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ABSTRACT |
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Evolution of lung damage is highly variable in cystic fibrosis (CF) even in patients with the same cystic
fibrosis transmembrane conductance regulator (CFTR) mutations. The analysis of genetic factors
other than CFTR may help our understanding of genotype-phenotype relationships in CF. As human
leukocyte antigen (HLA) class II polymorphism has been associated with a number of diseases including autoimmune and inflammatory diseases, asthma, and allergy, we investigated the possibility that
HLA polymorphism contributes to CF-associated pulmonary inflammation. Among the 98 adult CF patients tested, the genotypic frequencies of DR4 and DR7 alleles (serologic group DR53) and DR7/
DQA*0201 haplotype were higher than in 39 selected control subjects without atopy (p 
10
6, relative risk [RR] = 22, and p 5.104, RR = 27, respectively) and in a random population. No significant difference of these allelic distributions was found according to the CFTR genotype. In the CF patients,
the DR7 allele was significantly associated with an increase in total IgE and with chronic Pseudomonas aeruginosa colonization (100% of DR7 versus 83% of non-DR7 patients being colonized, p < 0.05).
Our results suggest that genetic factors known to modulate the immune response might contribute
to chronic infection with Pseudomonas, increased total IgE, and pulmonary outcome in CF.
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INTRODUCTION |
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ABSTRACT
INTRODUCTION
METHODS
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DISCUSSION
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Cystic fibrosis (CF), the most common genetic disease in the white population, results from mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene (1). The CF respiratory and intestinal disease is characterized by a wide variability in clinical phenotypic expression. The identification of various CFTR gene mutations has allowed analysis of genotype-phenotype associations: pancreatic function closely relates to specific mutations, whereas the relationship between genotype and phenotype is not clear in the airway (2, 3). Although CF is a monogenic disease, it appears that the extent of pulmonary involvement differs among patients with the same mutations. Studies in mouse models of CF have shown that the severity of the intestinal disease and presentation of respiratory disease was influenced by factors present in their genetic backgrounds (4). Similarly, a genetic approach by sib-pair analysis has implicated a major modifier at 19q13 as a contributor to the variable presentation of digestive disease, although no modifier locus has been correlated to the variable severity of lung disease (5).
Allergic manifestations (such as positive skin tests, elevation in total serum IgE, presence of precipitating antibodies) are frequently found in CF (6, 7) and some studies have suggested that atopic patients suffered from more severe disease conditions than nonatopic patients (7). Therefore, genes that mediate susceptibility to atopy may influence disease severity. An association between human leukocyte antigen (HLA) class II antigens and the IgE response has been reported (8) and we have previously found strong associations between some major histocompatibility complex (MHC) class II alleles (DR4-DR7) and allergic diseases (9). It has also been shown that HLA-DR was the only class II antigen expressed in nasal polyps of CF patients (12). Based on this empirical background, our hypothesis was that HLA class II genes might act as modifier genes in CF.
We investigated the distribution of haplotypes and alleles in different HLA class II loci (DR, DQA, DQB) in a group of unrelated white European CF adult patients with various CFTR mutations. As the rate of atopy in the random population is high (13), we compared our CF patients first with control subjects selected for the absence of atopy, then with a random French population. We looked for relationships between HLA class II haplotypes and criteria of pulmonary phenotype, including Pseudomonas aeruginosa infection, pulmonary function parameters, or allergy (total IgE serum levels). We found an increased incidence of HLA class II DR4 and DR7 in CF, whereas DR7/DQA*0201 haplotype was associated with an increase in total IgE and P. aeruginosa colonization.
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This study was conducted according to the principles of the Declaration of Helsinki, with informed patient consent and institutional approval.
Control Subjects
We studied 39 (15 males and 24 females; mean age 41 ± 2.6 yr) European-born, unrelated whites, living in France. They were administered a standardized questionnaire by physicians with extensive experience in allergic diseases. The prevalence of allergic symptoms or atopy- related conditions among their first-degree relatives was thoroughly investigated. The criteria for admission to the study included the absence of any personal and familial history of atopy through three generations. Skin tests (n = 14) and bronchial reactivity challenges (n = 6) were also performed on some of these control volunteers. Individuals were included only if they had no history of cancer, diabetes, cardiovascular disease, CF or any other major disease. This selection explains why only one control subject was carrier of DR4 and none of DR7 (11).
Random Population
The CF patients were also compared with a random French population whose HLA allele frequencies (DRB1: n = 158; DQA: n = 181) have been reported (14).
CF Patients
Ninety-eight adult patients with CF were included in this study (53 males and 45 females; mean age 28 yr). All were European-born, unrelated, and white, and attended the adult CF Center at Cochin Hospital between January 1, 1994 and June 30, 1997. All had bronchiectasis confirmed by computed tomographic (CT) scan. Diagnosis was confirmed by an abnormal chloride concentration (> 70 mmol/L) as determined by pilocarpine iontophoresis sweat test and/or the identification of mutations in both alleles of the CFTR gene.
Clinical Assessment
Data included age, sex, age at diagnosis, colonization with P. aeruginosa and age at colonization, history of nasal polyps, and diabetes. Patients with P. aeruginosa growth for at least 6 mo were considered to be colonized with this microorganism. Pulmonary function tests were regularly performed in all patients using an Autospiro AS500 spirometer (Minato, Osaka, Japan), and the best values for forced vital capacity (FVC) and forced expiratory volume in one second (FEV1) over the previous 6 mo were used, expressed as the percentage of predictive values (% pred). Arterial oxygen tension (PaO2) and arterial carbon dioxide tension (PaCO2) were measured at rest.
IgE
Total IgE was measured by a standard immunoenzymatic method,
IMx System (Abbott, Rungis, France). Normal serum levels for adults
are 150 UI/ml. The mean value of two measurements was used.
DNA Extraction and Analysis
A panel of genomic DNA samples was previously obtained from nonatopic control subjects (9, 11). The panel of CF genomic DNA samples was extracted from peripheral blood lymphocytes using the phenol-chloroform method (15). Analysis of the CF mutations was performed as previously described (16).
HLA Typing
All DNA samples were typed for HLA class II DRB1, DQA1, and DQB1 alleles and haplotypes using the polymerase chain reaction/ restriction fragment length polymorphism (PCR-RFLP) method, as previously described (17).
Statistical Analysis
Frequencies of each allele were compared using the chi-square test. Relative risk (RR) was calculated using the Wolf procedure with Haldane modification (18, 19). For p value determination, Fisher exact test was used.
Group data were expressed as the median (range) for both age and age at P. aeruginosa colonization, because the distribution of these variables is not normal. All other variables were expressed as mean ± 1 SD. Comparisons of frequency for CFTR genotypes and P. aeruginosa colonization between patients carrying and not carrying DR4, and between patients carrying and not carrying DR7, were performed using the chi-square method. Comparisons for age, age at diagnosis, and age at P. aeruginosa colonization were performed with the unpaired Mann-Whitney U test and those for the pulmonary function values and the IgE levels with the unpaired Student's t test.
Values of p < 0.05 were considered as statistically significant.
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RESULTS |
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Distribution of DRB1 Alleles
In the 98 CF patients tested, the frequency of DR4 was significantly increased (p 4.103) compared with the healthy 39 control subjects, with a RR of 8 (Table 1). The frequency of
DR7 was even more elevated (p 4.104) with a RR of 29 (Table 1). Thus, the serologic group DR53 (DR4 and DR7)
was strongly represented (p 106) among the CF patients
compared with the selected control population. The subtypes
of DR4 (eight subtypes could be detected) were the same as in
the random French population (not shown). The subtypes of
DR7 (0701 and 0702) could not be differentiated. In contrast, there was a tendency for a decrease in DR10 among the CF
population, although RR did not reach significance.
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Distribution of DQA1 Alleles
A significant increase in the DQA*0201 allele was also observed in the CF patients compared with the 37 control subjects (p 5.103; RR = 4) (Table 2). The DQA*0301 allele
was more frequent among the patients than among the control
group (p 0.04; RR = 3). On the basis of known linkage disequilibrium reported in white populations (14), DQA*0201 is
in disequilibrium with DR7 allele and DQA*0301 with DR4.
The haplotype DR7/DQA*0201 appeared to be the most frequent in the CF population and significantly higher than in
the selected control group (p 5.104; RR = 27).
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Distribution of DQB1 Alleles
The distribution of DQB1 alleles among the 98 CF patients and 36 healthy control subjects was not significantly different despite a tendency toward an increase in frequency of DQB*0201 in the CF patients (not shown).
Comparison between CF Population and a Random Population
The comparison of our CF patients with a random French
population showed a significant p value for DR4, DR7, and
DQA*0201 alleles (p = 0.02, 0.012, and 0.001, respectively)
(Table 3). DR7/DQA*0201 haplotype remained more frequent in our CF population than in the general population
(p 0.01).
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Distribution According to CFTR Mutations
In order to determine whether the DR and DQA1 associations were related to the type of CFTR mutations, we compared three CF patient subgroups, i.e., 
F508 homozygotes
(n = 45), F508/non-F508 compound heterozygotes (n = 37)
and non-F508/non-F508 compound heterozygotes (n = 16)
(Table 4). There was no significant difference in the distribution of DR4, DR7, and DQA alleles among the three subgroups. We did not find either any relationship between the CFTR genotype and P. aeruginosa colonization.
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HLA Class II Polymorphism and Total IgE
No significant increase in total IgE was noticed among the CF
with DR4 allele (DR4+) (Table 5). In contrast, levels of IgE were significantly increased in the carriers of DR7 allele
(DR7+), compared with the noncarriers (DR7
) (p < 0.02).
Although the number of patients (n = 4) did not allow for significance calculations, the increase of IgE levels was more
marked among the carriers of both DR4 and DR7 alleles
(DR4+, DR7+) (880 ± 1,014 IU/ml) compared with the noncarriers (not shown). In our cohort, three patients had allergic
bronchopulmonary aspergillosis (ABPA) with high total IgE
levels; two were DR7+ and none was DR4+. The small number of patients precluded any separate analysis of this group of
patients with ABPA.
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HLA Class II Polymorphism and P. aeruginosa Colonization
P. aeruginosa colonization is an important step in the course
of CF because it largely contributes to pulmonary damage.
P. aeruginosa colonization was significantly decreased among
the DR4 carriers (DR4+) (74%; p 0.03) (Table 5). In contrast, we noticed an increase among the DR7 allele carriers
(DR7+) compared with the noncarriers (DR7) (100%, versus 83%; p < 0.03). However, no difference was found in the
age at P. aeruginosa colonization between the carriers of DR4
and DR7 alleles.
HLA Class II Polymorphism, Pulmonary Function Values, Nasal Polyposis and Diabetes
No relationship was found between DR4 and/or DR7 carriers or noncarriers for FVC, FEV1, PaO2, PaCO2, history of nasal polyposis, and diabetes (Table 5).
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DISCUSSION |
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ABSTRACT
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In this study, we found that HLA-DR7, HLA-DR4, and HLA-DQA*0201 were overrepresented among a group of 98 adult CF patients in comparison to control subjects and to a random French population. There is no reason to suspect a priori that the genetic background of our CF population differs from that of the random French or European populations, because all our patients were white and we excluded brothers and sisters. We also found a higher level of total IgE and a more frequent P. aeruginosa colonization among the CF patients carrying the DR7/DQA*0201 haplotype.
Patients with CF demonstrate a substantial variability in pulmonary involvement that does not appear to correlate with the type of CFTR mutations, which is in contrast with pancreatic involvement, pancreatic sufficiency being associated with mild CF mutations (20). Thus, genes other than CFTR could modulate the severity of the bronchopulmonary disease (4). We investigated genes of the MHC that encode molecules involved in immune response by presenting antigens for T cell recognition (21). We have previously reported an increase in the HLA class II alleles DR4 and DR7 in atopic and asthmatic patients (11). HLA-DR has also been found to be of prognostic significance in sarcoidosis, a systemic disease with prominent pulmonary involvement (22). In contrast, previous studies have reported that HLA class I does not affect susceptibility to CF (6, 23, 24) and no association in CF between HLA-DR2 or HLA-DR3 and pulmonary disease was found (25). However, HLA alleles known to be associated with insulin-dependent diabetes in the general population, in particular HLA-DQB1*0201, have also been found in diabetics with CF (26).
The haplotype DR7/DQA*0201 appeared to be significantly increased in the adult CF population tested, compared both with selected controls and with a random French population. HLA-DQA*0201 is known to be in strong linkage disequilibrium with DR7 allele in the white population. These results cannot be explained by an association with diabetes, as we did not observe any difference between patients with or without DR7 or DR4 in terms of diabetes. Furthermore, no association between HLA class II subgroups and CF mutations was observed in this study.
Because our results were obtained in adult CF patients, we
had an adequate opportunity to examine the long-term outcome of lung disease and to test whether there is an influence
of HLA class II genes on pulmonary phenotype. Because
chronic colonization with P. aeruginosa is a prominent feature
in CF (27), we investigated possible associations between
HLA haplotypes and this clinical manifestation of disease.
Positive and negative associations have already been described between HLA class II haplotypes and mycobacterial infections (28), influencing the type and severity of disease. We found that HLA-DR7 allele was more frequently observed among CF patients with P. aeruginosa colonization:
among the patients with DR7 (n = 26), 100% were colonized
with P. aeruginosa, versus 83% in the noncarriers of DR7. In
addition, we found that the DR4 allele was less frequently observed in patients with P. aeruginosa colonization: 74% versus
92% in the noncarriers of DR4. Although a high proportion of
adult CF patients was colonized (87%) and there was no difference for the age at first P. aeruginosa colonization among
the various groups mentioned previously, it appeared of interest to focus on those patients not yet infected in adulthood. None of these 12 patients carried HLA-DR7 while six of them
carried DR4. This observation is consistent with the fact that
absence of DR7 or presence of DR4 might confer some protection against P. aeruginosa colonization. In contrast, the link
between CFTR genotype and P. aeruginosa colonization suggested by Kubesch and coworkers (29) was not confirmed in
this study. The lack of difference in FEV1, FVC, and arterial
blood gases between HLA-DR7+, and DR7, DR4+, and
DR4 subgroups is not surprising according to large variations in each subgroup, but is consistent with the hypothesis
that the severity of pulmonary involvement is governed by
multiple genetic determinants (30).
In this study, the carriers of HLA-DR7 also presented a
higher mean concentration of total IgE in comparison to the
DR7 noncarriers. Associations between total IgE levels, allergy, and the DR7 allele have been reported (31). Furthermore, CF patients with allergy-like symptoms also have increased total IgE (6, 32), although a pathogenetic connection
between high serum IgE levels and CF disease cannot be
made. Allergy in CF has been diversely associated with pulmonary severity (7, 33), but patients colonized with P. aeruginosa are more often allergic and P. aeruginosa colonization appears as a factor of bad prognosis. In a previous study, DR7 was found to be associated with allergy and asthma (11). In the present work, DR7 is associated with an increase both in
total IgE and in colonization with P. aeruginosa, so that the
possibility that antigen presentation by DR7 would deviate
the immune response toward a preferentially T helper cell
type 2 (Th2) response should be considered. Indeed, the cytokine imbalance associated with Th2 responses (increased interleukin-4 [IL-4], decreased interferon-
) could explain both
the increase in IgE and a decreased ability to prevent colonization. This hypothesis should be tested by comparing lymphocyte subpopulations and cytokine profiles in DR7+ and
DR7 CF patients.
On the basis of these results, we suggest that the genetic variation in resistance and susceptibility to P. aeruginosa in CF patients could implicate HLA class II loci. This study must be considered as an initial study that will have to be confirmed by testing larger populations.
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Correspondence and requests for reprints should be addressed to Dominique Hubert, M.D., Service de Pneumologie, Hôpital Cochin, 27 rue du Faubourg Saint-Jacques, 75679 Paris cedex 14, France. E-mail: dominique.hubert{at}cch.ap-hop-paris.fr
(Received in original form July 10, 1998 and in revised form November 30, 1998).
Y. Aron is supported by the Association Claude Bernard and B. S. Polla by INSERM.Acknowledgments: The authors are grateful to Josué Feingold, M.D., Ph.D., University Paris VII, and Catherine Figarella, M.D., Ph.D., University of Marseilles, for stimulating discussions, advice, and critical review; to Sarah Kreps, Universities of Harvard and Oxford, for reading the manuscript; to Patricia Ansquer and Guity Thévenot for their help in collecting and extracting the DNA samples; to Catherine Cazalet, M.D., Laboratory of Biochemistry A, Hôpital Cochin, Paris, for IgE determinations; and to Gerard Paul, M.D., Laboratory of Bacteriology, Hôpital Cochin, Paris, for bacteriological analysis.
Supported by the Association Française de Lutte contre la Mucoviscidose (AFLM).
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References |
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