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(Chest. 2002;121:1S-6S.)
© 2002 American College of Chest Physicians

Genetic Epidemiology of COPD*

Edwin K. Silverman, MD, PhD

* From the Channing Laboratory and Pulmonary and Critical Care Division, Department of Medicine, Brigham and Women’s Hospital, Boston, MA.

Correspondence to: Edwin K. Silverman, MD, Channing Laboratory, Pulmonary and Critical Care Division, Department of Medicine, Brigham and Women’s Hospital, 181 Longwood Ave, Boston, MA 02115; e-mail: ed.silverman{at}channing.harvard.edu

Although cigarette smoking is the major environmental risk factor for the development of COPD, there is marked variability in the development of airflow obstruction in response to smoking. A dose-response relationship between FEV1 % predicted and the number of pack-years of cigarette smoking was demonstrated by Burrows and colleagues.1 Heavier smokers were more likely to develop airflow obstruction, which is indicated by reduced FEV1 levels. However, many smokers had pulmonary function values within the normal range. Although the number of pack-years was the smoking-related variable that correlated most closely with FEV1 in the study by Burrows et al,1 it only accounted for 15% of the variability in FEV1. Mounting evidence suggests that genetic factors likely influence the variable susceptibility to develop COPD. We will briefly review {alpha}1-antitrypsin (AAT) deficiency, discuss the case-control genetic association studies that have been performed in patients with COPD, and describe our ongoing research into the genetic determinants of severe, early-onset COPD.


   AAT
TOP
 AAT
Case-Control Association Studies...
 Risk to Relatives for...
 Linkage Analysis of COPD:...
 Conclusion
 References
 
The frequent development of COPD in individuals with severe AAT deficiency (eg, PI Z individuals), which is a proven genetic risk factor for COPD, has provided a foundation for the protease-antiprotease hypothesis for the pathogenesis of emphysema.2 Although only a small percentage of COPD patients (estimated at 1 to 2%) inherit severe AAT deficiency,3 AAT deficiency can serve as a model of the manner in which genetic and environmental factors may interact to lead to COPD.

AAT, specified by the protease inhibitor (PI) locus, is the major plasma protease inhibitor of leukocyte elastase, a serine protease that has been hypothesized to play a role in the development of emphysema.4 The PI locus is polymorphic. In white populations, the most common alleles are: M, which accounts for 95% of the alleles and is associated with normal AAT levels; S, which accounts for 2 to 3% of the alleles and is associated with mildly reduced AAT levels; and Z, which accounts for 1% of the alleles and is associated with severely reduced AAT levels. PI type is typically determined by the isoelectric focusing of serum, which reflects the genotype at the PI locus for these common alleles.

A small percentage of subjects inherit null alleles at the PI locus, which lead to the absence of any AAT production through a heterogeneous collection of mutations.5 Individuals with two Z alleles or one Z and one null allele (referred to as PI Z) have approximately 15% of the normal plasma AAT levels, because the Z protein polymerizes and aggregates within the endoplasmic reticulum of hepatocytes.6 PI Z subjects who smoke cigarettes tend to develop more severe pulmonary impairment at an earlier age than do nonsmoking PI Z individuals.7 8 9

However, the development of COPD in PI Z subjects is not absolute. In a study performed at Washington University in St. Louis (The St. Louis AAT Study10 ), we assembled 52 PI Z subjects. Significant variability in pulmonary function was found among PI Z subjects, which related to the method of ascertainment. Index PI Z subjects, who were tested for AAT deficiency because they had COPD and were the first PI Z identified in their family, all had significantly reduced FEV1 values. Nonindex PI Z subjects—who were ascertained by a variety of other means, including family studies, population screening, and the presence of liver disease—suggested a much different natural history for severe AAT deficiency than did index PI Z subjects. Many nonindex PI Z subjects had pulmonary function values within the normal range. Part of the variability in pulmonary function among PI Z individuals is explained by cigarette smoking, however, some smokers maintain normal FEV1 values at least into middle age when some nonsmokers already have developed significant airflow obstruction.10 Additional genetic determinants, which have not yet been identified, likely influence the variable development of airflow obstruction in PI Z individuals.11


   Case-Control Association Studies in COPD
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 AAT
 Case-Control Association Studies...
Risk to Relatives for...
 Linkage Analysis of COPD:...
 Conclusion
 References
 
A variety of association studies have compared the distribution of variants in candidate genes that were hypothesized to be involved in the development of COPD in patients and control subjects. A partial list of loci that have been associated with COPD is presented in Table 1 . A representative study supporting the association is shown for polymorphic variants located in the vitamin D-binding protein gene, the cystic fibrosis transmembrane regulator gene, the ABO blood group, {alpha}1-antichymotrypsin, microsomal epoxide hydrolase, tumor necrosis factor-{alpha}, and beyond the 3' end of the AAT gene.12 13 14 15 16 17 18 In some cases, more than one study exists to support an association, however, for each of these candidate loci, at least one study refutes the association.19 20 21 22 23 24


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  		Table 1.. Case-Control Association Studies in COPD—Conflicting Evidence*

 
Several factors could contribute to the inconsistent results of case-control genetic association studies in patients with COPD. Genetic heterogeneity between study populations could contribute to the difficulty in replicating associations between studies. Of course, as in any study design, false-positive or false-negative results could contribute to inconsistent replication. A potentially important factor is that case-control association studies are susceptible to supporting associations based purely on population stratification. Population stratification can result from incomplete matching between cases and control subjects, including differences in ethnicity. No association studies in COPD have been reported that used family-based methods, a study design that is not susceptible to such population stratification effects. There also have been a variety of study design and analytic problems with the reported case-control association studies in COPD, including a failure to correct for the multiple comparisons involved in testing multiple genetic loci with multiple phenotypes, control groups that are selected based on convenience rather than on careful matching, and small sample sizes such that the reclassification of a few individuals would lead to a loss of statistical significance.25 In summary, a variety of candidate genes have been examined with case-control genetic association studies in patients with COPD, but none of these candidate loci have been proven as risk factors for COPD.


   Risk to Relatives for COPD
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 AAT
 Case-Control Association Studies...
 Risk to Relatives for...
Linkage Analysis of COPD:...
 Conclusion
 References
 
Several studies of pulmonary function measurements performed in the general population and in twins have suggested that genetic factors influence variation in pulmonary function.26 Studies in relatives of COPD patients also have supported a role for genetic factors. Several studies in the 1970s12 27 28 29 reported higher rates of airflow obstruction in first-degree relatives of COPD patients than in control subjects.

In an effort to identify novel genetic risk factors for COPD, our research group has focused on families of subjects with severe, early-onset COPD. Probands in this Boston Early-Onset COPD Study30 had FEV1 values < 40% of predicted at ages < 53 years without severe AAT deficiency. Probands were recruited from Lung Transplant and Lung Volume Reduction Surgery Program referrals and from pulmonary clinics. All available first-degree relatives and spouses were invited to participate. All available older second-degree relatives (ie, aunts, uncles, and grandparents) also were included.

Although no significant differences in age or number of pack-years of smoking were noted, highly significant differences in FEV1 and FEV1/FVC ratio were found when smoking first-degree relatives of early-onset COPD probands were compared to smoking control subjects. The distribution of FEV1 values in first-degree relatives who smoked and control subjects who smoked is shown in Figure 1 . No significant differences in FEV1 or FEV1/FVC ratio were found when lifelong nonsmoking first-degree relatives of early COPD probands were compared to lifelong nonsmoking control subjects. This pattern would be consistent with genetic risk factors that interact with smoking to result in COPD.



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  		Figure 1.. FEV1 % predicted in currently smoking or ex-smoking first-degree relatives of early-onset COPD probands and currently smoking or ex-smoking control subjects from the Boston Early-Onset COPD Study. Solid bars correspond to first-degree relatives of early-onset COPD probands, and open bars correspond to control subjects. Although 7% of first-degree relatives had FEV1 values < 40% of predicted, this degree of severe impairment was not observed in the control group. From Silverman et al.30

 
To account for potential familial correlations and for the effects of age and number of pack-years of smoking, generalized estimating equations were used to calculate the odds ratios of developing chronic bronchitis and various levels of reduction in FEV1.30 When all first-degree relatives of early-onset COPD probands were compared to all control subjects, an increased risk of FEV1 < 80% of predicted was seen. However, stratification by smoking status revealed that this risk was exclusively found in first-degree relatives who smoked, with significant odds ratios of 4.5 for FEV1 values < 80% of predicted, 3.6 for chronic bronchitis, and a nearly significant odds ratio of 3.5 for FEV1 values < 60% of predicted. Lifelong nonsmoking first-degree relatives had no increased risk for reduced FEV1 or chronic bronchitis. A similar pattern of smoking-related susceptibility also was seen for bronchodilator responsiveness to albuterol therapy.31 Thus, we have identified a variety of phenotypes that demonstrate smoking-related susceptibility in first-degree relatives of early-onset COPD probands, including FEV1, FEV1/FVC ratio, bronchodilator responsiveness, and chronic bronchitis. We are focusing on these phenotypes in linkage analysis of early-onset COPD.

We were surprised to find such a high percentage of women (80%) among our early-onset COPD probands. This female predominance differs from the values of previous studies32 33 34 35 of patients with severe COPD, which typically have found a male predominance. Because a female predominance was noted among early-onset COPD probands, we examined the first-degree relatives of early COPD probands for gender effects as well.36 To adjust for the effects of age and smoking, as well as for common familial correlations, generalized estimating equations were used to compare male and female first-degree relatives for various levels of reduction in FEV1, chronic bronchitis, and bronchodilator responsiveness. Among all first-degree relatives, greater bronchodilator responsiveness and fewer cases of chronic bronchitis were noted among women, but no significant differences in FEV1 were found. Among first-degree relatives who smoked, women had an increased risk of reduced FEV1 below the thresholds of 80% and 40% of predicted, as well as increased risk of bronchodilator responsiveness. Similar patterns emerged when the analysis was limited to siblings. Female siblings who smoked had a significantly increased risk of increased bronchodilator responsiveness and of severely reduced FEV1 values (< 40% of predicted). The etiology of the observed female predominance is uncertain, however, it is certainly possible that there is a biological basis for the increased female susceptibility, due to hormonal or other factors, that could mediate a genotype-by-gender interaction in early-onset COPD pedigrees.


   Linkage Analysis of COPD: AAT Deficiency as a Model
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 AAT
 Case-Control Association Studies...
 Risk to Relatives for...
 Linkage Analysis of COPD:...
Conclusion
 References
 
Our goal is to use the early-onset COPD pedigrees that we have collected to perform linkage analysis. To gain insight into the optimal phenotypes and methods to use for linkage analysis in early-onset COPD pedigrees without severe AAT deficiency, we thought it would be instructive to examine the results of a linkage analysis in AAT-deficient pedigrees using PI type as a genetic marker rather than as a disease gene.37 Thirty-five years of experience confirms that the PI Z type exerts a significant genetic influence on AAT level and pulmonary function, but can linkage analysis detect this? And which methods and phenotypes are optimal?

We used 155 individuals from the St. Louis AAT study that we described earlier. We used the PI type as a polymorphic marker, rather than the disease gene, in linkage analysis to see which phenotypes and methods gave the strongest evidence for linkage. We used FEV1 % predicted and AAT serum level as phenotypes with a parametric linkage approach to both qualitative and quantitative phenotypes in the LINKAGE program, a nonparametric linkage approach to qualitative phenotypes in the GENEHUNTER program, a nonparametric approach to quantitative phenotypes using generalized estimating equations in the RELPAL program, and a semiparametric variance-components approach to quantitative phenotypes in the SOLAR program.38 39 40 41

Quantitative linkage analysis results with FEV1 % predicted and AAT serum level are shown in Table 2 . Multiple regression analysis revealed that the number of pack-years of smoking was the strongest predictor of FEV1. To determine the optimal approach to adjust for smoking effects, we compared the evidence for linkage in various models including the following: (1) all subjects and no adjustment for smoking; (2) all subjects with pack-years incorporated as a covariate in the linkage analysis model; (3) all subjects with preadjustment for pack-years of smoking by regression analysis; and (4) smokers only with pack-years as a covariate in the model. The significance values in linkage analysis are much more stringent than in standard statistical tests to adjust for the multiple comparisons throughout the genome. At a genome-wide level, the criteria of Lander and Kruglyak42 in pedigree-based linkage analysis are p values < 2 x 10-3 to indicate suggestive linkage, and p values < 5 x 10-5 to indicate significant linkage. For an assessment of linkage with a candidate locus (PI), we have chosen p values < 0.01 as being significant.


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  		Table 2.. p Values From Linkage Analysis of PI Type to Quantitative Phenotypes in St. Louis AAT Study Families*

 
For AAT level, SOLAR found evidence for significant linkage with all groups. p Values were not as impressive for RELPAL, but significant evidence for linkage was still found. With FEV1 % predicted as a quantitative phenotype, RELPAL and LINKAGE showed no evidence for linkage, and there was only a very weak linkage signal with SOLAR using smokers only.

We have also investigated qualitative phenotypes in linkage analysis within the AAT-deficient families using a nonparametric, affected-relative approach in the GENEHUNTER program and a parametric approach with one dominant and one recessive genetic model in the LINKAGE program (Table 3 ). We used two thresholds to define affection status, moderate airflow obstruction (ie, FEV1 < 60% of predicted with FEV1/FVC ratio of < 90% of predicted) and mild airflow obstruction (ie, FEV1 < 80% of predicted with FEV1/FVC < 90% of predicted). Significant evidence for linkage to qualitative phenotypes was found, with much more impressive p values than were noted with the quantitative spirometric phenotypes. In the parametric analysis, p values were lower for the recessive than for the dominant models, corresponding to the recessive mode of inheritance of AAT deficiency on pulmonary function. With the parametric linkage approach, limiting the population to affected subjects only or to smokers only gave improved evidence for linkage compared to all subjects, suggesting that an adjustment for smoking status was important. With GENEHUNTER, which only uses phenotypic information from affected individuals, the results for all subjects and affected subjects only were therefore identical. Limiting the analysis to smokers only did not improve the evidence for linkage. The mild airflow obstruction phenotype showed slightly better evidence for linkage than did the more stringent phenotype of moderate airflow obstruction.


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  		Table 3.. p Values From Linkage of PI Type to Qualitative Airflow Obstruction Phenotypes in St. Louis AAT Study Families*

 
Although PI M and PI MZ subjects had a relatively normal distribution of FEV1 values, the distribution of PI Z subjects was markedly non-normal. This non-normality, which violates the assumptions of the variance-component methods for quantitative traits, may contribute to the improved power to detect linkage for qualitative traits rather than for quantitative traits.

Although these AAT linkage results may not apply to patients with other forms of COPD, our results suggest that, in this case at least, quantitative phenotypes are not necessarily more powerful than qualitative phenotypes. Even with a well-defined major gene effect like PI, the detection of linkage to disease-related phenotypes like FEV1 may be difficult. Our results suggest that an adjustment for smoking effects is important, but the optimal manner to adjust for smoking may depend on the method used. Using the AAT linkage results as a guide, we are in the process of performing a linkage analysis of a 10-cM genome scan with short tandem repeat markers performed by the National Heart, Lung, and Blood Institute Mammalian Genotyping Service in 585 individuals from 72 pedigrees from the Boston Early-Onset COPD Study.


   Conclusion
TOP
 AAT
 Case-Control Association Studies...
 Risk to Relatives for...
 Linkage Analysis of COPD:...
 Conclusion
References
 
Severe AAT deficiency is a proven genetic risk factor for COPD. However, the development of COPD in PI Z subjects is variable, and genetic modifiers likely contribute to this variability. Case-control genetic association studies have examined multiple candidate gene variants as potential contributors to the development of COPD, but the results have not been consistent across studies. Finally, linkage analysis and family-based association studies have the potential to be valuable tools in the identification of novel genetic risk factors for COPD.


   Footnotes
 
Abbreviations: AAT = {alpha}1-antitrypsin; PI = protease inhibitor

This work was supported by grant R01 HL61575 from the National Institutes of Health.


   References
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 AAT
 Case-Control Association Studies...
 Risk to Relatives for...
 Linkage Analysis of COPD:...
 Conclusion
 References
 

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