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(Chest. 2001;119:762-767.)
© 2001 American College of Chest Physicians

Frequency of Cystic Fibrosis Transmembrane Conductance Regulator Gene Mutations and 5T Allele in Patients With Allergic Bronchopulmonary Aspergillosis*

Eric Marchand, MD; Christine Verellen-Dumoulin, PhD; Michel Mairesse, MD; Luc Delaunois, PhD, FCCP; Pierre Brancaleone, MD; Jean-François Rahier, BSc and Olivier Vandenplas, PhD

* From the Service de Pneumologie (Drs. Marchand, Delaunois, Brancaleone, and Vandenplas), Cliniques Universitaires de Mont-Godinne, Université Catholique de Louvain, Yvoir; Service de Pneumologie (Dr. Mairesse), Clinique Saint-Luc, Bouge; and Centre de Génétique Humaine et Unité de Génétique Médicale (Dr. Verellen-Dumoulin and Mr. Rahier), Université Catholique de Louvain, Brussels, Belgium.

Correspondence to: Eric Marchand, MD, Service de Pneumologie, Cliniques Universitaires de Mont-Godinne, 5530-Yvoir, Belgium; e-mail: eric.marchand{at}pneu.ucl.ac.be


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Study objective: To assess the frequency of cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in patients with allergic bronchopulmonary aspergillosis (ABPA).

Design: Case-control study. All subjects in the study were screened for the presence of 13 mutations in the CFTR gene (R117H, 621 + 1G->T, R334 W, {Delta}F508, {Delta}I507, 1717–1G->A, G542X, R553X, G551D, R1162X, 3849 + 10kbC->T, W1282X, and N1303K). Moreover, they were also screened for the presence of the 5T variant in intron 8.

Setting: University hospital and community-based hospital.

Patients: Twenty-one white patients with ABPA participated in the study. The presence of CFTR mutations was also investigated in 43 white subjects with allergic asthma who did not show sensitization to Aspergillus fumigatus and in 142 subjects seeking genetic counseling for diseases other than cystic fibrosis (CF).

Results: Six patients with ABPA were found to be heterozygous for one CFTR mutation, including {Delta}F508 (n = 2), G542X (n = 1), R1162X (n = 1), 1717–1G->A (n = 1), and R117H (n = 1). The 5T allele was not detected in ABPA patients. None of the ABPA patients showed sweat chloride concentrations > 60 mEq/L. The frequency of CFTR mutation carriers was significantly higher in ABPA patients (6 of 21 patients; 28.5%) than in control asthmatic subjects (2 of 43 subjects; 4.6%; p = 0.01) and in subjects seeking genetic counseling (6 of 142 subjects; p < 0.001).

Conclusion: These findings indicate that in patients without a clinical diagnosis of CF, CFTR gene mutations could be involved in the development of ABPA, in association with other genetic or environmental factors.

Key Words: allergic bronchopulmonary aspergillosis • cystic fibrosis • cystic fibrosis transmembrane conductance regulator gene.


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Allergic bronchopulmonary aspergillosis (ABPA) is an inflammatory disorder of the airways related to the production of specific IgE and IgG directed against Aspergillus fumigatus.1 2 This disease is characterized by recurrent episodes of eosinophilic inflammation of the airways associated with peripheral blood eosinophilia, high levels of total IgE, asthma, mucoid impactions of proximal bronchi, and pulmonary infiltrates. The airway inflammatory process may have a progressive course leading to the development of chronic obstructive lung disease and bronchiectasis of proximal distribution.

The pathophysiology of ABPA remains largely speculative. Familial occurrence of ABPA has been reported, suggesting a possible genetic contribution to the disease.3 4 This possibility is further suggested by the development of ABPA-like features in a substantial proportion of patients with cystic fibrosis (CF).5 6 7 8 9 10 CF is an autosomal recessive hereditary disorder caused by mutations of the CF transmembrane conductance regulator (CFTR) gene, which encodes for a cyclic-adenosine monophosphate–regulated chloride channel in epithelial cells.11 CF is characterized by chronic airway disease with proximal bronchiectasis, pancreatic exocrine insufficiency, male infertility, and elevated concentrations of electrolytes in sweat. Clinical ABPA has been documented in 2 to 11% of patients with CF, although immunologic sensitization to A fumigatus may occur with a much higher frequency.5 6 7 8 9 10 The possibility that CFTR could play a role in the pathogenesis of ABPA is also supported by the finding12 of a high frequency of the {Delta}F508 mutation in ABPA patients with bronchiectasis. The aim of this study was to assess the frequency of CFTR mutations in a case series of patients with ABPA, as compared with a control group of subjects with allergic asthma whodid not show evidence of immunologic sensitization toA fumigatus.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Subjects
Subjects included all patients identified as having ABPA (both with signs of disease activity and in remission) in the diagnostic registries of the chest medicine departments of one university hospital (Cliniques Universitaires de Mont-Godinne) and one community-based hospital (Cliniques St Luc, Bouge), both located in nearby Namur. The first institution cares for patients from all Wallonia (the French-speaking part of Belgium), while the latter mostly recruits in the Namur province. The diagnosis of ABPA was based on the presence of at least seven of the following eight criteria adapted from Greenberger2 : (1) asthma (documented by a 15% reversibility in FEV1 in response to inhaled bronchodilator); (2) transient pulmonary infiltrates or atelectasis; (3) peripheral blood eosinophilia (absolute eosinophil count > 500/µL); (4) immediate skin-prick test reactivity toA fumigatus extract (wheal diameter > 3 mm as compared with negative control); (5) specific IgE to A fumigatus > 0.35 IU/mL by radioallergosorbent test (Phadebas Radioallergosorbent Testing or CAP; Pharmacia; Uppsala, Sweden); (6) increased total IgE level (> 450 IU/mL); (7) presence of precipitating antibodies to A fumigatus determined using agar gel double-diffusion technique; and (8) proximal bronchiectasis. The presence of bronchiectasis was ascertained by high-resolution CT. Bronchiectasis was deemed to be present if the bronchial diameter was greater than that of the accompanying artery and the bronchial wall was thickened as compared with uninvolved areas.13 14 Atopy was defined by the presence of a positive skin-prick test to at least one common allergen other than molds. Patients with ABPA were requested to perform a sweat test using the pilocarpine iontophoresis method.15 Chloride concentrations < 40 mEq/L were considered to be in the normal range, and values between 40 mEq/L and 60 mEq/L were in the intermediate range.16

The frequency of CFTR mutations in ABPA patients was compared with the frequency found in 43 white individuals with allergic asthma. These were unrelated consecutive patients with allergic asthma seen by one of the authors (O.V.) at the Cliniques Universitaires de Mont-Godinne. Accordingly, they were not recruited from a registry. The absence of ABPA was based on normal chest radiographic findings and the lack of specific IgE and precipitins directed against A fumigatus. CFTR mutations were also analyzed in 142 unrelated subjects seeking genetic counseling at the Centre de Génétique Humaine (which is part of the Cliniques Universitaires St Luc in Brussels) for reasons other than CF in order to obtain an estimate of the frequency of CFTR mutations in the general Belgian population (control subjects). This center recruits in the all French-speaking Belgian population. It is located 50 kilometers from Namur.

Patients and control subjects were informed of the purpose and procedures of the study, and each signed a statement of informed consent. The study protocol and consent form were approved by the Ethics Committee of the Cliniques Universitaires de Mont-Godinne.

Mutation Analysis
DNA was isolated from peripheral blood lymphocytes using the NaCl extraction method and conventional techniques. Mutations and polymorphism analysis were obtained from different polymerase chain reaction amplifications. Genomic DNA samples were screened for the following CFTR mutations: R117H/exon 4, 621 + 1G->T/intron 4, R334 W/exon 7, {Delta}F508/exon 10, {Delta}I507/exon 10, 1717–1G->A/intron 10, G542X/exon 11, R553X/exon 11, G551D/exon 11, R1162X/exon 19, 3849 + 10kbC->T/intron 19, W1282X/exon 20, and N1303K/exon 21. The studied mutations accounted for approximately 85% of alleles causing CF in the Belgian population.17 18 The {Delta}I507 mutation was detected by the formation of heteroduplex following electrophoresis on acrylamide gel (8%). The 12 other mutations were identified using the Elucigene CF 12 mutations kit (Astra Zeneca Diagnostics; London, UK) based on the Amplification Refractory Mutation System (Astra Zeneca Diagnostics) technology. The length of the intron 8 polythymidine tract was investigated with the nested-polymerase chain reaction method followed by electrophoresis. The stretch was characterized using the Gene Scan 672 software of a 373A Sequencer Perkin-Elmer/Applied Biosystem (Perkin-Elmer; Norwalk, CT).

Statistics
Proportions were compared using two-tailed Fisher’s Exact Test or {chi}2 test. The former was calculated as the sum of the probability of obtaining the observed contingency table plus the probabilities of obtaining all other hypothetical tables (constructed without changing the row or column totals) that were even less likely.19 The 95% confidence intervals (CIs) of the differences of proportions and odds ratios were calculated using usual methods.20 A p < 0.05 was considered significant.

As others,21 22 23 we choose to analyze CFTR mutations and variants of the intron 8 polythymidine tract separately. Indeed, a linkage disequilibrium has been described between some CFTR mutations (as {Delta}F508) and the intron 8 polythymidine tract alleles.23 Moreover, in opposition to CFTR mutations, the 5T allele in intron 8 alone has never been shown to be associated with various pathologic conditions, such as atypical sinopulmonary disease,22 23 or congenital bilateral absence of vas deferens.21 The presence of the 5T allele in intron 8 rather potentates the effects of CFTR mutations in these conditions. Accordingly, we think that CFTR mutations and intron 8 polythymidine tract alleles deserve a separate analysis, both from a statistical and from a physiologic point of view.

Despite a small number of patients with ABPA, the power of the study was accurate (> 80%) to detect differences between the groups when hypothesizing a 30% prevalence of CFTR mutations in ABPA patients and a normal prevalence (4%) in allergic asthmatics. When hypothesizing (1) a fourfold increase in the prevalence of the 5T allele in ABPA as compared to control subjects (prevalence, 5%),21 and (2) a normal prevalence of 5T allele in allergic asthmatics, the power of the study to detect a difference between patients with ABPA and allergic asthmatics was 43%. The power was 53% when comparing the frequency of the 5T allele in ABPA patients and control subjects.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Of the 28 patients with a diagnosis of ABPA and who were alive at the time of the study, 1 patient did not agree to participate in the study and 6 patients (2 patients from the community-based hospital) were excluded because they did not meet the above-detailed diagnostic criteria for ABPA. From the remaining 21 patients, 4 patients came from the community-based hospital (patients 5, 16, 17, 18; Table 1 ). The characteristics of the 21 patients with ABPA are presented in Table 1 . Six patients (patients 1 to 6) were identified to carry one CFTR mutation, including {Delta}F508 (n = 2), G542X (n = 1), R1162X (n = 1), 1717–1G->A (n = 1), and R117H (n = 1). The 5T intron 8 variant was not detected in ABPA patients. One patient (patient 12) declined sweat testing. None of the ABPA patients demonstrated a sweat chloride level > 60 mEq/L, while two patients (patients 5 and 13) showed a sweat chloride concentration in the intermediate range (54 mEq/L and 40 mEq/L, respectively; Table 2 ). There was no significant difference between ABPA patients with CFTR mutation and those without, regarding sex, atopy, smoking habits, age at the time of ABPA diagnosis, and presence of A fumigatus in sputum. The frequency of documented Pseudomonas aeruginosa infection was not different in patients with a CFTR mutation (1 of 6 patients) from that found in those who showed no CFTR mutation (2 of 12 patients).


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  		Table 1. Clinical Features of Patients With ABPA*

 

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  		Table 2. CF-Related Features of Patients With ABPA*

 
Among the 43 control asthmatics without sensitization to A fumigatus, 2 asthmatics (4.6%) were identified as being heterozygous for one CFTR mutation, including {Delta}F508 and 1717–1G->A. In the group of control subjects, 6 of 142 subjects (4.2%) were found to be heterozygous for a CFTR mutation and 7 other subjects (4.9%) were heterozygous for the 5T allele. The proportion of CFTR mutation carriers in ABPA patients (6 of 21 patients; 28.5%) was significantly higher than that found in control asthmatics (2 of 43 asthmatics; 4.6%; p = 0.01, Fisher’s Exact Test; 95% CI for difference in proportions, 3.6 to 44.2%) and in the control subjects (6 of 142 subjects; 4.2%; p < 0.001, {chi}2 test; 95% CI for difference in proportions, 4.7 to 43.9%). This corresponds to odds ratios of 8.2 (95% CI, 1.5 to 45.2) and 9.1 (95% CI, 2.6 to 31.7) when comparing patients with ABPA with allergic asthmatics and control subjects, respectively.

Two allergic asthmatics (4.6%) and seven control subjects (4.9%) were found to be heterozygous for the 5T variant in intron 8. None of the 5T carriers were heterozygous for CFTR mutations. The differences in proportions of 5T carriers were not statistically significant between the three groups (Fisher’s Exact Test).


   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In this study, we found the frequency of the studied CFTR mutations to be significantly higher in ABPA patients than it was in either allergic asthmatics without sensitization to A fumigatus or in subjects seeking genetic counseling for reasons other than CF. These findings are consistent with those reported in a study by Miller et al,12 although we identified a wider spectrum of CFTR mutations in ABPA patients. These investigators12 analyzed the coding region of the CFTR gene in 11 white patients from four university centers who were identified as having ABPA, central bronchiectasis, and normal sweat chloride levels. One of these patients was identified as a compound heterozygote ({Delta}F5085/R347H), and she was reclassified as having atypical CF. Five patients were found to carry one CFTR mutation, including {Delta}F508 in four patients and R117H in one patient. The proportion of patients who were excluded because they did not fulfill the proposed diagnostic criteria for ABPA was higher in our population (21%) than in the study by Miller et al12 (4%). However, participation in genetic testing was higher in our group of ABPA patients (95% vs 24%). As our sample of patients with ABPA came from both community-based and university hospitals, we think that it was representative for the cases of ABPA that come to the attention of lung specialists.

The higher-than-expected frequency of CFTR mutations among ABPA patients raises two hypotheses. First, the patients found to be heterozygous for the studied mutations could actually present an atypical form of CF, as they could carry another rare CFTR mutation on the second chromosome. Because we did not analyze the complete coding sequence of the CFTR gene, we cannot formally exclude that our ABPA patients were compound heterozygotes for unidentified CFTR mutations. This possibility, however, would imply that a substantial proportion of patients with ABPA have unrecognized CF. None of our patients with ABPA showed elevated sweat chloride concentrations. Accordingly, they did not meet the usual diagnostic criteria for CF.11 One patient with a CFTR mutation was found to have a sweat chloride level in the intermediate range. This patient did not show other evidence of CF, such as P aeruginosa infection or pancreatic insufficiency. However, previous genetic studies24 25 26 27 28 29 have provided accumulating evidence that some CFTR mutations are associated with milder CF phenotypes and normal sweat electrolytes. In the study by Miller et al,12 only one ABPA patient was identified as carrying two CFTR mutations ({Delta}F508/R347H). This patient presented with recurrent P aeruginosa pneumonia, normal sweat electrolytes, and abnormal values of nasal transepithelial voltage measurements. The presence ofP aeruginosa in sputum was not more frequent in our ABPA patients with a CFTR mutation than in those without mutation. Nasal potential differences were not measured in our patients. This test deserves further investigation in patients with ABPA, as it could represent a more reliable indicator of CFTR function than the sweat test.

Besides mutations of the CFTR gene, genetic polymorphism of noncoding regions may have an impact on the level of functional CFTR and CF phenotype.30 In addition, mutations of the noncoding regions of CFTR have been associated with atypical CF phenotypes. For instance, the 5T allele sequence in intron 8 results in the deletion of exon 9 in CFTR messenger RNA, leading to reduced levels of the normal CFTR protein. The combination of one CFTR mutation with the 5T allele has been involved in the pathogenesis of congenital bilateral absence of vas deferens21 and atypical sinopulmonary disease.22 23 Among the ABPA patients studied by Miller et al,12 the 5T intron 8 variant was identified in two patients without other mutations in the CFTR gene.12 By contrast, we did not detect the 5T allele in our ABPA patients. This is probably explained by the small number of ABPA patients that is inherent to the rarity of the disorder and which precludes to draw definitive conclusions on the role of this variant in ABPA.

Alternatively, our findings, together with those of Miller et al,12 could indicate that heterozygosity for CFTR mutations has a specific effect on the development of ABPA, at least in a subset of patients. Heterozygosity for CFTR mutations could either predispose to the development of bronchiectasis with secondary sensitization to A fumigatus or promote immune response to A fumigatus, leading to airway inflammation and bronchiectasis. Whether CF carrier status is associated with an increased risk of pulmonary disease remains a matter of debate. A higher prevalence of bronchial hyperresponsiveness to methacholine, wheezing, and lung disease during childhood, as well as a decrease in expiratory volumes and flows have been found in obligate heterozygotes for CF.31 32 An increased prevalence of reported asthma in adult heterozygotes for the {Delta}F508 mutation has been reported in some33 but not all studies.34 35 Previous studies36 37 have convincingly documented a high prevalence of CFTR mutations in adult patients with disseminated bronchiectasis of unknown etiology. By altering the mucociliary clearance process, bronchiectasis could lead to chronic airway colonization with A fumigatus hyphae, which is thought to be a prerequisite to the development of immunologic sensitization to A fumigatus.1 2 In the study by Gervais et al,36 the presence of ABPA was not mentioned, while 2 of the 16 patients studied by Pignatti et al37 had ABPA, and 1 of these 2 patients was heterozygous for a rare mutation (3667 ins 4). Another possibility is that CFTR mutations contribute to enhanced immunologic and inflammatory responses to A fumigatus. An epidemiologic survey35 found a higher prevalence of positive skin-prick tests to A fumigatus in {Delta}F508 carriers than in noncarriers, although there was no difference in the prevalence of asthma. In addition, there is emerging evidence that CF is associated with altered production of cytokines in the airways, including interferon-{gamma}, interleukin (IL)-8, and IL-10, which could result in inappropriately regulated inflammatory and immunologic processes.38 39 Peripheral CD4+ T cells derived from CF patients have been found to produce reduced levels of IL-10 after polyclonal activation.40 IL-10 has potent anti-inflammatory effects by reducing the release of various proinflammatory cytokines. Assessing the prevalence of CF carriers in ABPA patients who lack demonstrable bronchiectasis41 would help to elucidate the role of CFTR mutations in the development of ABPA. None of the three ABPA patients without bronchiectasis included in our study was found to carry CFTR mutations, although their number was too low to draw any reliable conclusions.

A limitation of this study is the small number of subjects included, particularly in the group of patients with ABPA. This is inherent to the rarity of the disorder. However, the power of the study was accurate (see "Materials and Methods") to detect differences in CFTR-mutations frequency. In ABPA as in other conditions associated with CFTR mutations,21 22 23 the difference in prevalence of the 5T allele with a control population seems to be less dramatic. Regarding the 5T allele frequency, the power of our study was relatively weak. Still, we choose to analyze the 5T allele in the present study because of its potential role when associated with a CFTR mutation. Larger multicentric studies including a greater number of patients are needed to resolve the issue of the association of the 5T allele and ABPA as well as the prevalence of CFTR gene mutations in patients suffering from ABPA without bronchiectasis. The present study as well as that by Miller et al12 demonstrate a high odds ratio for carrying a CFTR mutation in patients with ABPA. However, the CIs for odds ratios were wide. Larger studies would also allow to confirm these impressive odds ratios.

In conclusion, this study indicates that CFTR gene mutations, in combination with environmental or other genetic factors, could be involved in the pathogenesis of ABPA in patients who do not meet the clinical criteria for CF. Further investigation is warranted to assess the impact of CFTR dysfunction on airway response to A fumigatus. The high frequency of heterozygotes for a CFTR mutation among ABPA patients suggests that CFTR genotyping should be proposed to patients with this disease in order to provide appropriate genetic counseling.


   Acknowledgements
 
The authors thank Mss. N. Lanoy and C. Walon for their assistance in performing genetic studies, Dr. J. Jamart for performing statistical analysis, and Mrs. L. Schubert for reviewing the article.


   Footnotes
 
Abbreviations: ABPA = allergic bronchopulmonary aspergillosis; CF = cystic fibrosis; CFTR = cystic fibrosis transmembrane conductance regulator; CI = confidence interval; IL = interleukin

Received for publication December 29, 1999. Accepted for publication November 1, 2000.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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