 Gene Polymorphism in
Chronic Bronchitis
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ABSTRACT |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Airway inflammation is an important pathologic feature in chronic bronchitis, and we hypothesized
that individuals with greater inflammatory responses may be more likely to acquire the disease. A
polymorphism at -308 position of the tumor necrosis factor-
(TNF-) gene has been described, with
the rarer allele, TNF2, demonstrated to have higher inducibility in vitro. We investigated the distribution of this polymorphism in a case-control study. The genotype was determined in 42 male patients
with chronic bronchitis, 42 sex-, age-, and smoking index-matched control subjects, and 99 random-sampled schoolchildren. We report here that the TNF2 allele is overrepresented in the patient group.
The allele frequency of TNF2 is 5.1% in the schoolchildren, 2.4% in the control group, and 19% in the
bronchitis group (p < 0.01). Carriage of the TNF2 allele confers a higher risk to the development of
chronic bronchitis (odds ratio = 11.1, 95% CI = 2.89-42.57). The results demonstrate the important
pathologic role of TNF- in chronic bronchitis and suggest that greater inflammatory response may
predispose an individual to this disease.
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Cigarette smoking is an environmental factor clearly associated with chronic bronchitis and obstructive pulmonary function impairment. Not all smokers develop chronic bronchitis, however, and the mechanisms for the apparent difference in the host susceptibility are not well understood. Genetic factors may contribute to determining pulmonary function in adults, as suggested by hereditability path analysis and twin studies (1, 2). The nature of the genetic influence remains undefined. Since the respiratory system is exposed directly to inhalational insults, factors that regulate the inflammatory responses may be important. For example, bombesin-like peptide was implicated in the susceptibility to cigarette smoking-related diseases (3).
Differences in cytokine production in vitro have been demonstrated with peripheral blood mononuclear cells from healthy
subjects. Significant interindividual differences in the level of
tumor necrosis factor- (TNF-) inducibility were observed,
the differences were maintained irrespective of the methods
and doses of stimulation, and the levels of TNF- production
in the same subject were highly reproducible (4). Similarly,
stable differences in secretion of interleukin-1, TNF- , and
prostaglandin E2 by endotoxin-stimulated human monocyte
were documented. Furthermore, the secretions of interleukin-1 and prostaglandin E2 from different subjects were strongly
correlated with their TNF- production level (5).
The expression of TNF- can be regulated at the transcriptional level (6), and differences in TNF- production may partly be determined at the genetic level. It has been demonstrated
in transfection studies that the less common allele, TNF2, was
associated with higher baseline and induced expression (7, 8).
Positive association with the TNF2 allele was found in some
diseases, such as cerebral malaria (9) and dermatitis herpetiformis (10), but not in others, such as ankylosing spondylitis
(11), rheumatic arthritis (12), and ulcerative colitis (13). In this
study, we compared the genotype distribution of a bi-allelic
polymorphism of the TNF- gene in a case-control study and
examined the relationship between this genetic polymorphism
and chronic bronchitis.
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METHODS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Study Subjects
The patient group consisted of 42 male adults with chronic bronchitis. They had histories of chronic or recurrent productive cough present on most days for more than 2 successive yr. Presence of other bronchopulmonary or cardiac diseases as the cause of their symptoms was excluded by appropriate clinical and radiographic examinations (14). Patients who visited one of the authors (S.-C.C.) at the outpatient clinic of the Veterans General Hospital-Taipei in January and February of 1995 who met the following criteria were asked to participate in the study. The criteria of enrollment were as follows: (1) spirometry data available in recent 2 yr, (2) FEV1 < 80% of predicted value, (3) FEV1/FVC < 69%, and (4) patient's consent. All patients who met the criteria agreed to participate. The control group was from subjects who visited the same hospital for health checkup. They were sex-, age (± 3 yr)-, and smoking (± 5 pack-yr)-matched subjects with normal pulmonary function (both FEV1 and FVC > 80% of predicted values; FEV1/FVC > 70%). Peripheral blood was taken from patients and control subjects. As a population reference, all fourth-, fifth-, and sixth-grade students of a primary school in southern Taiwan were included (n = 99; 51 boys and 48 girls) for genotype analysis. Three freshly plucked hairs from these students were collected.
Genotype Analysis by NcoI Restriction Fragment Length Polymorphism
Genomic DNA from whole blood was prepared by standard phenol/
chloroform extraction procedures. The hair roots were directly immersed in 300 µl PCR buffer with nonionic detergent (50 mM KCl, 10 mM Tris, 2,5 mM MgCl2, 0.1 ml/ml gelatin, 0.45% NP-40, 0.45% Tween 20); 0.1 mg/ml of proteinase K was added later and the buffer was treated at 42° C for 1 h. The proteinase K was inactivated by heating at 95° C for 10 min, and the lysate used in polymerase chain reaction (PCR) (15). The 5' region of TNF- gene (
331 to 14) was amplified, and the PCR condition was similar to that described (7), with
some modifications: the 5' primer was 5'-AGGCAATAGGTTTTGAGGGCCAT and the 3' primer was 5'-GAGCGTCTGCTGGCTGGGTG (Perkin Elmer, Taiwan). PCR conditions: genomic DNA
(20 µl of the cell lysate from above) was amplified using 0.2-µM concentrations of the primers, 100 µM each of dNTP, 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 (Boehringer Mannheim, Mannheim, Germany)
and analyzed on a 2% MetaPhor agarose gel (FMC BioProducts,
Rockland, ME). DNA products were visualized by ethidium bromide
staining. The TNF1 allele would not be digested (345 bp), while TNF2
allele would be digested into two fragments (325 and 20 bp).
Statistical Methods
The difference in allele distribution and allele frequency among each group was examined for statistical significance by Mantel-Haenszel chi-square test, with Fisher exact test when appropriate. The age, smoking index expressed as pack-year, and pulmonary function of patients and control subjects were compared using unpaired Student's t test.
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RESULTS |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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The patient group consisted of 42 male adults with chronic bronchitis. Spirometric data showed that they had various degrees of airway obstruction (mean FEV1: 56.7% of predicted value; mean FEV1/FVC: 55.3%). The same number of sex-, age-, and smoking index-matched subjects with normal pulmonary function were selected as controls. Two female patients who met the selection criteria were excluded from the final analysis. The age, smoking index, and spirometric data are summarized in Table 1. There are no significant differences in age and smoking index between patient and control groups. To assess the genotype distribution of the general population in Taiwan, we also analyzed samples from 99 schoolchildren.
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The base composition at position 308 of the TNF- gene
was determined by PCR followed by NcoI restriction digestion. The results are summarized in Table 2. TNF1 homozygote is the predominant genotype in each group, while TNF2
homozygote is very uncommon in the Taiwanese population;
only one individual with this genotype was found in the patient group. By Mantel-Haenszel chi-square test, the distribution of the genotype is significantly different between patients
and control subjects, as well as between patients and the
schoolchildren, whereas there is no difference between control subjects and the schoolchildren. The genotype distributions of the control and population groups conform to the
Hardy-Weinberg equilibrium.
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The allele frequency of the rarer allele, TNF2, is 19.0% in patients, 2.4% in control subjects, and 5.1% in the population samples (Table 3). Chi-square analysis shows that the patient group has a significantly higher TNF2 frequency than both the control and population groups (p < 0.001). The difference between patient and control groups remains when the data is stratified by smoking status (Table 4).
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Carriage of the TNF2 allele (including both homozygous and heterozygous subjects) is associated with an increased risk for chronic bronchitis (odds ratio = 11.1; 95% CI = 2.89- 42.57) compared with TNF1 homozygosity. The odds ratio among smokers is 8.25 (95% CI = 1.89-35.96).
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DISCUSSION |
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ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
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We examined the genotype distribution of a polymorphism at
the 5' region of the TNF- gene in bronchitis patients and
control subjects. The base difference is located at nucleotide
308 relative to the transcription start site. The results
showed that the frequency of the TNF2 allele was higher in
patients than in control subjects and suggested that carriers of
TNF2, either homozygote or heterozygote, had a higher risk
of developing chronic bronchitis.
Although the actual biologic effect of this polymorphism in
vivo has not been clearly demonstrated, the TNF2 allele was
shown to confer a 6- to 7-fold higher basal and induced mRNA
expression in reporter gene transfection studies (8). The effect
of this allele in vivo was supported by a study that found that
children who developed cerebral complications of malaria had
higher TNF- levels and were also more likely to carry the TNF2
homozygote genotype (9). Positive effect of the TNF2 allele is
also suggested by its association in other diseases such as dermatitis herpetiformis (10).
The results of this study suggest that greater TNF- production is associated with a higher risk of developing chronic
bronchitis, both in smokers or nonsmokers. The positive association of the TNF2 allele with chronic bronchitis is unexpected, considering that the pathogenesis of chronic bronchitis
is complex, that TNF- is but one of many factors involved in
the process of inflammation, and that the TNF2 allele may account for a minor part of the regulation of TNF- production
in vivo. Furthermore, the effect of increased TNF- production, if any, may be offset by other mechanisms at the site of
inflammation, such as altered numbers or affinity of TNF receptors, or compensatory expression of other cytokines locally.
We examined whether the polymorphism at position 308 is
associated with other base differences in the 5' promoter region with confirmed effect on transcription regulation, such as
AP-1 and 
B motifs (16, 17). To identify base differences in
the promoter region of the TNF- gene, we amplified the region 246 to +14 and examined by single-strand conformation polymorphism (SSCP) according to a published method
(18). A total of 40 bronchitis patients and 83 schoolchildren
were examined, and no abnormal gel mobility on SSCP was
detected (data not shown). This is in accordance with the results of McGuire and colleagues (9), who sequenced 502 to
+250 in 20 subjects and found no polymorphism other than
the single base substitution at 308.
Compared with phenotype analysis, such as quantifying
monocyte TNF- production, genotype analysis is an indirect
measure of the inflammatory response, provides only categorical data, and thus is less informative than phenotype analysis.
However, the phenotype may change with either environmental exposure or disease process, whereas the genotype remains
constant. This offers some advantage in interpreting data in a
cross-sectional study. To strengthen the correlation between
genotype and TNF- production, the analysis in this study was
restricted to male patients. It was shown that TNF- production by peripheral blood lymphocytes was reproducible in
male and postmenopausal female subjects, while considerable
variation was observed in premenopausal females (4).
The TNF gene resides in the class III region of the major histocompatibility complex, and the TNF2 allele was found to be in linkage disequilibrium with some HLA alleles, such as the HLA-A1, -B8, and -DR3 alleles in the Caucasian population (19). The increased frequency of the TNF2 allele in some immunologic diseases, such as systemic lupus erythematosus and insulin-dependent diabetes mellitus, may be dependent on its association with HLA-DR3 (20, 21). In contrast, the development of neurologic sequelae due to cerebral malaria was independent of HLA class I and class II variation (9). We did not analyze the HLA alleles of our patients, however, since chronic bronchitis is related to inhalational insults that elicit a nonspecific inflammatory response and therefore the role of HLA association may be minimal.
The odds ratio of developing chronic bronchitis for TNF2 allele carriers is high, but it is similar to the risk of 11.25 found in patients with dermatitis herpetiformis (10). The TNF2 allele seems to be less common in the Taiwanese population than in Caucasians. The allele frequency ranged from 16% (10) to 27% (19) in European populations. In contrast, here we found that the allele frequency in the population sample was only 5.1% (Table 3). The low allele frequency in Taiwanese population may make the odds ratio of TNF2 allele carriers in acquiring chronic obstructive airway disease higher than that of Caucasian populations. Restricting the analysis to only male patients may have also increased the odds ratio.
In summary, the results show that the TNF2 allele is a
significant risk factor for developing chronic bronchitis. This
stresses the importance of TNF- in inflammatory processes
that may lead to tissue injury and also suggests that this polymorphism may be used as a marker to identify individuals who
are more susceptible to inhalational insults.
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Footnotes |
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Supported by Grant NSC-84-2621-P-010-001 from the National Science Council, Republic of China.
Correspondence and requests for reprints should be addressed to Dr. Song-Lih Huang, Institute of Public Health, National Yang Ming University, 155 Sec. 2, Li-Nong St., Taipei 11221, Taiwan.
(Received in original form September 27, 1996 and in revised form June 12, 1997).
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References |
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ABSTRACT
INTRODUCTION
METHODS
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DISCUSSION
REFERENCES
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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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E. L. CORBETT, N. MOZZATO-CHAMAY, A. E. BUTTERWORTH, K. M. DE COCK, B. G. WILLIAMS, G. J. CHURCHYARD, and D. J. CONWAY Polymorphisms in the Tumor Necrosis Factor-alpha Gene Promoter May Predispose to Severe Silicosis in Black South African Miners Am. J. Respir. Crit. Care Med., March 1, 2002; 165(5): 690 - 693. [Abstract] [Full Text] [PDF]
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 C.-J. Chiu, C.-P. Chiang, M.-L. Chang, H.-M. Chen, L.-J. Hahn, L.-L. Hsieh, Y.-S. Kuo, and C.-J. Chen Association between Genetic Polymorphism of Tumor Necrosis Factor-a and Risk of Oral Submucous Fibrosis, a Pre-cancerous Condition of Oral Cancer Journal of Dental Research, December 1, 2001; 80(12): 2055 - 2059. [Abstract] [PDF]
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H. HAKONARSON, U. S. BJORNSDOTTIR, E. OSTERMANN, T. ARNASON, A. E. ADALSTEINSDOTTIR, E. HALAPI, D. SHKOLNY, K. KRISTJANSSON, S. A. GUDNADOTTIR, M. L. FRIGGE, et al. Allelic Frequencies and Patterns of Single-nucleotide Polymorphisms in Candidate Genes for Asthma and Atopy in Iceland Am. J. Respir. Crit. Care Med., December 1, 2001; 164(11): 2036 - 2044. [Abstract] [Full Text] [PDF]
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J.R. Hoidal Genetics of COPD: present and future Eur. Respir. J., November 1, 2001; 18(5): 741 - 743. [Full Text] [PDF]
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T. Ishii, N. Keicho, S. Teramoto, A. Azuma, S. Kudoh, Y. Fukuchi, Y. Ouchi, and T. Matsuse Association of Gc-globulin variation with susceptibility to COPD and diffuse panbronchiolitis Eur. Respir. J., November 1, 2001; 18(5): 753 - 757. [Abstract] [Full Text] [PDF]
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L.-I. Ho, H.-J. Harn, C.-J. Chen, and N.-M. Tsai Polymorphism of the {beta}2-Adrenoceptor in COPD in Chinese Subjects Chest, November 1, 2001; 120(5): 1493 - 1499. [Abstract] [Full Text] [PDF]
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K.F. Chung Cytokines in chronic obstructive pulmonary disease Eur. Respir. J., July 2, 2001; 18(34_suppl): 50S - 59s. [Abstract] [Full Text] [PDF]
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S. SAKAO, K. TATSUMI, H. IGARI, Y. SHINO, H. SHIRASAWA, and T. KURIYAMA Association of Tumor Necrosis Factor {alpha} Gene Promoter Polymorphism with the Presence of Chronic Obstructive Pulmonary Disease Am. J. Respir. Crit. Care Med., February 1, 2001; 163(2): 420 - 422. [Abstract] [Full Text]
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A. J. SANDFORD, T. CHAGANI, T. D. WEIR, J. E. CONNETT, N. R. ANTHONISEN, and P. D. PARÉ Susceptibility Genes for Rapid Decline of Lung Function in the Lung Health Study Am. J. Respir. Crit. Care Med., February 1, 2001; 163(2): 469 - 473. [Abstract] [Full Text]
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S. Teramoto, T. Ishii, M. Luisetti, and P. F. Pignatti No Association of Tumor Necrosis Factor-{{alpha}} Gene Polymorphism and COPD in Caucasian Smokers and Japanese Smokers Chest, January 1, 2001; 119(1): 315 - 316. [Full Text] [PDF]
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J. WAHLSTRÖM, K. KATCHAR, H. WIGZELL, O. OLERUP, A. EKLUND, and J. GRUNEWALD Analysis of Intracellular Cytokines in CD4+ and CD8+ Lung and Blood T Cells in Sarcoidosis Am. J. Respir. Crit. Care Med., January 1, 2001; 163(1): 115 - 121. [Abstract] [Full Text]
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V. M. Keatings, S. J. Cave, M. J. Henry, K. Morgan, C. M. O'Connor, M. X. FitzGerald, and N. Kalsheker A Polymorphism in the Tumor Necrosis Factor-{alpha} Gene Promoter Region May Predispose to a Poor Prognosis in COPD Chest, October 1, 2000; 118(4): 971 - 975. [Abstract] [Full Text] [PDF]
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P. BRESSER, T. A. OUT, L. van ALPHEN, H. M. JANSEN, and R. LUTTER Airway Inflammation in Nonobstructive and Obstructive Chronic Bronchitis with Chronic Haemophilus influenzae Airway Infection . Comparison with Noninfected Patients with Chronic Obstructive Pulmonary Disease Am. J. Respir. Crit. Care Med., September 1, 2000; 162(3): 947 - 952. [Abstract] [Full Text]
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M. WHYTE, R. HUBBARD, R. MELICONI, M. WHIDBORNE, V. EATON, C. BINGLE, J. TIMMS, G. DUFF, A. FACCHINI, A. PACILLI, et al. Increased Risk of Fibrosing Alveolitis Associated with Interleukin-1 Receptor Antagonist and Tumor Necrosis Factor-alpha Gene Polymorphisms Am. J. Respir. Crit. Care Med., August 1, 2000; 162(2): 755 - 758. [Abstract] [Full Text] [PDF]
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 P. J. Barnes Chronic Obstructive Pulmonary Disease N. Engl. J. Med., July 27, 2000; 343(4): 269 - 280. [Full Text] [PDF]
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C. Patuzzo, L. S. Gile, M. Zorzetto, E. Trabetti, G. Malerba, P. F. Pignatti, and M. Luisetti Tumor Necrosis Factor Gene Complex in COPD and Disseminated Bronchiectasis Chest, May 1, 2000; 117(5): 1353 - 1358. [Abstract] [Full Text] [PDF]
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W. MacNee Oxidants/Antioxidants and COPD Chest, May 1, 2000; 117(5_suppl_1): 303S - 317S. [Abstract] [Full Text] [PDF]
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T Ishii, T Matsuse, S Teramoto, H Matsui, M Miyao, T Hosoi, H Takahashi, Y Fukuchi, and Y Ouchi Glutathione S-transferase P1 (GSTP1) polymorphism in patients with chronic obstructive pulmonary disease Thorax, August 1, 1999; 54(8): 693 - 696. [Abstract] [Full Text]
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P. J Barnes Genetics and pulmonary medicine bullet 9: Molecular genetics of chronic obstructive pulmonary disease Thorax, March 1, 1999; 54(3): 245 - 252. [Full Text]
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J. Hull and A. H Thomson Contribution of genetic factors other than CFTR to disease severity in cystic fibrosis Thorax, December 1, 1998; 53(12): 1018 - 1021. [Abstract] [Full Text]
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