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(Chest. 2002;122:416-420.)
© 2002 American College of Chest Physicians

Association of Tumor Necrosis Factor-{alpha} Gene Promoter Polymorphism With Low Attenuation Areas on High-Resolution CT in Patients With COPD*

Seiichiro Sakao, MD; Koichiro Tatsumi, MD; Hidetoshi Igari, MD; Reiko Watanabe, MD; Yuji Shino, MD; Hiroshi Shirasawa, MD and Takayuki Kuriyama, MD, FCCP

* From the Association of Non-University Pulmonary Specialist Physicians Affiliated to the Chiba University School of Medicine, Department of Respirology (B2) [Drs. Sakao, Tatsumi, Igari, Watanabe, and Kuriyama], and Molecular Virology (E2) [Drs. Shino and Shirasawa], Graduate School of Medicine, Chiba University, Chiba, Japan.

Correspondence to: Seiichiro Sakao, MD, Department of Respirology (B2), Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuou-ku, Chiba 260-8670, Japan; e-mail: sakao{at}virolo3.m.chiba-u.ac.jp


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Study objectives: Alveolar septal cell apoptosis may contribute to the pathogenesis of emphysema. Because tumor necrosis factor (TNF)-{alpha} is assumed to play an important role in the induction of apoptosis, and allele 2 of the polymorphism at position - 308 in the promoter of the TNF-{alpha} gene has been associated with alteration of TNF-{alpha} secretion in vitro, we hypothesized that genotypes containing this allele would show more destructive emphysematous changes of the lung.

Design: The percentage ratio of the low attenuation area to the corresponding lung area was evaluated using a visual scoring system for CT findings in patients with COPD (n = 84), and these patients were classified into two groups: those with a visual score < 11 and those with a visual score >= 11. A polymerase chain reaction-based assay was developed to determine the TNF-{alpha} genotype (TNF-{alpha}-308*1/2) between subjects with high and low visual scores on chest CT scans.

Results: The TNF-{alpha}-308*1/2 allele frequency tended to differ between patients with a visual score < 11 (0.90/0.10) and those with a visual score >= 11 (0.81/0.19) [odds ratio, 2.15; 95% confidence interval, 0.87 to 5.30; p = 0.09].

Conclusion: These results indicate that the TNF-{alpha}-308 allele 2 may be partly associated with the extent of emphysematous changes in patients with COPD.

Key Words: apoptosis • COPD • emphysema • tumor necrosis factor-{alpha}


   Introduction
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 Abstract
 Introduction
Materials and Methods
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 Discussion
 References
 
CT has been recognized to detect the histologic structure of the lung and to be useful in the diagnosis and evaluation of various kinds of lung parenchyma diseases. In patients with COPD, low attenuation areas on CT scans have been reported to represent emphysematous changes of the lung.1 2 3

There are two established hypotheses in the pathogenesis of emphysematous changes of the lung in patients with COPD. One is the protease-antiprotease hypothesis, and the other is the oxidant-antioxidant hypothesis. Recent studies4 5 suggest that apoptosis may also occur in vascular endothelial and/or alveolar epithelial cells in COPD patients with emphysematous changes of the lung, potentially contributing thereby to the lung tissue destruction observed in these patients.

Tumor necrosis factor (TNF)-{alpha} is a potent modulator of immune and inflammatory responses, and has been implicated in a variety of diseases, including COPD. TNF-{alpha} was found to be elevated in BAL fluid, bronchial biopsy specimens, and induced sputum of patients with COPD.6 TNF-{alpha} promotes tracheal smooth-muscle proliferation,7 alters smooth-muscle function,8 and inhibits synthesis of phosphatidylcholine, which serves as an integral component of pulmonary alveolar surfactant.9 These studies suggest that TNF-{alpha} may contribute to the airway remodeling and alter smooth-muscle cell function in patients with COPD. In addition to these properties, TNF-{alpha} activates sphingomyelin hydrolysis, leading to the increase of ceramide levels that temporally precedes the occurrence of apoptosis.10 11 Therefore, TNF-{alpha} may play an important role in the occurrence of apoptosis of alveolar epithelial cells.

A polymorphism at the - 308 position of the TNF-{alpha} gene promoter has been described. This is a guanine to adenine substitution in the TNF-{alpha} gene at position - 308 in the promoter region (the guanine allele was denoted as 1, and the adenine allele was denoted as 2). TNF-{alpha}-308*2, the rarer allele, has been associated with higher baseline and induced expression of TNF-{alpha}.12 Several studies have demonstrated a positive association with the presence of the TNF-{alpha}-308*2 allele in a number of inflammatory diseases, such as asthma13 and sarcoidosis.14 A prior study15 showed an association between the TNF-{alpha}-308*2 allele and the risk of development of chronic bronchitis in a male Taiwanese population. And we have previously shown an association between the TNF-{alpha}-308*2 allele and the risk of the development of COPD in a Japanese population.16 However, another study17 showed no association between the TNF-{alpha}-308*2 allele and the severity of cigarette smoking-related COPD in a white population.

The differences in the association between COPD in Oriental and white populations may not be explained by differences in TNF-{alpha}-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 cigarette smoking-related COPD to exclude other factors related to diffuse panbronchiolitis that are mainly observed in Japanese and Southeast Asians. The purpose of the present study was to determine whether TNF-{alpha}-308*1/2 polymorphism was associated with the emphysematous changes revealed by high-resolution CT (HRCT) in patients with COPD.


   Materials and Methods
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 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Subjects
The subjects consisted of 84 patients with cigarette smoking-related COPD who underwent HRCT, recruited from the Respiratory Outpatient Department of Chiba University Hospital and affiliated hospitals. COPD was diagnosed on the basis of history, physical examination, and spirometric data, according to the American Thoracic Society guidelines.18 Pulmonary function tests were performed to determine FVC and FEV1 using a standard spirometer (Fudac-60; Fukuda Denshi; Tokyo, Japan) in the standing position. Chronic airflow obstruction was defined as FEV1/FVC < 70% and FEV1 < 80% of predicted values. Predicted values were calculated according to the Japanese Thoracic Society criteria on standardized lung function testing. Subjects were excluded if they had a 3-month history of productive cough in each of 2 successive years (chronic bronchitis). The Research Ethics Committee of Chiba University School of Medicine, Chiba, Japan, approved the study, and all subjects gave their informed consent in writing.

Detection of TNF-{alpha} Polymorphism
Genotype was analyzed by the polymerase chain reaction (PCR) restriction fragment-length polymorphism technique. Genomic DNA was obtained from blood lymphocytes using QIAamp DNA Blood Mini Kit (Qiagen; Valencia, CA). The 5' region of TNF-{alpha} gene (331 to 14) was amplified, and the PCR conditions were similar to those already described19 with some modifications16 : the 5' primer was 5'-AGGCAATAGGTTTTGAGGGCCAT and the 3'-primer was 5'-GAGCGTCTGCTGGCTGGGTG. As for PCR conditions, genomic DNA was amplified using 0.2 mol/L concentrations of the primers, 100 mol/L each of deoxynucleoside triphosphate, 10 mM Tris, 1.5 mM MgCl2, 50 mM KCl, and 0.1% Triton X-100. As for cycling, incubation was at 94°C for 1 min, 60°C for 1 min, and 72°C for 1 min for 30 cycles followed by incubation at 60°C for 1 min and 72°C for 5 min. The PCR product was ethanol precipitated and digested with Nco1 (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 base pair [bp] and 20 bp, respectively), while the TNF2 allele would not be digested (345 bp).

CT
HRCT was performed in the supine position with 2-mm collimation and scanning time of 1.0 s. Scanning was performed at full inspiration at three selected anatomic levels: (1) 1 cm above the superior margin of the aortic arch (upper lung fields), (2) 1 cm below the carina (middle lung fields), and (3) 3 cm above the top of the diaphragm (lower lung fields).20 Hardcopy images were photographed using a window setting appropriate for the lungs (level, 900 Hounsfield units; width, 700 Hounsfield units).

The images obtained at each examination were scored for emphysema. The degree of emphysema was judged subjectively using the scoring method of Goddard and coworkers1 for the three HRCT slices. Emphysematous destruction was identified as areas of low attenuation and hypovascularization in the lungs.1 2 21 Using a 5-point scale, the percentage of the lung affected by emphysema was determined for each level: 0, no emphysema; 1, 1 to 25% involvement; 2, 26 to 50% involvement; 3, 51 to 75% involvement; and 4, 76 to 100% involvement. The emphysema score was calculated by adding together the scores for the six hemislices obtained at the three anatomic lung levels and dividing it by the total possible maximal score for each individual. Herein, we designate the sum of these grades (0 to 24 points) as the visual score. Because Wright and coworkers21 demonstrated the feasibility of scoring an entire lung by using only the upper or lower lobe, we used the data for three selected anatomic levels. Three pulmonary physicians, who were blind to the clinical or physiologic results of individual patients, independently evaluated the magnitude of emphysematous changes. The average of the scores given by the three physicians was used. Previous reports22 23 have already shown good intraobserver and interobserver correlations for the subjective estimation of emphysema. In the present study, COPD patients were classified based on their median visual score into those with severe emphysematous changes (visual score >= 11) and those with mild or moderate emphysematous changes (visual score < 11). This system was chosen because leaving two groups of approximately the same size usually maximizes the statistical power of any comparison.

Statistical Analysis
Allele and genotype frequencies among the groups were compared with values predicted by the Hardy-Weinberg equilibrium. The difference in allele frequency among the groups was examined for statistical significance by {chi}2 test for independence, and with Fisher exact test when appropriate. Age, smoking index expressed as pack-years, and pulmonary function parameters were compared using the Mann-Whitney U test. The correlation between visual scores and FEV1/FVC was evaluated by Spearman rank correlation test. Differences were considered significant at p < 0.05.


   Results
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 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Fifty-three men and 31 women were recruited to the cigarette smoking-related COPD group. Age, smoking history, and pulmonary function data of COPD patients are summarized in Table 1 . COPD patients were classified by the median visual score: those with a visual score >= 11 and those with a visual score < 11. No significant differences were observed in age or smoking history between patients with a visual score >= 11 and patients with a visual score < 11. FEV1/FVC and FEV1 percent predicted were significantly lower in patients with a visual score >= 11. The correlations between the visual score and the severity of COPD are shown in Figure 1 . A significant correlation was observed between the visual scores and FEV1/FVC (r = 0.63, p < 0.0001).


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  		Table 1.. Age, Smoking, and Pulmonary Function in Patients With Smoking-Related COPD*

 


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  		Figure 1.. Visual score and severity of COPD. The emphysema score was calculated by adding together the scores for the six hemislices obtained at the three anatomic lung levels, and dividing it by the total possible maximal score for each individual. Herein, we designate the sum of these grades (0 to 24 points) as the visual score. Pulmonary function tests were performed to determine FVC and FEV1 using a standard spirometer in the standing position. A significant correlation was observed between visual scores and FEV1/FVC (r = 0.63, p < 0.0001).

 
The results of the comparison of the base composition at position - 308 of the TNF-{alpha} gene are summarized in Table 2 . The allele and genotype frequencies for the study population are consistent with that predicted by the Hardy-Weinberg equilibrium. The distribution of the genotype did not differ between the two groups (p = 0.2186). However, the frequency of the TNF-{alpha}-308*2 allele tended to be higher in patients with a visual score >= 11 than in patients with a visual score < 11 (p = 0.09) [odds ratio, 2.15; 95% confidence interval, 0.87 to 5.30].


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  		Table 2.. Genotype and Allele Frequencies in Patients With Cigarette Smoking-Related COPD*

 

   Discussion
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In the present study, we compared the frequency of a polymorphism in the promoter region of the TNF-{alpha} gene (designated TNF-{alpha}-308*1/2) in Japanese patients with cigarette smoking-related COPD showing severe (visual score >= 11) and mild or moderate emphysematous changes (visual score < 11). The ages and smoking habits were similar between these two groups. The frequency of the TNF-{alpha}-308*2 allele tended to be higher in patients with a visual score >= 11 than in patients with a visual score < 11 (p = 0.09). This suggested that the presence of the TNF-{alpha}-308*2 allele could be partly associated with an increased risk for the extent of emphysematous changes in COPD patients compared with TNF-{alpha}-308*1 homozygous subjects.

In Japan, panlobular emphysema, which is classically associated with {alpha}1-antitrypsin deficiency, is extremely rare, and centrilobular emphysema associated with tobacco smoking is most common.24 Although HRCT represents a great advance in the diagnosis of centrilobular emphysema, it may not be sensitive enough to detect early abnormalities, such as dilation of respiratory bronchioles. However, this may not have influenced our results, because we classified COPD patients into two groups. HRCT is a noninvasive radiographic technique that detects findings that correlate closely with the morphologic diagnosis of emphysema.1 2 3 20 21 22

TNF-{alpha}-308*2 rare allele was found to be associated with higher baseline and inducible TNF-{alpha} expression in transcription studies in vitro12 ; thus, the possibility of an association between this allele and disease manifestation has been evaluated in various diseases. The results of these studies, however, have been inconsistent. Some investigators25 showed that TNF-{alpha} genotypes do influence the severity of infectious diseases, while others13 have concluded that TNF-{alpha} promoter polymorphisms are of no functional consequence and exist solely because they are in linkage disequilibrium with selected human leukocyte antigen alleles. The actual biological effect of this rare allele in vivo has not been clearly demonstrated, and no effect of TNF-{alpha}-308*1/2 genotype on circulating TNF-{alpha} has been observed.26 However, a review27 regarding the polymorphism of TNF-{alpha} promoter presented a new analysis of the available data that suggests that the polymorphism in the TNF-{alpha} promoter is not randomly distributed and that, therefore, it is most likely to have some functional and selected effect.

A higher frequency of TNF-{alpha}-308*2 allele was found in the patients with a visual score >= 11 on CT scans (p = 0.09). This suggests that higher production of TNF-{alpha} in the patients with the TNF-{alpha}-308*2 allele may accelerate an inflammatory process induced by direct exposure to inhaled agents, such as cigarette smoke, leading to the destructive changes manifested by low attenuation areas in COPD patients with emphysematous changes. The previously reported differences of the TNF-{alpha}-308*2 allele frequency between COPD patients and control subjects may be due to the subgroup of severe COPD patients.16 Alternatively, a yet-to-be-defined marker in linkage disequilibrium with the TNF-{alpha}-308 polymorphism on chromosome 6 might be functionally implicated. In addition, COPD is a complex genetic disease, because only 10 to 20% of smokers have symptomatic COPD develop, and the number of packs of tobacco that patients smoked per year varied widely. Therefore, different risk alleles may be important in different populations because of differences among populations in amount or type of exposure to environmental factors.

It has been demonstrated that alveolar type II epithelial cells treated with TNF-{alpha} undergo a gradual increase in apoptosis after prolonged culture, a process that is accelerated by exposure of cells to ultraviolet light.28 This suggests that TNF-{alpha} may induce changes in alveolar cells that make them susceptible to apoptosis by any stress. A prior study29 showed that in adult humans with diffuse alveolar injury, alveolar type II epithelial cells become hyperplastic and undergo apoptosis. Another study30 also demonstrated that fibroblasts isolated from patients with pulmonary fibrosis secrete a factor that induces apoptosis of alveolar epithelial cells. This body of evidence led us to hypothesize that TNF-{alpha} may play an important role in the pathogenesis of emphysematous changes in patients with COPD by inducing apoptosis of alveolar type II cells that serve as stem cells for the repair of the alveolar injury.

In conclusion, we found that the TNF-{alpha}-308*1/2 gene promoter polymorphism may partly play a role in the development of emphysematous changes in COPD patients. However, the determinants between patients having COPD-prone emphysematous changes develop and patients resistant to it may not be explained by a single gene polymorphism.


   Acknowledgements
 
We thank Drs. Katsutoshi Nakayama and Mutsuo Yamaya, Department of Geriatric Medicine, Tohoku University School of Medicine for technical assistance.


   Footnotes
 
Abbreviations: bp = base pair; HRCT = high-resolution CT; PCR = polymerase chain reaction; TNF = tumor necrosis factor

This study was in part supported by a Grant-in-Aid for Scientific Research (C) from the Ministry of Education, Science, and Culture, and a research grant by Respiratory Failure Research Group from the Ministry of Health and Welfare, Japan.

Received for publication July 16, 2001. Accepted for publication February 5, 2002.


   References
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 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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