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(Chest. 2003;123:1435-1440.)
© 2003 American College of Chest Physicians

A Longitudinal Study of {alpha}1-Antitrypsin Phenotypes and Decline in FEV1 in a Community Population*

Graciela E. Silva, MPH; Duane L. Sherrill, PhD; Stefano Guerra, MD, MPH{dagger} and Robert A. Barbee, MD, FCCP

* From the Arizona Respiratory Center, University of Arizona, College of Medicine, Tucson, AZ. {dagger} At the time of the study, Dr. Guerra was a fellow from the Institute of Respiratory Diseases, Istituto di Ricovero e Cura a Carattere Scientifico Policlinico Hospital, University of Milan, Milan, Italy.

Correspondence to: Duane L. Sherrill, PhD, Arizona Respiratory Center, University of Arizona, 1501 N Campbell Ave, PO Box 245073, Tucson, AZ 85724-5073; e-mail duane{at}resp-sci.arizona.edu


   Abstract
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 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Background: It is well-known that the homozygous deficiency of {alpha}1-antitrypsin, phenotype PiZZ, is associated with an increased risk of COPD. However, studies evaluating the association between the heterozygous forms of the {alpha}1-antitrypsin phenotype PiMZ and rapid decline in lung function, both in patient and community populations, have yielded conflicting results.

Study objective: To assess the relationship between {alpha}1-antitrypsin phenotypes and decline in FEV1 values of 2,016 adult subjects in a community population in Tucson, AZ.

Design and methods: Prospective cohort study. Standardized questionnaires and lung function measurements were administered 1.5 to 2 years apart during 12 surveys.

Results: The frequency distribution for PiMM, PiMS, and PiMZ phenotypes did not differ significantly by physician-confirmed diagnoses of emphysema, chronic bronchitis, or asthma. There was no statistically significant difference in mean FEV1 slope values between PiMM, PiMS, and PiMZ phenotypes (-22.5, -21, and -7 mL per year, respectively). After controlling for smoking and other potential confounders, the FEV1 slope was associated with an initial FEV1 level and age for the initial questionnaire but not with the different phenotypes. Selecting cutoff values, we identified rapidly declining and nondeclining subgroups, based on the percent predicted changes in FEV1. They also were not associated with {alpha}1-antitrypsin phenotypes.

Conclusions: We conclude that the data from this longitudinal community study suggest that having the PiMZ phenotype is not a significant risk factor for an accelerated decline in FEV1.

Key Words: {alpha}1-antitrypsin • asthma • chronic bronchitis • protease inhibitors • pulmonary emphysema • trypsin inhibitors


   Introduction
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 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
The main function of the proteinase inhibitor {alpha}1-antitrypsin is to inhibit the activity of elastase, which is generated by neutrophils in the lung. A deficiency of {alpha}1-antitrypsin results in accelerated elastin degradation, leading to a loss of ventilatory function and to the subsequent development of emphysema.1 The association of {alpha}1-antitrypsin deficiency and COPD has been studied for several decades. While there is no doubt that homozygosity for the {alpha}1-antitrypsin deficiency (PiZZ phenotype) is associated with an increased risk of developing COPD,2 controversy continues about whether heterozygosity (PiMZ phenotype) is also a COPD risk factor. Cross-sectional studies3 4 5 6 7 on patient populations and case control studies have produced results that support an increased risk of lower lung function for subjects with the PiMZ phenotype. However, community population studies have shown no such association.8 9 10 11 12 13 14 15 Similarly, longitudinal studies have produced conflicting results when comparing the rate of decline of lung function among subjects with PiMZ and PiMM phenotypes.16 17 18

Whether or not PiMZ is found to be a risk factor for the rapid decline of FEV1 or the development of COPD may be due in part to the differences in the types of populations studied. Studies that utilize patient populations or that include family members of PiZZ subjects may be selecting for additional predisposing genetic factors.5 6 19 A longitudinal study utilizing a community population would minimize possible selection bias and, with a long enough follow-up, would compensate for the low frequency of the disease.

In order to assess the relationship between {alpha}1-antitrypsin phenotypes and FEV1 slopes, we analyzed data from a longitudinal community study. To investigate the effect that utilizing data from different populations (ie, community vs patient populations) would have on this relationship, these results then were compared to those from the study by Sandford et al.20


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Details of the study design have been published previously.11 21 Briefly, the data are derived from the Tucson Epidemiologic Study of Airways Obstructive Diseases. The study included subjects who were selected from a random, stratified cluster sample of white, non-Mexican-American households in Tucson, AZ, in 1972. There were 12 follow-up surveys over a period of 20 to 22 years. Standardized questionnaires assessing respiratory symptoms and disease history, occupation, smoking history, and family health were completed by all subjects during each survey. Spirometric and flow-volume data were obtained during each survey with a pneumotachograph using American Thoracic Society criteria,22 with the exception of survey 4. Questionnaire data derived from survey 4 were included in the analyses. This includes smoking and medical history data. The total population sample consisted of 1,655 households containing > 3,500 subjects. {alpha}1-Antitrypsin phenotypes were determined in 2,949 subjects by discontinuous acid starch-gel electrophoresis followed by crossed immunoelectrophoresis in agarose gel (ie, the Fagerhol and Laurell method23 ). A diagnosis of chronic bronchitis, emphysema, or asthma was defined as having ever received a diagnosis of such disease by a physician. In the present analyses, we included 2,016 subjects who were >= 18 years of age at their initial survey and who had at least 5 years of follow-up to ensure sufficient lung function measurements to allow the accurate estimation of FEV1 slopes. The mean (± SD) number of years of follow-up for the population was 14.9 ± 4.4 years, the minimum was 5 years, and the maximum was 20 years. Of the 2,016 subjects in the study, 811 were current smokers, 113 were triers, 334 were ex-smokers, and 758 were never-smokers. Subjects were classified as current smokers if they reported smoking at least one cigarette per day. Triers were defined as subjects who smoked but did not meet this criterion. We dichotomized these categories into smokers and nonsmokers. Smokers were defined as ever-smokers, which included all current smokers, triers, and ex-smokers. The Tucson Epidemiologic Study of Airways Obstructive Diseases was approved by the institutional review board for human studies, and informed written consent was obtained from all subjects at the time of their enrollment into the study.

Data Analysis
The FEV1 slope was determined for each subject utilizing all their FEV1 measurements by fitting simple linear regression lines against age. There were 1,903 subjects who had sufficient numbers of FEV1 measurements and follow-up to estimate the FEV1 slope. The mean number of FEV1 measurements that was used to compute the slope was 6.4 ± 3.04, the minimum was 2, and the maximum number was 11. The percent predicted FEV1 decline per year also was determined for each subject.24 This continuous variable then was dichotomized into rapid decliners (ie, those persons with a decrease of >= 3% predicted FEV1 per year) and nondecliners (ie, those persons with an increase of >= 0.4% predicted FEV1 per year), which are similar to the groups reported by Sandford et al.20 The difference in proportions between each of the three phenotype frequencies was analyzed by the {chi}2 test with 2 degrees of freedom. Analyses of variance were used to compare differences in mean values. Multivariate linear regressions (for the continuous FEV1 slope variable) and logistic regressions (for the dichotomous FEV1 percent predicted slope variable) were fitted to evaluate changes in FEV1 slope and increases in risk in relation to the {alpha}1-antitrypsin phenotypes. Potential confounders like age at initial survey, sex, smoking, and initial FEV1 measurement (at survey 1) also were assessed in the regression models.

To analyze the potential effect that PiMZ may have on premature death, the ages at death of 645 subjects that occurred during the study period are also presented. All statistical tests were performed using statistical software (Intercooled Stata, version 7.0 for Windows; Stata Corp; College Station, TX) and a significance level of 0.05.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
The basic {alpha}1-antitrypsin phenotype distribution was similar to frequencies reported by other authors,10 14 18 and did not differ significantly by sex, smoking status, emphysema, chronic bronchitis, or asthma diagnoses. The frequency for PiMZ did not differ significantly between rapid-decliners and nondecliners (Table 1 ). Means for FEV1 slope, initial FEV1 measurements, age at initial survey, and number of years of follow-up were not significantly different among the different phenotypes (Table 2 ). The overall mean age at death was 78 years (minimum age at death, 26 years; maximum age at death, 104 years). The age at death was not associated with either emphysema or asthma diagnoses, but it was significantly reduced for subjects with chronic bronchitis diagnosis (76.5 years [213 subjects] vs 78.7 years [431 subjects]; p = 0.03). The mean age at death, however, did not differ for the different phenotypes. Medians and data distributions for FEV1 slopes were similar for the different phenotypes (Fig 1 ).


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  		Table 1.. Frequency of {alpha}1-Antitrypsin Phenotypes in the Study Population

 

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  		Table 2.. Mean Distribution by {alpha}1-Antitrypsin Phenotypes for the Different Covariates*

 


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  		Figure 1.. FEV1 slope medians by {alpha}1-antitrypsin phenotypes. The lines in the middle of each box represent the median values for the FEV1 slopes. The boxes show similar medians (median for MM, -19.2 mL per year; median for MS, -16.6 mL per year; median for MZ, -15.5 mL per year; and median for the total population, -19.0 mL per year). The boxes extend from the 25th to the 75th percentiles of the data. Outliers are represented by circles and are shown outside the whisker lines.

 
The unadjusted FEV1 slope was greater for men than for women (-0.030 vs -0.010, respectively; p < 0.001), although once adjusted for all other factors included in the models this association was no longer significant. Although emphysema and chronic bronchitis diagnoses were associated with an increased FEV1 slope (p < 0.001 for both), they were not associated with {alpha}1-antitrypsin phenotypes (data not shown). There was no association between asthma diagnoses and an increase in FEV1 slope or with the different {alpha}1-antitrypsin phenotypes. None of these associations changed when analyzed separately for smokers and nonsmokers.

We used multivariate analyses to test whether differences in mean FEV1 slopes between phenotypes were being confounded. Only the initial FEV1 measurement and age at the initial survey were statistically associated with an increase in FEV1 slope after adjusting for sex and smoking status (Table 3 ). The different {alpha}1-antitrypsin phenotypes showed no association with an increase in FEV1 slope. We found no association between decliner categories and the different {alpha}1-antitrypsin phenotypes using logistic regression (Table 4 ). Only the initial FEV1 measurement and age at the initial survey were significantly associated with rapid decliners. There was no confounding seen by any of the variables. Variables, although not significant, were kept in the models in accordance with previously published studies. None of these associations changed when we looked only at subjects who smoked or when we looked at those subjects who had >= 20 pack-years of smoking (ie, were considered to be heavy smokers).


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  		Table 3.. Multiple Linear Regression Model of Predicted Change in FEV1 Slope by {alpha}1-Antitrypsin Phenotypes and Other Predictive Variables*

 

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  		Table 4.. Multiple Logistic Regression Model Predicting Decliner Status by {alpha}1-Antitrypsin Phenotypes and Other Independent Variables*

 

   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Sandford et al20 analyzed the association between the increased risk of rapid decline in lung function and having the PiMZ phenotype. The odds ratio (OR) was 2.8 comparing 283 rapid decliners (mean {Delta}FEV1, -154 ± 3 mL per year) to 308 nondecliners (mean {Delta}FEV1, +15 ± 2 mL per year). This association was stronger when family history of COPD was taken into account (OR, 9.7). Potential confounders like age, sex, and initial level of lung function were adjusted for in a logistic regression. Study subjects, all of whom were smokers who had spirometric signs of early COPD, were observed for 5 years. The authors concluded that the PiMZ phenotype was associated with an increased rate of decline of lung function and that this association was stronger when in addition the subjects had a family history of COPD.

We could not, however, establish an association between {alpha}1-antitrypsin phenotypes PiMZ or PiMS and an increase in FEV1 slope. Nor did we see any relationship when we utilized the dichotomized form of the FEV1 percent predicted into rapid decliners and nondecliners, as reported by Sandford et al.20 These associations did not change significantly when we analyzed the data only for those subjects who smoked, as was done in the study by Sandford et al,20 or when we looked at those subjects who had >= 20 pack-years of smoking.

Analyses also showed no association of {alpha}1-antitrypsin phenotypes with chronic bronchitis, emphysema, or asthma. {alpha}1-Antitrypsin phenotype frequencies remained consistent for the general population when analyzed separately by sex and for smoking status. The frequency distribution though, differed from that reported by Sandford et al20 for rapid decliners and nondecliners, where the frequency of the PiMZ phenotype for rapid decliners was 6% in the Sandford et al20 study vs 1.12% in our study. The fact that age at death did not differ significantly by {alpha}1-antitrypsin phenotype suggests that there is no survivor effect.

Previous analyses on this study population have been published by Morse et al11 as a cross-sectional study. Morse et al11 found no associations among the different {alpha}1-antitrypsin phenotypes (ie, PiM, PiMS, and PiMZ), and 20 different respiratory symptoms and diagnoses. These included chronic productive cough, attacks of dyspnea with wheezing, emphysema, chronic bronchitis, and asthma. No association was found among the different phenotypes of the 2,944 subjects and their initial FEV1, FVC, FEV1/FVC ratio, and forced expiratory flow at 75% of vital capacity, even after adjusting for age, sex, and smoking. Data that were analyzed as the percentage of subjects who had spirometric measurement values falling to < 95% of normal predicted values, showed no distinction among the different phenotypes. Further studies by Lebowitz et al12 showed no association between single-breath nitrogen and the different {alpha}1-antitrypsin phenotypes among 819 selected subjects who were 25 to 54 years of age.

Other longitudinal studies16 17 18 with varying results have observed patients for 3 to 6 years. Considering the low frequency of disease and the need to detect a significant difference in pulmonary function, it may be argued that a longer follow-up period may be needed. In the present study, with up to 22 years of follow-up we continue to find no association. It can be argued as well that studies that have utilized COPD patient populations have inadvertently introduced other hereditary risk factors into their studies. Sandford et al20 reported a higher association when family history of COPD was taken into account. In our study, we did not control for this variable.

One possible explanation for the differences between our findings and those of Sandford et al20 could be related to sampling. In the Lung Health Study (LHS) all subjects who were recruited were current smokers aged 35 to 60 years, who had spirometric signs of early COPD. In contrast, participants in the Tucson Epidemiologic Study were selected as a random stratified sample of households in the Tucson area, with no selection criteria based on smoking or levels of pulmonary function. These differences in selection criteria might suggest that participants in our study would have better lung function and fewer respiratory conditions than those in the LHS, leading to a possible explanation of the observed differences in the phenotype frequencies. However, using the same cutoff values that were proposed by Sandford et al20 (ie, a decrease of >= 3% predicted FEV1 for rapid decliners and an increase of >= 0.4% predicted FEV1 for nondecliners), our rapidly declining subjects had steeper rates of decline than those in the LHS (decline, 222 vs 154 mL per year, respectively). In order to determine whether extreme values had an effect on these results, we reevaluated the data. Repeated analyses excluding 23 extreme values (ie, those with > 3 SDs) yielded a slope of -155 mL per year for rapid decliners but did not make an appreciable difference in any other result. The use of more conventionally defined cutoff values, such as the 25th and 75th quartiles of the FEV1 percent predicted, also resulted in no differences in the phenotypic distribution for rapid decliners and nondecliners.

In addition, because our sample included members from the same family, which made their observations dependent or correlated, our estimated phenotype frequencies may not be representative of the general population. Phenotypic frequencies are generally based on random population samples in which the likelihood of having members from the same family would be extremely low.

In conclusion, the results from our study show no association between rapid decline in FEV1 and the PiMZ phenotype.


   Footnotes
 
Abbreviations: LHS = Lung Health Study; OR = odds ratio

This research was supported in part by National Institutes of Health fellowship grant No. HL10506–02 (to GES).

Received for publication June 18, 2002. Accepted for publication October 30, 2002.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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