes. Do they play a role in development of chronic obstructive pulmonary diseases? Chest1980;77:761–3.
      OpenUrlCrossRefPubMedWeb of Science
    80. Gishen P , Saunders AJ, Tobin MJ, et al. Alpha 1-antitrypsin deficiency: the radiological features of pulmonary emphysema in subjects of Pi type Z and Pi type SZ: a survey by the British Thoracic Association. Clin Radiol1982;33:371–7.
      OpenUrlCrossRefPubMedWeb of Science
    81. Hutchison DC, Tobin MJ, Cook PJ. Alpha 1 antitrypsin deficiency: clinical and physiological features in heterozygotes of Pi type SZ. A survey by the British Thoracic Association. Br J Dis Chest1983;77:28–34.
      OpenUrlPubMedWeb of Science
    82. Roberts A , Kagan A, Rhoads GG, et al. Antitrypsin and chronic obstructive pulmonary disease among Japanese-American men. Chest1977;72:489–91.
      OpenUrlCrossRefPubMedWeb of Science
    83. Turino GM, Barker AF, Brantly ML, et al. Clinical features of individuals with PI*SZ phenotype of alpha 1-antitrypsin deficiency. α1-Antitrypsin Deficiency Registry Study Group. Am J Respir Crit Care Med1996;154:1718–25.
      OpenUrlPubMedWeb of Science
    84. Kauffmann F , Kleisbauer JP, Cambon-De-Mouzon A, et al. Genetic markers in chronic air-flow limitation. A genetic epidemiologic study. Am Rev Respir Dis1983;127:263–9.
      OpenUrlPubMedWeb of Science
    85. ↵
      Seyama K . State of alpha 1-antitrypsin deficiency in Japan. Respirology2000;5:S35–8.
      OpenUrl
    86. ↵
      Bruce RM, Cohen BH, Diamond EL, et al. Collaborative study to assess risk of lung disease in Pi MZ phenotype subjects. Am Rev Respir Dis1984;130:386–90.
      OpenUrlPubMedWeb of Science
    87. ↵
      Buist AS, Sexton GJ, Azzam AM, et al. Pulmonary function in heterozygotes for alpha1-antitrypsin deficiency: a case-control study. Am Rev Respir Dis1979;120:759–66.
      OpenUrlPubMedWeb of Science
    88. ↵
      Cole RB, Nevin NC, Blundell G, et al. Relation of alpha-1-antitrypsin phenotype to the performance of pulmonary function tests and to the prevalence of respiratory illness in a working population. Thorax1976;31:149–57.
      OpenUrlAbstract/FREE Full Text
    89. ↵
      de Hamel FA, Carrell RW. Heterozygous alpha 1-antitrypsin deficiency: a longitudinal lung function study. NZ Med J1981;94:407–10.
      OpenUrlPubMed
    90. ↵
      Gerblich AA, Kleinerman J, Rynbrandt DJ, et al. Pi-Z phenotypes in a pulmonary clinic. Their prevalence and physiologic state. Am J Clin Pathol1978;69:509–13.
      OpenUrlPubMedWeb of Science
    91. ↵
      Horton FO 3rd, Mackenthun AV, Anderson PS Jr, et al. Alpha 1 antitrypsin heterozygotes (Pi type MZ). A longitudinal study of the risk of development of chronic air flow limitation. Chest1980;77:261–4.
    92. Kozarevic D , Laban M, Budimir M, et al. Intermediate alpha1-antitrypsin deficiency and chronic obstructive pulmonary disease in Yugoslavia. Am Rev Respir Dis1978;117:1039–43.
      OpenUrlPubMedWeb of Science
    93. ↵
      Siekmeier R , Schiller-Scotland CF. Convective gas mixing, airway dimensions and lung function parameters in patients homo- or heterozygote for hereditary alpha-1-antitrypsin deficiency. Toxicol Lett1998;96–97:325–33.
      OpenUrlCrossRef
    94. ↵
      Tattersall SF, Pereira RP, Hunter D, et al. Lung distensibility and airway function in intermediate alpha 1-antitrypsin deficiency (Pi MZ). Thorax1979;34:637–46.
      OpenUrlAbstract/FREE Full Text
    95. ↵
      Cohen BH, Ball WC Jr, Brashears S, et al. Risk factors in chronic obstructive pulmonary disease (COPD). Am J Epidemiol1977;105:223–32.
      OpenUrlAbstract/FREE Full Text
    96. Colp C , Talavera W, Goldman D, et al. Profile of bronchospastic disease in Puerto Rican patients in New York City. A possible relationship to alpha 1-antitrypsin variants. Arch Intern Med1990;150:2349–54.
      OpenUrlCrossRefPubMedWeb of Science
    97. ↵
      Corbo GM, Forastiere F, Agabiti N, et al. Passive smoking and lung function in alpha(1)-antitrypsin heterozygote schoolchildren. Thorax2003;58:237–41.
      OpenUrlAbstract/FREE Full Text
    98. Galdston M , Melnick EL, Goldring RM, et al. Interactions of neutrophil elastase, serum trypsin inhibitory activity, and smoking history as risk factors for chronic obstructive pulmonary disease in patients with MM, MZ, and ZZ phenotypes for alpha-antitrypsin. Am Rev Respir Dis1977;116:837–46.
      OpenUrlPubMedWeb of Science
    99. Kueppers F , Fallat R, Larson RK. Obstructive lung disease and alpha-1-antitrypsin deficiency gene heterozygosity. Science1969;165:899–901.
      OpenUrlAbstract/FREE Full Text
    100. ↵
      Kueppers F . Alpha-1-antitrypsin: 1. Evidence for two genes causing low concentrations in serum; 2. Association of heterozygosity and chronic obstructive lung disease. Chest1971;59 (Suppl) :15S.
    101. ↵
      Fallat R , Powell M, Kueppers F, et al. Chronic obstructive pulmonary disease with intermediate alpha-1-antitrypsin deficiency. Chest1971;59 (Suppl) :20S.
    102. Hepper NG, Black LF, Gleich GJ, et al. The prevalence of alpha 1-antitrypsin deficiency in selected groups of patients with chronic obstructive lung disease. Mayo Clin Proc1969;44:697–710.
      OpenUrlPubMedWeb of Science
    103. Lieberman J . Heterozygous and homozygous alpha-antitrypsin deficiency in patients with pulmonary emphysema. N Engl J Med1969;281:279–84.
    104. Lieberman J , Mittman C, Schneider AS. Screening for homozygous and heterozygous alpha 1-antitrypsin deficiency. Protein electrophoresis on cellulose acetate membranes. JAMA1969;210:2055–60.
      OpenUrlCrossRefPubMed
    105. Smith JP, Falk GA, Siskind GW. Serum immunoglobulins and alpha-1-antitrypsin: variation with clinical type of chronic obstructive pulmonary disease. Chest1971;59 (Suppl) :17S.
    106. ↵
      Sveger T . Plasma protease inhibitors in alpha 1-antitrypsin-deficient children. Pediatr Res1985;19:834–5.
      OpenUrlPubMedWeb of Science
    107. ↵
      Seersholm N , Wilcke JT, Kok-Jensen A, et al. Risk of hospital admission for obstructive pulmonary disease in alpha(1)-antitrypsin heterozygotes of phenotype PiMZ. Am J Respir Crit Care Med2000;161:81–4.
      OpenUrlPubMedWeb of Science
    108. ↵
      Silva GE, Sherrill DL, Guerra S, et al. A longitudinal study of alpha1-antitrypsin phenotypes and decline in FEV1 in a community population. Chest2003;123:1435–40.
      OpenUrlCrossRefPubMedWeb of Science
    109. ↵
      Dahl M , Nordestgaard BG, Lange P, et al. Molecular diagnosis of intermediate and severe alpha(1)-antitrypsin deficiency: MZ individuals with chronic obstructive pulmonary disease may have lower lung function than MM individuals. Clin Chem2001;47:56–62.
      OpenUrlAbstract/FREE Full Text
    110. Miller RD, Hepper NG, Kueppers F, et al. Host factors in chronic obstructive pulmonary disease in an upper Midwest rural community. Design, case selection, and clinical characteristics in a matched-pair study. Mayo Clin Proc1976;51:709–15.
      OpenUrlPubMedWeb of Science
    111. ↵
      Shigeoka JW, Hall WJ, Hyde RW, et al. The prevalence of alpha-antitrypsin heterozygotes (Pi MZ) in patients with obstructive pulmonary disease. Am Rev Respir Dis1976;114:1077–84.
      OpenUrlPubMedWeb of Science
    112. ↵
      Vance JC, Hall WJ, Schwartz RH, et al. Heterozygous alpha-1-antitrypsin deficiency and respiratory function in children. Pediatrics1977;60:263–72.
      OpenUrlAbstract/FREE Full Text
    113. ↵
      von Ehrenstein OS, von Mutius E, Maier E, et al. Lung function of school children with low levels of alpha-1-antitrypsin and tobacco smoke exposure. Eur Respir J2002;19:1099–106.
      OpenUrlAbstract/FREE Full Text
    114. ↵
      Silverman EK, Province MA, Rao DC, et al. A family study of the variability of pulmonary function in alpha 1-antitrypsin deficiency. Quantitative phenotypes. Am Rev Respir Dis1990;142:1015–21.
      OpenUrlPubMedWeb of Science
    115. ↵
      Duncan PE, Griffin JP. Physiological studies in a large sibship with antitrypsin deficiency. Br J Dis Chest1975;69:107–17.
      OpenUrlPubMedWeb of Science
    116. ↵
      Pritchard JK, Rosenberg NA. Use of unlinked genetic markers to detect population stratification in association studies. Am J Hum Genet1999;65:220–8.
      OpenUrlCrossRefPubMedWeb of Science
    117. ↵
      Glasziou P , Irwig L, Bain C, et al.How to review the evidence: systematic identification and review of the scientific literature. Canberra, Australia: National Health and Medical Research Council, 1999.
    118. ↵
      Silverman EK, Palmer LJ. Case-control association studies for the genetics of complex respiratory diseases. Am J Respir Cell Mol Biol2000;22:645–8.
      OpenUrlCrossRefPubMedWeb of Science
    119. ↵
      Silverman EK, Miletich JP, Pierce JA, et al. Alpha-1-antitrypsin deficiency. High prevalence in the St Louis area determined by direct population screening. Am Rev Respir Dis1989;140:961–6.
      OpenUrlCrossRefPubMedWeb of Science
    120. ↵
      Rothman KJ, Greenland S. Case-control studies. In: Rothman KJ, Greenland S, eds. Modern epidemiology. 2nd ed. Philadelphia: Lippincott Williams & Wilkins, 1998:93–114.
    121. ↵
      Novoradovsky A , Brantly ML, Waclawiw MA, et al. Endothelial nitric oxide synthase as a potential susceptibility gene in the pathogenesis of emphysema in alpha-1-antitrypsin deficiency. Am J Respir Cell Mol Biol1999;20:441–7.
      OpenUrlPubMedWeb of Science

    Footnotes

    • C P Hersh and M Dahl contributed equally to this report.

    • This study was supported by National Institutes of Health grants T32-HL07427 and R01-HL68926 and by grants from the Danish Lung Association and the Danish Heart Foundation.

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