Molecular Biology Reports

, Volume 38, Issue 1, pp 219–227

TNF-308 gene polymorphism is associated with COPD risk among Asians: meta-analysis of data for 6,118 subjects

Authors

  • Ping Zhan
    • First Department of Respiratory MedicineNanjing Chest Hospital
  • Jing Wang
    • Department of HematologyThe Affiliated Drum Tower Hospital of Nanjing University School of Medicine
  • Shu-Zhen Wei
    • Department of Respiratory Medicine, Jinling HospitalNanjing University School of Medicine
  • Qian Qian
    • Department of Respiratory Medicine, Jinling HospitalNanjing University School of Medicine
  • Li-Xin Qiu
    • Department of Medical Oncology, Cancer Hospital, Shanghai Medical CollegeFudan University
    • First Department of Respiratory MedicineNanjing Chest Hospital
    • Department of Respiratory Medicine, Jinling HospitalNanjing University School of Medicine
Article

DOI: 10.1007/s11033-010-0098-y

Cite this article as:
Zhan, P., Wang, J., Wei, S. et al. Mol Biol Rep (2011) 38: 219. doi:10.1007/s11033-010-0098-y

Abstract

Chronic obstructive pulmonary disease (COPD) is a complex polygenic disease in which gene–environment interactions play a critical role in disease onset and progression. The gene encoding tumor necrosis factor (TNF) is one of several candidate loci for the pathogenesis of COPD and is highly polymorphic. A number of studies have investigated the association between the TNF-308 polymorphisms and COPD risk in different populations, and resulted in inconsistent results. A systematic review and meta-analysis of the published studies were performed to gain a clearer understanding of this association. The PubMed, Embase, Web of Science, and CNKI databases were searched for case–control studies published from 1966 to April 2009. Data were extracted and pooled odds ratios (OR) with 95% confidence intervals (CI) were calculated. Twenty-four eligible studies, comprising 2,380 COPD cases and 3,738 controls, were included in the meta-analysis. The pooled result showed that the TNF-308 polymorphisms were significantly associated with an increased risk of COPD (OR = 1.335, 95% CI: 1.172–1.522, for allele A carriers versus G/G; OR = 1.330, 95% CI = 1.174–1.505, for allele A versus allele G). Subgroup analysis supported the results in the Asian populations, but not in the Caucasian populations. When the analysis was limited to only those studies in which the COPD cases and controls were smokers/ex-smokers, the pooled results supported the conclusion. This meta-analysis suggested that the TNF-308 A allele is a more significant risk factor for developing COPD among Asian populations, but not among Caucasians.

Keywords

TNFPolymorphismCOPDMeta-analysis

Introduction

Chronic obstructive pulmonary disease (COPD) is a major and increasing cause of morbidity and mortality worldwide. It is characterized by progressive irreversible airflow limitation, which is associated with an abnormal inflammatory response of the lungs to noxious particles or gases [1]. It is generally accepted that cigarette smoke is the most important risk factor for COPD. However, only 10–15% of smokers develop COPD [2]. Moreover, there appears to be a familial clustering of both lung function and COPD [3, 4]. These insights suggest that susceptibility to COPD may be influenced by genetic factors. α1-Antitrypsin deficiency, which is the most well-documented genetic risk factor for COPD, accounts for only an estimated 1–2% of cases [5]. Other host factors are suspected of being involved in the pathogenesis of COPD. A number of studies have been performed to identify other genetic susceptibility factors for COPD; so far, more than 25 different candidate genes have been tested [6].

Tumor necrosis factor (TNF) is a cytokine released primarily from macrophages, and is thought to play a critical role in the progression of COPD by increasing the expression of various pro-inflammatory mediators, such as interleukin-8 [7]. In 1992, the genomic polymorphism resulting in substitution of the nucleotide adenine (A) for guanine (G) at position -308 was discovered within a regulatory region of the TNF-α locus [8]. The predominant homozygous allele, the heterozygous allele and the homozygous rare allele of the TNF-308 polymorphism are known as the homozygous wild-type genotype (G/G), the heterozygote (G/A) and the homozygote (A/A), respectively. Presence of the A substitution has been shown to result in increased binding of nuclear factors and enhanced transcription of the gene [9, 10].

A relatively large number of studies have been published on the association of TNF-308 polymorphisms and COPD risk, but the findings have been inconsistent. It is possible that a single study may have been underpowered for detection of a small effect of the polymorphisms on COPD risk, especially when the sample size was relatively small. In addition, the past studies may not have been properly controlled for the potential confounding effect of smoking, a possible risk determinant for COPD. Different types of study populations and study design may also contribute to the disparate findings.

Two early studies [11, 12] which performed meta-analysis on the associations of TNF-308 polymorphisms with COPD risk, indicated that the results of the two studies identified were not in agreement with one another. In addition, there were some obvious limitations in their meta-analysis procedure. First, not all studies included were in Hardy–Weinberg equilibrium (HWE). Second, the meta-analysis [12] did not obtain information from most studies on the presence or absence of smoking history. Third, the association between the alleles of TNF-308 and COPD risk was not evaluated. Furthermore, subgroup analysis was not performed on the different types of study populations in either of the two meta-analyses. The above-cited reasons granted sufficient argument to continue research on the TNF-308 and COPD association. Therefore, we performed an updated meta-analysis on the published studies to ascertain whether the polymorphisms of TNF-308 increased the risk of COPD.

Materials and methods

Publication search

Since our study was a meta-analysis based on published articles, we did not draft a statement of patient consent or seek the approval of internal review boards. The electronic databases of PubMed, Embase, Web of Science, and China National Knowledge Infrastructure (CNKI) were searched for studies to include in the present meta-analysis, by using the terms “TNF”, “tumor necrosis factor”, “polymorphism” and “COPD”. An upper date limit of April 30, 2009 was applied; we used no lower date limit. The search was done without restriction on language, but was limited to studies that had been conducted on human subjects. We also reviewed the Cochrane Library for relevant articles. The reference lists of reviews and retrieved articles were hand searched simultaneously. Only published studies with full text articles were included. When more than one of the same patient population was included in several publications, only the most recent or complete study was included in this meta-analysis.

Inclusion criteria

The included studies met the following criteria: (1) evaluated TNF-308 polymorphism and COPD risk; (2) case–control studies; (3) supplied the number of individual genotypes in COPD cases and controls; and, (4) indicated that the distribution of genotypes among controls were in Hardy–Weinberg equilibrium.

Data extraction

Information was carefully extracted from all eligible publications independently by two authors according to the inclusion criteria listed above. Disagreement was resolved by discussion between the two authors. The following data were collected from each study: first author’s surname, year of publication, ethnicity (country of origin), source of controls, COPD definition, total numbers of cases and controls, the smoking status of cases and controls, and numbers of cases and controls with G, A, G/G, G/A, A/A genotypes. If data from any of the above categories were not reported in the primary study, items were treated as “not applicable”. We did not contact the author of the primary study to request the information. Different ethnicity descent was categorized as Asian and Caucasian. We also abstracted the information of smoking status from available studies. Subjects were divided into smokers group (including former and current smokers), non-smokers group and mixed group. We did not define any minimum number of patients as required to include a study in our meta-analysis.

Statistical analysis

Odds ratios (OR) with 95% confidence interval (CI) were used to assess the strength of association between the TNF-308 polymorphism and COPD risk. The OR of COPD associated with TNF-308 genotype, the A allele carriers (G/A + A/A) versus G/G genotype, allele A versus allele G were calculated, respectively. Subgroup analyses were carried out with respect to ethnicity and smoking status. Heterogeneity assumption was checked by the chi-square-based Q-test [13]. A P value greater than 0.10 for the Q-test indicated a lack of heterogeneity among studies, so that the pooled OR estimate of each study was calculated by the fixed-effects model (the Mantel–Haenszel method) [14]. Otherwise, the random-effects model (the DerSimonian and Laird method) was used [15]. One-way sensitivity analyses were performed to assess the stability of the results, namely, a single study in the meta-analysis was deleted each time to reflect the influence of the individual data-set on the pooled OR [16]. An estimate of potential publication bias was carried out by using the funnel plot, in which the standard error of log (OR) of each study was plotted against its log (OR). An asymmetric plot suggested a possible publication bias. Funnel plot asymmetry was assessed by the method of Egger’s linear regression test, which is a linear regression approach to measure the funnel plot asymmetry on the natural logarithm scale of the OR. The significance of the intercept was determined by the t-test, as suggested by Egger (P < 0.05 was considered representative of statistically significant publication bias) [17]. All of the calculations were performed using STATA version 10.0 (Stata Corporation, College Station, TX).

Results

Study characteristics

A total of 25 publications [11, 12, 1840] met the inclusion criteria. Of these studies, one was excluded because the same data were available in other studies [18]. Thus, a total of 24 studies [11, 12, 1940] involving 2,380 COPD cases and 3,738 controls were ultimately analyzed. Tables 1 and 2 present the main characteristics and data of these studies. Among the 24 publications, 15 were published in English and 9 in Chinese. The sample sizes ranged from 80 to 484. Almost all of the cases were confirmed by the diagnostic criteria of COPD [1, 4144]. Controls were mainly comprised of healthy populations. Twenty-one of the total 24 studies provided the number of allele A and allele G in both COPD cases and controls. There were 15 groups of Asians and 9 groups of Caucasians. Eleven studies contained enough information for subgroup analyses by smoking status. Hardy–Weinberg equilibrium had been tested for all polymorphisms in the control subjects and all were found to be in Hardy–Weinberg equilibrium.
Table 1

Main characteristics of studies included in the meta-analysis

First author-year

Ethnicity (country of origin)

Source of controls

COPD definition

Gingo MR-2008

Caucasian (American)

Healthy population

GOLD [1]

Hsieh MH-2008

Asian (China)

Healthy population

GOLD [1]

Zhang YQ-2008

Asian (China)

Healthy population

CMA criteria of 2002 [41]

Du Y-2008

Asian (China)

Healthy population

GOLD [1]

Gong Y-2008

Asian (China)

General population

CMA criteria of 2002 [41]

Shi YZ-2007

Asian (China)

Hospitalized healthy population

CMA criteria of 2002 [41]

Zhang Y-2007

Asian (China)

Hospitalized healthy population

CMA criteria of 2002 [41]

Papatheodorou A-2007

Caucasian (Greece)

Healthy smokers and a general population

GOLD [1]

Brogger J-2006

Caucasian (Norway)

General population

American Thoracic Society criteria [42]

Broekhuizen R-2005

Caucasian (Dutch)

General population-renal and bone marrow donors

GOLD [1]

Seifart C-2005

Caucasian (Germany)

General population and matched hospitalized population

Symptoms and signs; FEV1% < 80%; FEV1%FVC < 70%

Chierakul N-2005

Asian (Thailand)

General population and outpatient clinic

GOLD [1]

Hegab AE-2005

Asian (Egypt and Japan)

Hospital population

GOLD [1]

Ma ZM-2005

Asian (China)

Lung cancer patients

CMA criteria of 2002 [41]

Jiang L-2005

Asian (China)

General smoker population

CMA criteria of 2002 [41]

Zui FZ-2004

Asian (China)

Hospitalized healthy population

CMA criteria of 2002 [41]

Ma ZM-2004

Asian (China)

General population

CMA criteria of 1997 [43]

Ferrarotti I-2003

Caucasian (Italy)

Healthy smokers

American Thoracic Society criteria [42]

He B-2003

Asian (China)

General population matched age

CMA criteria of 2002 [41]

Küçükaycan M-2002

Caucasian (Dutch)

Hospital population

American Thoracic Society criteria [42]

Sakao S-2001

Asian (Japan)

General population

American Thoracic Society criteria [42]

Higham MA-2000

Caucasian (England)

General population and healthy smokers

British Thoracic Society criteria of 1997 [44]

Keatings V-2000

Caucasian (Ireland)

Outpatient clinic

FEV1 < 70% predicted, FEV1/FVC < 70%, smoking history > 20 pack-years, and improvement in FEV1 following inhalation of 200 mg albuterol < 10% of baseline FEV1.

Huang SL-1997

Asian (China)

Healthy population matched age, sex, smoking status.

FEV1 < 80% of predicted value, FEV1/FVC < 69%

GOLD Global Initiative for Chronic Obstructive Lung Disease, CMA Chinese Medicine Association

Table 2

Main data of studies included in the meta-analysis

First author-year

Number of cases/controls

COPD cases

Controls

Smoking

G

A

G/G

G/A

A/A

Smoking

G

A

G/G

G/A

A/A

Gingo MR-2008

298/125

Yes

NA

NA

220

67

11

Yes

NA

NA

105

18

2

Hsieh MH-2008

30/506

Mixed

50

8

23

6

1

Mixed

326

32

148

30

1

Zhang YQ-2008

50/50

NA

64

36

23

18

9

NA

82

18

33

16

1

Du Y-2008

128/112

Mixed

NA

NA

90

34

4

Mixed

NA

NA

94

18

0

Gong Y-2008

59/84

Yes

114

4

55

4

0

Mixed

162

30

69

24

3

Shi YZ-2007

88/96

Mixed

123

53

46

31

11

Mixed

162

30

69

24

3

Zhang Y-2007

66/51

Mixed

113

18

48

17

1

Mixed

96

6

45

6

0

  

Yes

NA

NA

28

8

0

Yes

NA

NA

17

2

0

Papatheodorou A-2007

116/309

Yes

NA

NA

101

14

1

Mixed

NA

NA

257

47

5

Brogger J-2006

244/240

Yes

391

97

159

73

12

Yes

382

98

154

74

12

Broekhuizen R-2005

99/234

NA

157

41

64

29

6

NA

380

88

158

64

12

Seifart C-2005

113/254

Mixed

182

44

73

36

4

Mixed

397

111

151

95

8

Chierakul N-2005

57/183

Yes

105

9

48

9

0

Mixed

345

21

162

21

0

        

Yes

124

10

57

10

0

Hegab AE-2005

88/61

Yes

174

2

86

2

0

Yes

122

0

61

0

0

Ma ZM-2005

50/30

NA

84

16

35

14

1

NA

57

3

27

3

0

Jiang L-2005

65/41

Yes

125

5

60

5

0

Yes

79

3

38

3

0

  

No

65

7

30

5

1

No

107

3

52

3

0

Zui FZ-2004

58/60

Mixed

96

20

42

12

4

Mixed

111

9

53

5

2

Ma ZM-2004

104/44

NA

171

37

72

27

5

NA

83

5

39

5

0

Ferrarotti I-2003

63/86

Yes

117

9

54

9

0

Yes

158

14

72

14

0

He B-2003

101/96

Mixed

191

13

90

10

1

Mixed

186

6

90

6

0

Kucukaycan M-2002

163/335

Yes

275

51

113

49

1

Mixed

565

105

237

91

7

Sakao S-2001

106/239

Yes

177

35

77

23

6

Mixed

440

38

209

22

8

        

Yes

202

18

96

10

4

Higham MA-2000

86/262

Yes

146

26

62

22

2

Mixed

436

88

181

74

7

        

Yes

107

19

45

17

1

Keatings V-2000

106/99

Yes

162

50

62

38

6

Yes

155

43

59

37

3

Huang SL-1997

42/141

Yes

68

16

27

14

1

Mixed

270

12

129

12

0

        

Yes

82

2

40

2

0

NA not applicable

Meta-analysis results

Table 3 lists the main results of this meta-analysis. Overall, for the A allele carriers (G/A + A/A), the pooled OR for all the 24 studies combined 2,380 cases and 3,738 controls was 1.335 (95% CI = 1.172–1.522; P = 0.000 for heterogeneity) (Fig. 1), when compared with the homozygous wild-type genotype (G/G). For the allele A versus allele G, 21 studies were included in the meta-analysis, and the pooled OR was 1.330 (95% CI = 1.174–1.505; P = 0.000 for heterogeneity; Fig. 2).
Table 3

Main results of pooled odds ratios with CI in the meta-analysis

 

Number of cases/controlsb

(G/A + A/A) versus G/G

A versus G

OR (95% CI)

P

P (Q-test)

OR (95% CI)

P

P (Q-test)

Total

2,380/3,738

1.335 (1.172–1.522)

0.000

0.000

1.330 (1.174–1.505)

0.000

0.000

Asian

1,092/1,794

2.189 (1.756–2.729)

0.000

0.099

2.331 (1.883–2.884)

0.000

0.477

Caucasian

1,288/1,944

1.012 (0.858–1.194)

0.886

0.458

0.978 (0.836–1.145)

0.784

0.966

Asiana

760/1,009

2.242 (1.796-2.856)

0.037

0.003

2.392 (1.935–2.749)

0.000

0.689

Caucasiana

849/948

1.104 (0.834–1.350)

0.359

0.035

0.945 (0.812–1.235)

0.468

0.699

P(Q-test): P value of Q-test for heterogeneity

aOnly the cases and controls with smoking history

bThe studies included the data for (G/A + A/A) versus G/G

https://static-content.springer.com/image/art%3A10.1007%2Fs11033-010-0098-y/MediaObjects/11033_2010_98_Fig1_HTML.gif
Fig. 1

Forest plot (random-effects model) of COPD risk associated with TNF-308 polymorphism for the A allele carriers (G/A + A/A) versus G/G genotype. Each box represents the OR point estimate, and its area is proportional to the weight of the study. The diamond (and broken line) represents the overall summary estimate, with CI represented by its width. The unbroken vertical line is set at the null value (OR = 1.0)

https://static-content.springer.com/image/art%3A10.1007%2Fs11033-010-0098-y/MediaObjects/11033_2010_98_Fig2_HTML.gif
Fig. 2

Forest plot (random-effects model) of COPD risk associated with TNF-308 polymorphism for allele A versus allele G

In the stratified analysis by ethnicity, significant risks were identified among Asians for both the A allele carriers versus G/G (OR = 2.189, 95% CI = 1.756–2.729; P = 0.099 for heterogeneity) and allele A versus allele G (OR = 2.331, 95% CI = 1.883–2.884; P = 0.477 for heterogeneity). Among Caucasians, no significant association was found in the A allele carriers versus G/G (OR = 1.012, 95% CI = 0.858–1.194; P = 0.458 for heterogeneity) or allele A versus allele G (OR = 0.978, 95% CI = 0.836–1.145; P = 0.966 for heterogeneity).

Specific environmental factors, such as smoking, may contribute to the difference in the distribution of genetic polymorphisms. A subgroup analysis was conducted of those studies in which the COPD cases and the controls were current/former smokers. All these studies were performed in Asian populations, and the pooled OR was significant (OR = 2.242, 95% CI = 1.796–2.856, for the A allele carriers versus G/G; OR = 2.392, 95% CI = 1.935–2.749 for A versus G). Among Caucasians, however, there was no significant association between the TNF-308 polymorphism and COPD risk (OR = 1.104, 95% CI = 0.834–1.350, for the A allele carriers versus G/G; OR = 0.945, 95% CI = 0.812–1.235 for A versus G). Results have been summarized in Table 3.

Sensitivity analyses

A single study involved in the meta-analysis was deleted each time to reflect the influence of the individual data set on the pooled ORs, and the corresponding pooled ORs were not materially altered (data not shown).

Publication bias

Begg’s funnel plot and Egger’s test were performed to access the publication bias of the literature. Evaluation of publication bias for the A allele carriers versus G/G showed that the Egger test was significant (P = 0.049). The funnel plots for publication bias (Fig. 3) also showed some asymmetry. These results indicated a potential for publication bias. However, for A versus G the publication bias was not found (P = 0.368; data not shown).
https://static-content.springer.com/image/art%3A10.1007%2Fs11033-010-0098-y/MediaObjects/11033_2010_98_Fig3_HTML.gif
Fig. 3

Begg’s funnel plot of TNF-308 polymorphism and COPD risk for the A allele carriers (G/A + A/A) versus G/G genotype

Discussion

There is likely to be a complex interplay between environmental and genetic factors in the development of COPD. Although the pathogenesis of COPD is unknown, it is generally accepted that an excess of oxidants and free radicals in the lung promotes cellular and tissue damage [45], indicating that oxidant/anti-oxidant imbalance may be involved in the pathogenesis of COPD [46]. Polymorphisms in the genes controlling xenobiotic metabolism (hence, oxidant/anti-oxidant balance) may explain some of the observed differences in susceptibility to various diseases caused by environmental factors, including COPD [4, 47].

In 1997, Huang et al. [40] found that the -308 A allele in the TNF promoter was associated with an increased risk of bronchitis in the Taiwanese population. Subsequently, many investigators have sought to implicate polymorphisms in TNF in the pathogenesis of COPD. To date, the results of candidate gene case–control studies have been inconsistent. Some studies have found positive associations between the polymorphisms of TNF-308 and COPD risk, while others have not. Several factors may be influencing these differences. First, if another variant in or near the TNF gene was one of the causal variants, the true association could easily be missed. Different linkage disequilibrium patterns with the functional variant may lead to variable results in different populations. It is feasible that the TNF gene variant is playing a role in cooperation with other gene variants exhibiting more limited biology. Second, several COPD association studies have shown different results in different races, suggesting racial differences may be associated with genetic risk. Finally, small sample size and specific environmental exposures, such as smoking, are also confounding factors for diseases with a strong gene–environmental interactions and may help explain the inconsistencies among the observational studies.

In the present meta-analysis, we have combined 24 eligible studies with 2,380 cases and 3,738 controls to yield summary statistics, indicating that the TNF-308 polymorphisms were significantly associated with an increased risk of COPD; the -308 A allele in the TNF promoter was determined to be a more significant risk factor for developing COPD in all populations. When analysis was restricted to Asian populations, we found that the combined OR (2.19) was larger than the combined OR for all 24 eligible studies of different populations (1.34), suggesting that the A allele of TNF could play an important role in the pathogenesis of COPD in Asians. However, in Caucasian populations, the association with TNF-308 polymorphism and COPD risk was not found for all genetic models. These findings indicate that polymorphisms of TNF-308 may be important in specific ethnic groups of COPD patients, and that the effect of A allele on the risk of COPD may differ by ethnicity. Population stratification is an area of concern and can lead to spurious evidence supporting the association between a marker and a disease, in effect suggesting a possible role of ethnic differences in genetic backgrounds and the environment they lived in [48]. In addition, it also likely that the observed ethnic differences may be due to chance because studies with small sample size may have insufficient statistical power to detect a slight effect or may have generated a fluctuated risk estimate.

Limiting our meta-analysis to studies with COPD cases and controls who were smokers/ex-smokers yielded results that supported the association between TNF-308 polymorphism and COPD in both the Asian and Caucasian population, which indicating that the interaction between A allele carriers and/or A allele and smoking status may not be an independent factor.

The present results contrast with a previous meta-analysis that included only seven studies [11]; Brogger et al. did not find any association between TNF-308 polymorphism and COPD risk. A number of factors could explain the difference. First, the present analysis included several newly-published studies that were not included in the meta-analysis by Brogger et al. Second, the present analysis included a subgroup analysis of studies in populations of different ethnicity and different smoking status with COPD cases and controls. Third, Brogger et al.’s meta-analysis was stratified by disease outcomes (COPD, emphysema, COPD and emphysema) of the cases; the present meta-analysis was restricted to COPD outcomes only.

Our data were consistent with the results of a previous meta-analysis by Gingo et al. [12] that showed an association between TNF-308 polymorphism and COPD risk. This analysis included 15 published studies, and only three Asian population studies. Gingo et al. only analyzed the genotype of the TNF-308 polymorphism associated with COPD, but did not examine the association with the allele of TNF-308 gene and COPD. In addition, that meta-analysis did not include the subgroup analysis considering populations of different ethnicity. We have improved upon that previous meta-analysis; in particular, by including more Asian studies and using a generally more comprehensive search strategy. Moreover, study selection and quality assessment were performed independently and reproducibly by two reviewers. We also explored heterogeneity and potential publication bias in accordance with published guidelines.

Meta-analysis has been recognized as an effective method to solve a wide variety of clinical questions by summarizing and reviewing the previously published quantitative research. By using meta-analysis, a multitude of genetic polymorphisms have been associated with specific disease states. Monocyte chemoattractant protein-1 promoter -2518 [49], Fc receptor-like 3 C169T [50], STAT4 [51] and FcgammaRIIa-R/H131 [52] polymorphisms were associated with systemic lupus erythematosus risk. TGFBR1 [53, 54], COX-2 [55], and XPD [56] polymorphism were associated with cancer risk, while angiotensin-converting enzyme gene polymorphism was associated with type 2 diabetes. There are several limitations inherent to meta-analysis that should be considered when interpreting these results. Firstly, heterogeneity is a potential problem when interpreting any results obtained by meta-analyses. We minimized this likelihood by performing a careful search for published studies, using explicit criteria for study inclusion, precise data extraction and strict data analysis as best as we can. However, some pooled ORs were obtained from heterogeneous studies. Secondly, only published studies were included in this meta-analysis. The presence of publication bias indicates that non-significant or negative findings may be unpublished. Lastly, the studies included in the present meta-analysis are case–control studies, not randomized population-based surveys, and may be biased by problems of stratification. It is possible that controls were not recruited from exactly the same genetic population as the COPD patients.

In conclusion, the present meta-analysis suggests that the TNF-308 polymorphisms were significantly associated with an increased risk of COPD, and the A allele appeared to be a more significant risk factor for developing COPD among Asians, but not Caucasian populations.

Acknowledgements

This study was supported in part by a grant from the Great Medical Research Program of the Nanjing Sanitary Bureau of Jiangsu Province “Personalized Therapy of No Small Cell Lung Cancer Patients”, and the Jiangsu province Natural Science Foundation of China (BK2008326).

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