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Í
DRÁBEK,
RKOVÁ,
ZSLAV
KOLEK,  |
ABSTRACT |
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ABSTRACT
INTRODUCTION
METHODS
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DISCUSSION
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Members of the interleukin-1 (IL-1) family are implicated in the
pathogenesis of sarcoidosis and idiopathic pulmonary fibrosis (IPF).
We have, therefore, performed a case-control study to investigate a plausible association between sarcoidosis and the polymorphisms in the IL-1
, IL-1
, and IL-1 receptor antagonist (IL-1Ra)
genes. Further, as a separate question, we explored whether the
aforementioned genes of the IL-1 cluster are associated with IPF.
Using PCR with sequence-specific primers, IL-1 
889, IL-1 511,
IL-1 +3953, and IL-1Ra intron 2 VNTR polymorphisms were determined in 348 white subjects of West Slavonic ancestry (95 patients
with sarcoidosis, 54 patients with IPF, and 199 healthy control subjects). The IL-1 889 1.1 genotype was significantly overrepresented in patients with sarcoidosis in comparison with control subjects (60.0 versus 44.2%, p = 0.012, pcorr = 0.047). The distribution
of IL-1 511, IL-1 +3953, and IL-1Ra VNTR genotypes and alleles did not significantly differ between the cases and controls.
No association between IPF and the investigated polymorphisms
was found. Strong linkage disequilibrium between pairs of polymorphic loci was observed. Further population studies are warranted to confirm the observed association between sarcoidosis and
the IL-1 polymorphism and also to explore mechanisms of IL-1
889 participation in aberrant immune response in sarcoidosis.
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INTRODUCTION |
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ABSTRACT
INTRODUCTION
METHODS
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DISCUSSION
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Keywords: interleukin-1; interleukin-1 receptor antagonist; single nucleotide polymorphism; interstitial lung disease
Sarcoidosis and idiopathic pulmonary fibrosis (IPF) represent the most frequently occurring diffuse lung diseases with multifactorial etiology, which likely develop in genetically predisposed individuals in response to environmental triggers (1, 2). Observed differences in clinical presentation and severity of sarcoidosis between racial and ethnic groups, together with familial clustering in both diseases, favor a significant hereditary predisposition to these disorders. Because sarcoidosis and IPF are not inherited in a simple Mendelian pattern, multiple genetic loci are likely to be involved.
Interleukin-1 (IL-1) is a cytokine with proinflammatory and
fibrogenic effects. The most important members of the IL-1
family are the agonists IL-1, IL-1, and their naturally occurring inhibitor, IL-1 receptor antagonist (IL-1Ra) (3). Genes
encoding IL-1, IL-1, and IL-1Ra are clustered on chromosome 2q13-21 (4). Biallelic polymorphisms at positions IL-1
889, IL-1 511, and IL-1 +3953 have been described, all
representing a C/T single nucleotide polymorphism (SNP) (5-
7). The IL-1Ra gene (IL-1RN) contains an 86-bp variable
number tandem repeat (VNTR) polymorphism in intron 2 (8).
Within the IL-1 gene cluster linkage disequilibrium between
the polymorphic markers has been observed (9, 10).
These polymorphisms are located within the regulatory regions of the genes and are, therefore, of potential functional
importance by modulating IL-1 protein production. IL-1 is
known to be one of the pivotal mediators participating in aberrant immune responses in diffuse lung diseases. In sarcoidosis, alveolar macrophages release higher amounts of IL-1,
which are accompanied by lower IL-1Ra production (11). A
decreased IL-1Ra:IL-1 ratio in bronchoalveolar lavage (BAL)
fluid appears to be a prognostic marker related to the persistence of granulomatous lesions (12). In acute pulmonary fibrotic changes, IL-1 participates in initial processes leading to
the extensive deposition of intercellular matrix and tissue remodeling, regardless of the etiology of the disorder (13).
In previous studies, the IL-1 gene cluster containing the
"candidate genes" of sarcoidosis and also IPF has been implicated in genetic susceptibility to both diseases: sarcoidosis has
been associated with a polymorphic marker in the IL-1 gene,
and IPF with an IL-1RN +2018 single base variation, which is
totally linked to the IL-1RN VNTR (9, 14, 15). Therefore, we
have, in a case-control study, investigated whether the polymorphisms in the genes for IL-1, IL-1, and IL-1Ra are associated with sarcoidosis. We have also explored whether these
genes of the IL-1 gene cluster are associated with IPF.
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METHODS
RESULTS
DISCUSSION
REFERENCES
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Subjects
Enrolled in the study were 199 healthy control subjects, 95 patients with sarcoidosis, and 54 patients with IPF (Table 1). All subjects were unrelated, white, and of West Slavonic ancestry living in the Czech Republic.
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In patients with sarcoidosis the diagnosis and extent of disease have been determined on the basis of typical clinical, radiological, and laboratory criteria, together with the finding of noncaseating granulomas in biopsy specimens (16). The diagnosis was supported by a CD4+ lymphocytic BAL.
The diagnosis of IPF was based on the criteria according to the ATS/ERS International Consensus Statement (17): typical clinical features and abnormalities on chest high-resolution computed tomography (HRCT) scans, abnormal lung function tests with reduced diffusing capacity of the lung for CO (DLCO) and/or restrictive pulmonary deficit, exclusion of other known causes of interstitial lung disease (ILD), and confirmatory surgical biopsy (in 33 of 54 patients). In 21 individuals without surgical biopsy the bronchoalveolar lavage or transbronchial lung biopsy excluded other diagnoses.
The control population consisted of participants of the Czech Bone Marrow Donor Registry. Presence of any lung disease in the control subjects was excluded by health questionnaire and interview. The study was performed with the approval of the Ethics Committee of the Medical Faculty and University Hospital Olomouc.
Genetic Analysis
DNA was extracted from peripheral blood by the salting-out method
(18). The polymorphic regions of the IL-1, IL-1, and IL-1Ra genes
were amplified by polymerase chain reaction with sequence-specific
primers (PCR-SSP). The PCR products were analyzed on 2% agarose
gel stained with ethidium bromide. The detailed characteristics of particular polymorphisms and the primer sequences are reported in Table 2. For genotyping of each SNP IL-1 889, IL-1 511, and IL-1 +3953 two reactions were used with different primer mixes specific
to C or T alleles. The PCR conditions were established according to a
previously described phototyping method (19). The IL-1 +3953 genotype could not be unambiguously determined in 11 of 348 samples.
Genotyping of the IL-1RN VNTR polymorphism was performed as
described previously (8) with adopted thermocycling conditions: 94° C
for 2 min, then 34 cycles at 95° C for 10 s, 55° C for 30 s, 72° C for 45 s,
and finally 25° C for 1 s. Each allele was identified according to its size
(Table 2).
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Statistical Analysis
The genotype and allele frequencies were determined and compared
by a 2 × 2 
2 test based on the Woolf-Haldane analysis, and the relative risk (OR) was calculated. The p values were corrected by Bonferroni method according to the formula pcorr = 1 (1 p)n, where pcorr
is the corrected value, p is the uncorrected value, and n is the number
of loci. pcorr < 0.05 was considered to be significant. The groups were
tested for conformity to the Hardy-Weinberg equilibrium by 2 × 2 2
test comparing observed and expected numbers.
Frequencies of haplotypes (pairs of alleles at different polymorphic loci) were estimated by Estimating Haplotype-Frequencies software (ftp://linkage.rockefeller.edu/software/eh). Linkage disequilibrium (LD) was assessed between pairs of polymorphic markers by
calculating the relative linkage disequilibrium value (Drel) as Drel = Dij/Dmax (10). The Dij values were compared between cases and controls by comparison of confidence intervals (CI 1 = 0.95) (20).
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RESULTS |
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DISCUSSION
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The distribution of genotypes and alleles of the IL-1 889,
IL-1 511, IL-1 +3953, and IL-1Ra in healthy control subjects, patients with sarcoidosis, and patients with IPF is shown
in Table 3. All three groups were in Hardy-Weinberg equilibrium with nonsignificant 2 values comparing the observed
and expected genotype frequencies of each of the tested polymorphisms.
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IL-1 Polymorphism
Comparison of the IL-1 889 genotypes revealed that the
IL-1 889 1.1 homozygotes were significantly overrepresented in sarcoidosis compared with healthy control subjects
(60.0% versus 44.2%, p = 0.012, pcorr = 0.047), whereas the
frequency of IL-1 889 1.2 heterozygotes was decreased
(32.6% versus 47.7%, p = 0.015, pcorr = 0.059). The relative
risk (OR) for IL-1 889 1.1 homozygotes was 1.9 (95% CI
1.1-3.1). The allele frequency of the IL-1 889 allele 1 was
higher in patients with sarcoidosis than in healthy control subjects (76.3% versus 68.1%, p = 0.04, pcorr = 0.151), but after
Bonferroni correction the pcorr value was not significant. In patients with IPF the genotype and allele frequencies did not significantly differ either from healthy control subjects or patients with sarcoidosis.
IL-1 Polymorphisms
Regarding the IL-1 511 polymorphism among patients
with IPF in comparison with the control subjects there was a
nonsignificant trend toward a decrease of IL-1 511 1.1 homozygotes (29.6% versus 42.7%, p = 0.086) with a reciprocal
increase of IL-1 511 2.2 homozygotes (20.4% versus
12.1%, p = 0.103). Also, the allele frequency of the IL-1
511 allele 2 was increased in patients with IPF compared
with control subjects (45.4% versus 34.7%, p = 0.039, pcorr = 0.147). However, the difference between allele frequencies did
not attain significance after correction for multiple comparisons.
The distribution of IL-1 +3953 genotypes and alleles did not
significantly differ between the cases and controls.
IL-1Ra Polymorphism
The frequency of IL-1RN allele 1 tended to be increased in sarcoidosis in comparison with healthy controls (73.7% versus 67.3%, p = 0.1). However, no significant differences in genotype or allele frequencies were found between the groups.
Association between Pairs of Polymorphic Loci and Estimation of Linkage Disequilibrium
The estimated haplotype frequencies and Drel for pairs of
polymorphisms were calculated. In the control population
there was significant LD between the following pairs: IL-1
889 and IL-1 +3953; IL-1 511 and IL-1 +3953; IL-1RN and IL-1 511; and IL-1RN and IL-1 +3953. Comparing the linkage disequilibrium values (Dij) between the patients and control subjects no significant differences were
found in any pair of polymorphisms.
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DISCUSSION |
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DISCUSSION
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In the present study we compared the distribution of IL-1 889, IL-1 511, IL- +3953, and IL-1Ra intron 2 VNTR
polymorphisms between patients with sarcoidosis and control
subjects and also between patients with IPF and control subjects. We describe an association between the IL-1 889
polymorphism and sarcoidosis. Patients with the IL-1 889
1.1 genotype were nearly two times more prone to develop the
disease than those with the IL-1 889 1.2 and IL-1 889 2.2 genotypes. In patients with IPF we did not observe any significant genotype or allelic differences for the investigated polymorphisms. We further evaluated LD between the markers in
the IL-1 gene cluster. The cases did not significantly differ
from the control population in degrees of disequilibrium between the pairs of polymorphisms.
Our observation indicating the involvement of the IL-1
gene in sarcoidosis is consistent with the report of Rybicki and
coworkers (14), who have found an association of a microsatellite repeat marker IL-1 on 2q13 with sarcoidosis in African
Americans. In this group of Czech patients, in agreement with
recent findings in the Japanese population (21), we did not detect an association between the IL-1RN and IL-1 +3953
polymorphisms and sarcoidosis.
Increasing evidence shows that the secretion of IL-1,
IL-1, and IL-1Ra proteins exhibits interindividual variability
dependent on the pattern of IL-1 gene cluster polymorphisms.
The mechanisms of alteration of gene expression associated
with polymorphisms are still not clearly understood. Because
the investigated polymorphisms lie in the regulatory regions
of the genes (or in the coding sequence), they may affect the
level of protein expression (22). Recently the role of the
IL-1 889 polymorphism in IL-1 and IL-1 production has
been demonstrated in vivo. In severe periodontal disease, the
carriage of the IL-1 889 allele 2 is associated with elevated IL-1 concentrations in gingival crevicular fluid (25). In
healthy individuals homozygous for the IL-1 889 allele 2, IL-1 plasma levels are increased compared with subjects with
other genotypes; this elevation is linked to carriage of the IL-1 511 allele 2 (22).
The association of a gene polymorphism with altered protein production may occur due to linkage with another marker
directly affecting gene expression. El-Omar and coworkers
(26) demonstrated alteration of DNA-protein interactions by
a TATA box polymorphism, which was in almost total linkage
with IL-1 511. The association between IL-1 889 and
sarcoidosis observed in our study may, therefore, be indicative
of a linkage with functional variants in other loci in the near
vicinity. IL-1 889 is in strong LD with IL-1 +3953 in our
West Slavonic population as well as in U.K. whites (10). The
IL-1 +3953 polymorphism has also been shown to regulate
IL-1 in vitro production by peripheral blood mononuclear
cells (PBMC) (7). However, the assumption that the effect of
IL-1 889 on plasma IL-1 levels is mediated via IL-1
+3953 was not confirmed in the study of Hulkkonen and coworkers (22).
The IL-1 889 allele 2 has been previously associated
with juvenile rheumatoid arthritis, periodontitis, and Alzheimer's disease (5, 27, 28). In contrast to previous associations of
chronic inflammatory diseases with the less frequent IL-1 889 allele 2, which is associated with higher IL-1 plasma
levels, we observed an increased frequency of the IL-1 889
1.1 genotype in patients with sarcoidosis. In active sarcoidosis,
increased spontaneous and stimulated IL-1 production by alveolar macrophages is well recognized (11). The activation of
the alveolar mononuclear phagocytes seems to be compartmentalized to the sites of ongoing inflammation, that is, the
lung, whereas the PBMCs do not display enhanced IL-1 release (29). Because the influence of gene polymorphisms on
protein production may differ depending on the tissue and cell type, further studies are required to assess the regulatory role of IL-1 889 alleles in the local cytokine production in the affected lung (22).
In contrast to our finding in sarcoidosis, we did not observe any association between IL-1 gene cluster polymorphisms and IPF. Whyte and coworkers (15) described an association of IL-1RN +2018 polymorphism with fibrosing alveolitis in English and Italian white populations. IL-1RN +2018 is in total linkage with IL-1RN VNTR (9). Nevertheless, we did not find an association between IL-1RN VNTR alleles and IPF in our Czech patients. Because linkage is population dependent we cannot exclude that disequilibrium between these two markers in the IL-1RN gene is absent in West Slavonic whites. However, the observation of comparable degrees of LD between the polymorphic loci within the IL-1 gene cluster in our Czech and U.K. whites (10) would not support this possibility.
In conclusion, in this report we describe an association of
the IL-1 889 single nucleotide polymorphism with sarcoidosis in the Czech population. Whether IL-1 889 has a
direct functional effect on gene expression or this association
is mediated by linkage disequilibrium to another disease-causing polymorphism within or close to the IL-1 gene cluster remains to be investigated.
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Footnotes |
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Correspondence and requests for reprints should be addressed to Dr. Martin Pet rek, Department of Immunology, PalackýUniversity, I.P. Pavlova 6, 775 20 Olomouc, Czech Republic. E-mail: petrekm{at}fnol.cz
(Received in original form June 1, 2001 and accepted in revised form October 22, 2001).
This work was presented in part at the 97th International ATS Conference, San Francisco, CA, May 18-23, 2001.Primary financial support for this work was obtained from the Grant Agency of Czech Republic (Reg. No. 310/99/1676); partial funding was also obtained from PalackýUniversity (Reg. No. LF 14501103) and the Czech government (MSM 15110002).
This article has an online data supplement, which is accessible from this issue's table of contents online at www.atsjournals.org
Acknowledgments: The authors thank Dr. Huang (Karolinska Institute Stockholm) for providing PCR protocol for IL-1RN VNTR genotyping and the technical staff of the DNA laboratory in Olomouc for DNA extraction.
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References |
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METHODS
RESULTS
DISCUSSION
REFERENCES
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M. Zorzetto, I. Ferrarotti, R. Trisolini, L. L. Agli, R. Scabini, M. Novo, A. De Silvestri, M. Patelli, M. Martinetti, M. Cuccia, et al. Complement Receptor 1 Gene Polymorphisms Are Associated with Idiopathic Pulmonary Fibrosis Am. J. Respir. Crit. Care Med., August 1, 2003; 168(3): 330 - 334. [Abstract] [Full Text] [PDF]
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M. J. Tobin Tuberculosis, Lung Infections, Interstitial Lung Disease, and Journalology in AJRCCM 2002 Am. J. Respir. Crit. Care Med., February 1, 2003; 167(3): 345 - 355. [Full Text] [PDF]
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G. S. Warshamana, D. A. Pociask, P. Sime, D. A. Schwartz, and A. R. Brody Susceptibility to Asbestos-Induced and Transforming Growth Factor-{beta}1-Induced Fibroproliferative Lung Disease in Two Strains of Mice Am. J. Respir. Cell Mol. Biol., December 1, 2002; 27(6): 705 - 713. [Abstract] [Full Text] [PDF]
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D. R. Moller and E. S. Chen Genetic Basis of Remitting Sarcoidosis: Triumph of the Trimolecular Complex? Am. J. Respir. Cell Mol. Biol., October 1, 2002; 27(4): 391 - 395. [Full Text] [PDF]
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M. C. Iannuzzi, M. Maliarik, and B. A. Rybicki Nomination of a Candidate Susceptibility Gene in Sarcoidosis . The Complement Receptor 1 Gene Am. J. Respir. Cell Mol. Biol., July 1, 2002; 27(1): 3 - 7. [Full Text] [PDF]
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