 Gene Promoter
Polymorphism with the Presence of Chronic Obstructive
Pulmonary Disease
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ABSTRACT |
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ABSTRACT
INTRODUCTION
METHODS
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DISCUSSION
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Tumor necrosis factor 
(TNF-), a potent proinflammatory cytokine, may be involved in the development of chronic obstructive pulmonary disease (COPD). The production of TNF- is elevated in
the airways of these patients. A polymorphism at position 
308 of
the TNF- gene promoter (TNF--308*1/2) is known to be associated with alteration of TNF- secretion in vitro. In this study we examined the differences in TNF--308*1/2 allele frequency to investigate the association of this polymorphism with the presence of
smoking-related COPD. TNF--308*1/2 allele frequency in 106 patients (73 men and 33 women) was compared with 110 asymptomatic smoker/ex-smoker control subjects matched for sex and
age and population control subjects consisting of 129 blood donors. Genotype was analyzed by the polymerase chain reaction-restriction fragment length polymorphism technique on genomic
DNA isolated from peripheral blood lymphocytes. TNF--308*1/2
allele frequencies were significantly different among the groups:
0.835/0.165 in patients with COPD, 0.918/0.082 in smoker/ex-smoker control subjects, and 0.922/0.078 in population control subjects. These results indicate that TNF--308*1/2 alleles are significantly associated with the presence of smoking-related COPD.
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Chronic obstructive pulmonary disease (COPD), which includes chronic pulmonary emphysema (CPE) and chronic bronchitis (1), is basically a benign disease, but the prognosis is so poor that its mortality rate is similar to that of some malignant disease. It is generally accepted that cigarette smoking is the most important risk factor for COPD. Nevertheless, only 10-15% of smokers develop the severe impairment of pulmonary function associated with COPD (2); moreover, the factors that determine the susceptibility to cigarette smoking and disease progression are poorly understood. Among those factors, the genetic contribution to the disease has been implicated (3). Although the nature of the genetic influences remains undefined, factors that regulate the inflammatory responses to direct exposure to inhaled insults are important in the pathogenesis of COPD (4).
Tumor necrosis factor (TNF-) is a multifunctional cytokine. TNF- could promote tracheal smooth muscle proliferation (5) and alter smooth muscle function (6). The level of
TNF- is elevated in bronchoalveolar lavage fluid (7), bronchial biopsies (8), and induced sputum (9) of patients with
COPD. These studies suggest that TNF- may contribute to
the airway remodeling and alter smooth muscle cell function in COPD.
A polymorphism at position 308 of the TNF- gene promoter has been described. This is a guanine (G)-to-adenine
(A) substitution in the TNF- gene at position 308 in the
promoter region (the G allele was denoted as 1, and the A allele as 2). TNF--308*2, the rarer allele, has been associated
with higher baseline and induced expression of TNF- (10).
Several studies have demonstrated a positive association with
the presence of the TNF--308*2 allele in a number of inflammatory diseases, such as asthma (11) and sarcoidosis (14).
A prior study showed an association between the TNF--308*2 allele and the risk of development of chronic bronchitis
in a male Taiwanese population (15). However, one study
showed no association between the TNF--308*2 allele and the severity of smoking-related COPD in a white population
(16). The differences in the association between COPD in
Asian and white populations may not be explained by differences in TNF--308*2 allele frequency between the populations. There seems to be an ethnic difference in the prevalence, but the lack of association in a white population may
not be explained on this basis. In this study, the patient group
was restricted only to those with smoking-related COPD to
exclude other factors related to diffuse panbronchiolitis that
are observed mainly in Japanese and Southeast Asians. The purpose of the present study was to determine whether the
TNF--308*1/2 polymorphism was associated with the development of smoking-related COPD.
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METHODS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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Subjects
The patient group consisted of 106 patients with smoking-related COPD recruited from the Respiratory Outpatient Department at Chiba University Hospital and affiliated hospitals (Chiba, Japan). COPD was diagnosed on the basis of past history, physical examination, and spirometric data, according to American Thoracic Society guidelines (1). Pulmonary function tests were performed to determine forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1), using a standard spirometer (Fudac-60; Fukuda Denshi, Tokyo, Japan), in a standing position. Chronic airflow obstruction was defined as (1) FEV1/FVC less than 70% and (2) FEV1 less than 80% of predicted values. Predicted values were calculated according to the Japanese Thoracic Society statement on standardized lung function testing. Subjects were excluded if they had a history of productive cough for 3 mo in each of two successive years (chronic bronchitis).
Two control groups were used in the study: (1) a smoker control group (n = 110) that included asymptomatic smokers and ex-smokers matched for sex and age with a smoking history of at least 10 pack-years but without COPD and asthma. The control group included subjects who visited the same hospital for a health checkup. They had normal pulmonary function (FEV1/FVC > 70% and FEV1 > 80% of predicted values); (2) a population control group (n = 129) of adult Japanese blood donors from Chiba Prefecture, Japan. The study was approved by the Research Ethics Committee of Chiba University School of Medicine, and all subjects gave their informed consent in writing.
Detection of the TNF- Polymorphism
The base composition at position 308 of the TNF- gene was determined by the polymerase chain reaction-restriction fragment length
polymorphism (PCR-RFLP) technique. Genomic DNA was obtained from blood lymphocytes, using a QIAamp DNA blood minikit (Qiagen, Valencia, CA). The 5' region of the TNF- gene (positions 331 to 14) was amplified, and the PCR conditions were similar to those already described (17), with some modifications (15): the 5' primer
was 5'-AGGCAATAGGTTTTGAGGGCCAT and the 3'-primer
was 5'-GAGCGTCTGCTGGCTGGGTG. PCR conditions: genomic
DNA was amplified primers (0.2 µM each), dNTPs (100 µM each),
10 mM Tris, 1.5 mM MgCl2, 50 mM KCl, and 0.1% Triton X-100.
Cycling: 94° C for 1 min, 60° C for 1 min, and 72° C for 1 min for 30 cycles followed by 60° C for 1 min and 72° C for 5 min. The PCR product
was ethanol precipitated and digested with NcoI (Nippon Gene, Tokyo, Japan) and analyzed on a 3% NuSieve agarose gel (FMC BioProducts, Rockland, ME). DNA products were visualized by ethidium bromide staining. The TNF1 allele would be digested into two
fragments (325 and 20 bp, respectively), while the TNF2 allele would
not be digested (345 bp).
Statistical Analysis
The difference in allele distribution and allele frequency among the
groups was examined for statistical significance by the 
2 test for independence, and with the Fisher exact test when appropriate. Age,
smoking index expressed as pack-years, and pulmonary function parameters were compared with the Mann-Whitney U test.
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RESULTS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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Seventy-three men and 33 women were recruited into the COPD patient group. The smoker control group consisted of 66 men and 44 women. The population control group was composed of 129 blood donors, aged 22-72 yr. The smoking history of the population control subjects was unknown. Age, smoking history, and pulmonary function data of patients with COPD and smoker control subjects are summarized in Table 1. No significant differences were observed, in age or smoking history, between patients and control groups.
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The results of the comparison of the base composition at
position 308 of the TNF- gene are summarized in Table 2.
The distribution of the genotype was significantly different between patients and smoker control groups, as well as between
patients and population control groups. 2 analysis showed
that the patient group had a significantly higher TNF--308*2
frequency than either the smoker control group or the population control group (p < 0.01). The presence of the TNF--308*2 allele (including both homozygous and heterozygous
subjects) was associated with an increased risk for COPD
(odds ratio = 2.58; 95% confidence interval = 1.28-5.23) compared with TNF--308*1-homozygous subjects.
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DISCUSSION |
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ABSTRACT
INTRODUCTION
METHODS
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In the present study, we compared the frequency of a polymorphism in the promoter region of the TNF- gene (designated
TNF--308*1/2) in Japanese patients with smoking-related
COPD and asymptomatic smoker/ex-smoker control subjects
matched for age and sex. The results indicate that the TNF--308*2 allele frequency is higher in patients with COPD compared with control subjects, suggesting an association of TNF--308*1/2 alleles with the presence of COPD. It is possible that the
TNF2 allele, which is a G-to-A polymorphism at position 308
in the TNF- promoter, increases expression of TNF-, and this
may explain these associations. Alternatively, the polymorphism
could be in linkage disequilibrium with other causal mutations.
The TNF--308*2 rare allele is associated with higher baseline and inducible TNF- expression in transcription studies in vitro (10), thus, various authors have investigated the possibility of an association between the TNF--308*2 allele and disease manifestation. TNF- is a potent modulator of immune
and inflammatory responses and has been implicated in a variety of autoimmune diseases, including asthma. However, a
positive association with the TNF--308*2 allele and asthma
was not found in all studies (11). These inconsistent results
suggest that the association of the TNF--308 polymorphism with the inflammation underlying asthma may not be expressed through the influence of the polymorphism on TNF
secretion. The TNF- gene is located within the major histocompatibility complex (MHC) Class III region on chromosome 6p21.3. This is a highly polymorphic region, and some of
these polymorphisms form extended haplotypes with the
HLA Class I and II alleles. Thus, the TNF--308 polymorphism could be in linkage disequilibrium with HLA variants
associated with different inflammatory responses. For example, the TNF--308*2 allele is strongly associated with the
HLA-A1, -B8, and -DR3 alleles (18).
The etiology of COPD could be attributable to both environmental and genetic factors. Like asthma, it is probable that
COPD is a polygenic disorder with considerable genetic heterogeneity. Among the many gene products involved in the airway inflammation and remodeling, TNF- has been tested as
a candidate gene for COPD, because it is a potent proinflammatory cytokine that is found in increased concentration in
bronchoalveolar lavage fluid (7) and induced sputum (9). The
data from this study suggest that the TNF--308*2 allele is a
risk factor for the development of COPD. The result is unlikely to be confounded by population stratification given the
homogeneity of the Japanese population. However, there are
alternative interpretations of these results. The TNF--308*2
allele may not affect susceptibility to COPD but could be in
linkage disequilibrium with the true susceptibility allele in a
closely linked gene, because multiple genes may be involved
in the development of COPD. In addition, there are no obvious mechanisms for the involvement of TNF- in the pathogenesis of COPD. There may be another functional gene in
disequilibrium with the TNF--308*2 allele that could be responsible for an increased risk of COPD.
It is generally accepted that one of the significant risk factors for COPD is male sex. Female sex hormones, such as estrogen and progesterone, may play a protective role against
insults that injure lung tissues. It was demonstrated that TNF-
production by peripheral blood lymphocytes varied considerably in premenopausal females, while it was more constant in
men and postmenopausal females, suggesting that it may be
regulated by female sex hormones (19). However, the TNF--308*2 allele was not more frequently detected in male patients
with COPD than in female patients in the present study.
The odds ratio of patients with COPD among TNF--308*2
allele carriers is lower than that of patients with chronic bronchitis in the Taiwanese population (15). The frequency of the
TNF--308*2 allele seems to be much lower in the Taiwanese
population than in the Japanese population. The low allele
frequency in the Taiwanese population may account for the
higher odds ratio of TNF--308*2 allele carriers among patients with chronic bronchitis compared with that among Japanese patients with COPD.
There is the fact that two studies of Asian subjects have
been positive but that studies of white subjects have been negative. The one possible cause may be an ethnic difference affecting prevalence. The TNF--308*2 allele frequency ranged
from 8% (20) to 27% (18) in the white population and from
5% (15) to 14% (21) in the Asian population. Another possible cause may be that the allele could be in linkage disequilibrium with a specific HLA haplotype that increases susceptibility to COPD in smokers only in the Asian population.
In conclusion, we found that the TNF--308*1/2 polymorphism may play a role in the susceptibility to smoking-related
COPD, although the determinants between smokers susceptible to the development of COPD and those resistant to it cannot be explained by a single gene polymorphism.
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Footnotes |
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Correspondence and requests for reprints should be addressed to Seiichiro Sakao, M.D., Department of Chest Medicine, Chiba University School of Medicine, 1-8-1 Inohana, Chuou-ku, Chiba 260-8670, Japan. E-mail: sakao{at}virolo3.m.chiba-u.ac.jp
(Received in original form June 7, 2000 and in revised form August 28, 2000).
Acknowledgments: The authors thank Dr. Katsutoshi Nakayama and Dr. Mutuo Yamaya (Department of Geriatric Medicine, Tohoku University School of Medicine) for technical assistance, and also Dr. Shuji Hashimoto (Department of Epidemiology and Preventive Health Sciences, School of Health Sciences and Nursing, University of Tokyo) for help with the statistical analysis of data.
Supported by research grants from the Ministry of Education, Science and Culture, and by grants to investigate intractable diseases from the Ministry of Health and Welfare, Japan.
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References |
|---|
|
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
|
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1. American Thoracic Society. Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1995;152:S77-S120.
2. Hanrahan JP, Sherman CB, Bresnitzf EA, Emmons KM, Manion DM. Cigarette smoking and health. Am J Respir Crit Care Med 1996; 153: 861-865 [Abstract].
3. Redline S, Tishler PV, Lewitter RI, Tager IB, Munoz A, Speizer FE. Assessment of genetic and nongenetic influences on pulmonary function. Am Rev Respir Dis 1987; 135: 217-222 [Medline].
4. Saetta M, Stefano AD, Maestrelli P, Ferraresso A, Drigo R, Potena A, Ciaccia A, Fabbri LM. Activated T-lymphocytes and macrophages in bronchial mucosa of subjects with chronic bronchitis. Am Rev Respir Dis 1993; 147: 301-306 [Medline].
5.
Amrani Y,
Panettieri RA,
Frossard N,
Broner C.
Activation of the TNF
-p55 receptor induces myocyte proliferation and modulates agonist-evoked calcium transients in cultured human tracheal smooth muscle
cells.
Am J Respir Cell Mol Biol
1996;
15:
55-63
[Abstract].
6.
Emala CW,
Kuhl J,
Hungerfold CL,
Hirshman CA.
TNF-alpha inhibits
isoproterenol-stimulated adenylyl cyclase activity in cultured airway
smooth muscle cells.
Am J Physiol
1997;
272:
L644-L650
7. Sun G, Stacey MA, Vittori E, Marini M, Bellini A, Klemberg J, Mattoli S. Cellular and molecular characteristic of inflammation in chronic bronchitis. Eur J Clin Invest 1998; 28: 364-372 [Medline].
8. Mueller R, Chanez P, Campbell AM, Bousquet J, Heusser C, Bullock GR. Different cytokine patterns in bronchial biopsies in asthma and chronic bronchitis. Respir Med 1996; 90: 79-85 [Medline].
9.
Keatings VM,
Collins PD,
Scott DM,
Barnes PJ.
Differences in interleukin-8 and tumor necrosis factor- in induced sputum from patients
with chronic obstructive pulmonary disease or asthma.
Am J Respir
Crit Care Med
1996;
153:
530-534
[Abstract].
10.
Wilson AG,
Symons JA,
McDowell TL,
McDevitt HO,
Duff GW.
Effects of a polymorphism in the human tumor necrosis factor alpha
promoter on transcription activation.
Proc Natl Acad Sci USA
1997;
94:
3195-3199
11. Albuquerque RV, Hayden CM, Palmer LJ, Laing IA, Rye PJ, Gibson NA, Burton PR, Goldblat J, Lesouef PN. Association of polymorphisms within the tumour necrosis factor (TNF) genes and childhood asthma. Clin Exp Allergy 1998; 28: 578-584 [Medline].
12.
Brinkman BM,
Zuijdeest D,
Kaijzel EL,
Breedveld FC,
Verweij CL.
Relevance of the tumor necrosis factor alpha (TNF-)-308 promoter
polymorphism in TNF gene regulation.
J Inflamm
1995;
46:
32-41
[Medline].
13.
Moffatt MF,
Cookson WOCM.
Tumor necrosis factor haplotypes and
asthma.
Hum Mol Genet
1997;
6:
551-554
14. Seitzer U, Swider C, Stuber F, Suchnicki K, Lange A, Richter E, Zabel P, Quernheim JM, Flad HD, Gerdes J. Tumor necrosis factor alpha promoter gene polymorphism in sarcoidosis. Cytokine 1997; 9: 787-790 [Medline].
15.
Hung S-L,
Su C-H,
Chang S-C.
Tumor necrosis factor- gene polymorphism in chronic bronchitis.
Am J Respir Crit Care Med
1997;
156:
1436-1439
16.
Higham MA,
Pride NB,
Alikhan A,
Morrell NW.
Tumor necrosis factor- gene promoter polymorphism in chronic obstructive pulmonary
disease.
Eur Respir J
2000;
15:
281-284
[Abstract].
17.
Wilson AG,
Di Giovine FS.
Single base polymorphism in the TNF-
gene detectable by NcoI restriction of PCR products.
Hum Mol Genet
1992;
1:
353
18.
Wilson AG,
de Vries N,
Pociot F,
di Giovine FS,
van de Putte LVA,
Duff GW.
An allelic polymorphism within the human tumor necrosis
factor promoter region is strongly associated with HLA A1, B8, and
DR3 alleles.
J Exp Med
1993;
177:
557-560
19.
Jacob CO,
Fronek Z,
Lewis GD,
Koo M,
Hansen JA,
McDevitt HO.
Heritable major histocompatibility complex class II-associated differences in production of tumor necrosis factor-: relevance to genetic
predisposition to systemic lupus erythematosus.
Proc Natl Acad Sci
USA
1990;
87:
1233-1237
20.
Verjans GM,
Brinkman BNM,
Van Doornik CEM,
Kijlstra A,
Verweij CL.
Polymorphism of tumor necrosis factor-alpha (TNF-) at position
308 in relation to ankylosing spondylitis.
Clin Exp Immunol
1994;
97:
45-47
[Medline].
21. Chen CJ, Yen JH, Tsai WC, Wu CS, Chiang W, Tsai JJ, Liu HW. The TNF2 allele dose not contribute towards susceptibility to systemic lupus erythematosus. Immunol Lett 1997; 55: 1-3 [Medline].
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S. Sakao, K. Tatsumi, T. Hashimoto, H. Igari, Y. Shino, H. Shirasawa, and T. Kuriyama Vascular Endothelial Growth Factor and the Risk of Smoking-Related COPD Chest, July 1, 2003; 124(1): 323 - 327. [Abstract] [Full Text] [PDF]
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R. E. Walter, A. Beiser, R. J. Givelber, G. T. O'Connor, and D. J. Gottlieb Association between Glycemic State and Lung Function: The Framingham Heart Study Am. J. Respir. Crit. Care Med., March 15, 2003; 167(6): 911 - 916. [Abstract] [Full Text] [PDF]
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I. Ferrarotti, M. Zorzetto, M. Beccaria, L.S. Gile, R. Porta, N. Ambrosino, P.F. Pignatti, I. Cerveri, E. Pozzi, and M. Luisetti Tumour necrosis factor family genes in a phenotype of COPD associated with emphysema Eur. Respir. J., March 1, 2003; 21(3): 444 - 449. [Abstract] [Full Text] [PDF]
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A. Churg, J. Dai, H. Tai, C. Xie, and J. L. Wright Tumor Necrosis Factor-{alpha} Is Central to Acute Cigarette Smoke-induced Inflammation and Connective Tissue Breakdown Am. J. Respir. Crit. Care Med., September 15, 2002; 166(6): 849 - 854. [Abstract] [Full Text]
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S. Sakao, K. Tatsumi, H. Igari, R. Watanabe, Y. Shino, H. Shirasawa, and T. Kuriyama Association of Tumor Necrosis Factor-{alpha} Gene Promoter Polymorphism With Low Attenuation Areas on High-Resolution CT in Patients With COPD* Chest, August 1, 2002; 122(2): 416 - 420. [Abstract] [Full Text] [PDF]
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A J Sandford and E K Silverman Chronic obstructive pulmonary disease * 1: Susceptibility factors for COPD the genotype-environment interaction Thorax, August 1, 2002; 57(8): 736 - 741. [Abstract] [Full Text] [PDF]
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W. I. de Boer Cytokines and Therapy in COPD* : A Promising Combination? Chest, May 1, 2002; 121(5_suppl): 209S - 218S. [Abstract] [Full Text] [PDF]
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M. J. TOBIN Chronic Obstructive Pulmonary Disease, Pollution, Pulmonary Vascular Disease, Transplantation, Pleural Disease, and Lung Cancer in AJRCCM 2001 Am. J. Respir. Crit. Care Med., March 1, 2002; 165(5): 642 - 662. [Full Text] [PDF]
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E. K. Silverman Genetic Epidemiology of COPD Chest, March 1, 2002; 121(2007): 1S - 6S. [Abstract] [Full Text] [PDF]
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