A Polymorphism in the Tumor Necrosis Factor-α Gene Promoter Region May Predispose to a Poor Prognosis in COPD

doi:10.1378/chest.118.4.971

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Volume 118, Issue 4, October 2000, Pages 971-975

https://doi.org/10.1378/chest.118.4.971 Get rights and content

Study objectives:

To determine whether the adenine(A)-guanine (G) substitution polymorphism at position - 308 on thetumor necrosis factor-α gene confers susceptibility to COPD or to thedevelopment of a more severe form of disease.

Design:

A cross-sectional study was undertaken to compare the frequency of the A allele in a group of 106 patients with COPD with that in a controlpopulation (n = 99). Patients were followed up prospectively for aperiod of 2 years.

Participants and setting:

Participants included 106 COPD patients recruited from a respiratoryoutpatient clinic and 99 control subjects recruited from patientsadmitted for cardiac catheterization.

Measurements andresults:

DNA was extracted from venous blood, and each subjectwas genotyped for the polymorphism by polymerase chain reactionamplification and restriction digestion using Nco1. There was noincreased frequency of the A allele in patients compared to controlsubjects. AA homozygous patients had less reversible airflowobstruction (p < 0.05) and a significantly greater mortality (bothall-cause and respiratory deaths) on follow-up (p < 0.001), despitea shorter cigarette smoking history.

Conclusions:

Thisstudy suggests that homozygosity for this A allele predisposes to moresevere airflow obstruction and a worse prognosis in COPD.

Section snippets

Materials and Methods

One hundred six volunteers with stable COPD and 99 controlsubjects were recruited. The study was approved by St Vincent'sHospital Ethics Committee, and all subjects gave informed consent. Patients with COPD had stable disease and were recruited from therespiratory outpatient clinic at St Vincent's Hospital, Dublin. Inclusion criteria for patients with COPD were as follows: stabledisease, FEV₁ < 70% predicted, FEV₁/FVC < 70%, smoking history > 20pack-years, and improvement in FEV₁

Results

Patient and control characteristics are shown in Table 1. There was no statistical difference in age or smoking history betweengroups. There was no difference in the frequency of the GG and GAgenotypes in the COPD population compared with control subjects (Table 2). Six patients in the COPD and three patients in the control group wereAA homozygous, but this was not statistically significant. The genotypefrequencies in patient and control groups did not deviate fromHardy-Weinberg equilibrium.

Discussion

This study demonstrates that there is no difference in frequencyof the A and G alleles in patients with COPD compared to controlsubjects. The patients with AA homozygosity, however, had similardegree of airways obstruction despite a lower total cigarette smokinghistory. In addition, after almost 2 years of prospective follow-up, the patients with AA homozygosity had a significantly greater mortalitythan the heterozygote or GG homozygous groups.

The major etiologic factor for the development of

ACKNOWLEDGMENT

The authors also thank Drs. W. T. McNicholas, B. Maurer, and P. Quigley for permission to recruit patients under theircare.

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Lancet
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The -308 tumor necrosis factor-α promoter polymorphism effects transcription
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TD Tetley
New perspectives on basic mechanisms in lung disease: 6. Proteinase imbalance; its role in lung disease
Thorax
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Y Higashimoto et al.
Inhibition of alveolar macrophage production of TNFα by acute in vivo and in vitro exposure to cigarette smoke
Respiration
(1992)

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Association between single-nucleotide polymorphism of cytokines genes and chronic obstructive pulmonary disease: A systematic review and meta-analysis
2023, Cytokine
Chronic obstructive pulmonary disease (COPD) is a common chronic inflammatory disease with high morbidity and mortality rates worldwide. Cytokines, which are the main regulators of immune responses, play crucial roles in inflammatory diseases such as COPD. Moreover, certain genetic variations can alter cytokine expression, and changes in cytokine level or function can affect disease susceptibility. Therefore, investigating the association between genetic variations and disease progression can be useful for prevention and treatment. Several studies have explored the association between common genetic variations in cytokine genes and COPD susceptibility. In this study, we summarized the reported studies and, where possible, conducted a systematic review and meta-analysis to evaluate the genetic association between various cytokines and COPD pathogenesis.
We extracted relevant articles from PubMed and Google Scholar databases using a standard systematic search strategy. We included a total of 183 studies from 78 separate articles that evaluated 50 polymorphisms in 12 cytokine genes in this study. Our analysis showed that among all reported cytokine polymorphisms (including TNF-α, TGF-β, IL1, IL1RN, IL4, IL4R, IL6, IL10, IL12, IL13, IL17, IL18, IL27, and IL33), only four variants, including TNF-α-rs1800629, TGF-β1-rs6957, IL13-rs1800925, and IL6-rs1800796, were associated with the risk of COPD development.
This updated meta-analysis strongly supports the association of TNF-α-rs1800629, TGF-β1-rs6957, IL13-rs1800925, and IL6-rs1800796 variants with a high risk of COPD.
TNF-α −308 G/A variant and susceptibility to chronic obstructive pulmonary disease: A systematic review and meta-analysis
2019, Cytokine
TNF-α −308 G/A variant is recognized to play an important role in the pathogenesis of chronic obstructive pulmonary disease (COPD). Although many studies have investigated the association of TNF-α−308 and COPD risk, a deep understanding of this association is lacking due to small subjects sizes and insufficiently study designs among different investigations. In this study, a systematic review and meta-analysis was performed based on published reports on the association of TNF-α and COPD.
The published studies concerned the association between TNF-α and COPD were identified using a systematic research in Scopus, Google Scholar, and PubMed up to April 2018. A total of 46 different papers studying the rs1800629 variant in TNF-α gene were included. Then, human studies were selected to further analysis regardless of papers language.
Based on the results, the major outcome of this meta-analysis can be represented as follows: individuals with GG and GA genotypes possess less risk of developing COPD (OR = 0.58, 95%CI: (0.44–0.79), P < 0.00) compared to AA genotype carriers. In contrast, the AA genotype carriers of the TNF-α rs1800629 has a significantly higher risk of developing COPD (OR = 1.83, 95%CI: (1.34–2.51), P < 0.00) compared to GG carrier. Despite the previous meta-analysis results which reported significantly decreasing of heterogeneity with ethnicity, we found that the source of controls has a significant contribution to observed heterogeneity.
Thanks to the global burden of COPD studies, proving TNF-α 308 gene variant as an independent factor in its pathogenesis opens new insights to diagnosis and management of COPD.
Tumor necrosis factor-α (TNF-α)-308G/A promoter polymorphism in colorectal cancer in ethnic Kashmiri population - A case control study in a detailed perspective
2016, Meta Gene
Inflammation constitutes one of the important components of colorectal cancer (CRC) pathogenesis. Tumor necrosis factor-α (TNF-α), a cytokine and an important inflammatory mediator plays a pivotal role in the malignant cellular proliferation, angiogenesis, tissue invasion and metastasis in CRC. The studies on association of various polymorphisms in human TNF-α gene including TNF-α-308G/A single nucleotide polymorphism (SNP) are limited, mixed and inconclusive.
The aim of this study was to analyze the association of TNF-α-308G/A promoter SNP with colorectal cancer (CRC) susceptibility and development risk and also to evaluate the modifying effects of possible TNF-α-308G/A genotypes on different risk factors of CRC in ethnic population of Kashmir, India through a case–control setup. The genotype frequencies of TNF-α-308G/A promoter SNP were compared between 142 CRC patients and 184 individually matched healthy controls by using polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) method. The associations between the TNF-α-308G/A SNP and CRC risk were examined through conditional logistic regression models adjusted for multiple possible confounding (third) variables. Further, the associations between this SNP and various clinico-pathological parameters, demographic variables and environmental factors within the case group subjects with regard to CRC risk were also evaluated.
The association between the TNF-α-308G/A SNP and the modulation of risk of CRC was not found to be significant (p value = 0.156). The effect of less common TNF-α-308A allele on the risk of colorectal cancer was also not found to be significant (p value = 0.175). The variant genotype (AA) was nonexistent in the study population. Further, we found no significant effect modulation of CRC risk by wild and heterozygous TNF-α-308G/A SNP genotypes in presence of different possible risk factors (p > 0.05). We also found no significant association of TNF-α-308G/A SNP with the subsets of various characteristics of the case group subjects under study (p > 0.05).
This study indicates that there is no significant association between the TNF-α-308G/A promoter SNP and the risk of developing CRC in ethnic Kashmiri population. However, in order to substantiate our findings, this study needs to be replicated with bigger sample size and should involve other ethnically defined populations with high CRC risk.
Is TNF-α gene polymorphism related to pulmonary functions and prognosis as determined by FEV<inf>1</inf>, BMI, COPD exacerbation and hospitalization in patients with smoking-related COPD in a Turkish population?
2014, Revista Portuguesa de Pneumologia
Citation Excerpt :
The FEV1 value was the most commonly used parameter for monitoring disease progression.15 Only one report exists that evaluates the prognosis of TNF-α-308 gene polymorphism in COPD patients.12 Keatings et al. showed that AA homozygous patients had less reversible airflow obstruction and a significantly greater mortality (both all-cause and respiratory deaths) on follow-up despite a shorter cigarette smoking history.
Some conflicting results have been published about the relationship between TNF-α-308 gene polymorphism and chronic obstructive pulmonary disease (COPD). The aim of this study was to determine whether TNF-α-308 gene polymorphism was associated with smoking-related COPD and whether it was associated with pulmonary function parameters (PFTs), body mass index (BMI), and prognosis.
We studied the frequencies of TNF-α-308 gene polymorphism in 90 male subjects (60 subjects with COPD and 30 healthy smokers) in a Caucasian population.
There was no significant difference in the frequency of G/G and G/A gene polymorphisms in the COPD group compared with control subjects (p > 0.05). We compared COPD patients as G/A gene polymorphism and G/G gene polymorphism; the PFTs and BMI before and after one year were not statistically significant (p > 0.05). Also, the exacerbation and hospitalization data of COPD patients were not significant between these groups.
In conclusion, there was no difference between smoking-related COPD and the control group according to TNF α-308 gene polymorphism in a Caucasian population. In addition, it was shown that important determinants of prognosis of COPD such as FEV₁, BMI, COPD exacerbation and hospitalization were not associated with TNF-α-308 gene polymorphism.
Foram publicados alguns resultados contraditórios sobre a relação entre o polimorfismo do gene TNF-α -308 e a doença pulmonar obstrutiva crónica (DPOC). O objectivo deste estudo foi determinar se o polimorfismo do gene TNF-α -308 estava associado à DPOC ligada ao tabagismo e se foi associado aos parâmetros de função pulmonar (PFTs), índice de massa corporal (IMC), e prognóstico.
Estudámos as frequências do polimorfismo do gene TNF-α -308 em 90 indivíduos do sexo masculino (60 indivíduos com DPOC e 30 fumadores saudáveis) numa população caucasiana.
Não houve uma diferença significativa na frequência de polimorfismos genéticos G/G e G/A no grupo de DPOC, em comparação com o grupo de controlo (p>0,05). Comparámos os doentes com DPOC como polimorfismo genético G/A e polimorfismo genético G/G; os PFTs (parâmetros de função pulmonar) e o IMC (índice de massa corporal) antes e depois de um ano não eram estatisticamente significativos (p>0,05). Da mesma forma, os dados de agravamento e hospitalização dos doentes com DPOC não eram significativos entre estes grupos.
Em conclusão, não existiu uma diferença entre o grupo com DPOC ligada ao tabagismo e o grupo de controlo, de acordo com o polimorfismo do gene TNF α -308, numa população caucasiana. Além disso, foi mostrado que determinantes importantes do prognóstico da DPOC, tal como VEMS, IMC, exacerbações da DPOC e hospitalização não estavam associados ao polimorfismo do gene TNF-α -308.
Molecular heterogeneity of head and neck squamous cell carcinoma defined by next-generation sequencing
2014, American Journal of Pathology
Citation Excerpt :
Overall, the sequencing data showed key differences in the genetic alterations identified in the cancer-related genes and signaling pathways of HPV+ and HPV− HNSCC. Our analysis showed a higher incidence of the TNFA proinflammatory −308A allele (37.2%) in HNSCC patients, irrespective of HPV infection, compared with the documented allele frequency in different ethnic groups.21–24 This observation corroborates earlier report of an association between the −308 TNFA SNP and HNSCC in a European cohort25 and points toward a potential role for TNF-α as a risk factor in the pathogenesis of HNSCC.
Head and neck squamous cell carcinoma (HNSCC) can be divided into two different clinical entities based on their association with high-risk subtypes of human papilloma virus (HPV16 and HPV18). Dissimilarities in prognosis and molecular profiles have attracted much attention in recent years, in part because of increasing rates of HPV infection in HNSCC; however, the underlying mechanisms and detailed genetic profiles that set these tumors apart are still elusive. To elucidate oncogenic pathways in HNSCC with and without HPV infection, we used targeted next-generation sequencing to interrogate single-nucleotide polymorphisms (SNPs) in 50 cancer-related genes. We detected SNPs in 25 of these genes from HNSCC tissue specimens with and without HPV infection. In 5 of the 25 genes, variant patterns were similar regardless of HPV infection status. A greater number of sequence variants in genes from the tyrosine kinase receptors and their associated pathways were preferentially present in HPV⁺ specimens. SNPs in genes related to tumor-suppressor functions were more prevalent in HPV⁻ HNSCC specimens. The observations may help to elucidate mechanisms involved in the molecular pathogenesis of two clinically diverse subclasses of HNSCC. Over-representation of SNPs in either HPV⁺ or HPV⁻ HNSCC is another indicator of potentially actionable sequence variants for targeted therapy.
Effects of active smoking on airway and systemic inflammation profiles in patients with chronic obstructive pulmonary disease
2013, American Journal of the Medical Sciences
Citation Excerpt :
Therefore, smoking status should always be included as a confounder in studies directed to evaluate the inflammatory status in patients with COPD. In addition, as TNF-α appears to play a key role in the pathogenesis of COPD and to be related to systemic manifestation of the disease, downregulation of this cytokine may bring benefits to the disease management and could be obtained,18,19 at least partially, by smoking cessation.18 In this study, current and ex-smokers with COPD presented similar sputum concentrations of TNF-α, whereas in both groups the levels of TNF-α were higher than those observed in current smokers without COPD.
The markers that characterize local and systemic inflammation in chronic obstructive pulmonary disease (COPD) remain unclear, as do their correlations with smoking status and presence of disease. The aim of this study was to assess markers of inflammation in the peripheral blood and airways of current smokers without COPD, of current smokers with COPD and of ex-smokers with COPD.
In this study, 17 current smokers with COPD (mean age: 58.2 ± 9.6 years; mean forced expiratory volume in 1 second [FEV₁]: 56.1 ± 15.9%), 35 ex-smokers with COPD (mean age: 66.3 ± 7.3 years; mean FEV₁: 47.9 ± 17.2%) and 20 current smokers without COPD (mean age: 49.1 ± 6.2 years; mean FEV₁: 106.5 ± 15.8%) were evaluated. Spirometry findings, body composition and serum/induced sputum concentrations of tumor necrosis factor α (TNF-α), interleukin (IL)-6, IL-8 and IL-10, together with serum C-reactive protein (CRP) levels, were assessed.
Serum TNF-α concentration was higher in all current smokers than in ex-smokers with COPD. In current smokers without COPD, serum CRP level was lower than in ex-smokers with COPD and significantly lower than in current smokers with COPD. Sputum TNF-α concentration was higher in current and ex-smokers with COPD than in current smokers without COPD. Multiple regression analyses showed that serum TNF-α was associated with active smoking, and serum CRP and sputum TNF-α were associated with COPD diagnosis.
Smoking is associated with higher systemic inflammation in patients with COPD. Current findings also support the hypothesis that smoking and COPD have different effects on the regulation of airway and systemic inflammatory processes.

View all citing articles on Scopus

: Supported by EU Biomed 2 programme, grant No. BMH4-CT96–0152, andIrish Thoracic Society Travelling Fellowship 1998.

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Chest

Study objectives:

Design:

Participants and setting:

Measurements andresults:

Conclusions:

Section snippets

Materials and Methods

Results

Discussion

ACKNOWLEDGMENT

References (18)

Alternative projections of mortality and disability by cause 1990–2020: global burden of disease study

Lancet

The -308 tumor necrosis factor-α promoter polymorphism effects transcription

Mol Immunol

Morbidity and mortality from chronic obstructive pulmonary disease

Am Rev Respir Dis

Intraluminal airways inflammation in chronic bronchitis: characterization and correlation with clinical parameters

Am Rev Respir Dis

Differences in interleukin-8 and tumor necrosis factor-α in induced sputum from patients with chronic obstructive pulmonary disease and asthma

Am J Respir Crit Care Med

TNFα alters human bronchial reactivity and induces inflammatory cell influx

Am Rev Respir Dis

Extracellular proteolysis of fibronectin by neutrophils: characterization and the effects of recombinant cytokines

Am J Respir Cell Mol Biol

New perspectives on basic mechanisms in lung disease: 6. Proteinase imbalance; its role in lung disease

Thorax

Inhibition of alveolar macrophage production of TNFα by acute in vivo and in vitro exposure to cigarette smoke

Respiration

Cited by (102)

Association between single-nucleotide polymorphism of cytokines genes and chronic obstructive pulmonary disease: A systematic review and meta-analysis

TNF-α −308 G/A variant and susceptibility to chronic obstructive pulmonary disease: A systematic review and meta-analysis

Tumor necrosis factor-α (TNF-α)-308G/A promoter polymorphism in colorectal cancer in ethnic Kashmiri population - A case control study in a detailed perspective

Is TNF-α gene polymorphism related to pulmonary functions and prognosis as determined by FEV<inf>1</inf>, BMI, COPD exacerbation and hospitalization in patients with smoking-related COPD in a Turkish population?

Molecular heterogeneity of head and neck squamous cell carcinoma defined by next-generation sequencing

Effects of active smoking on airway and systemic inflammation profiles in patients with chronic obstructive pulmonary disease

Chest

Clinical InvestigationsCOPDA Polymorphism in the Tumor Necrosis Factor-α Gene Promoter Region May Predispose to a Poor Prognosis in COPD

Study objectives:

Design:

Participants and setting:

Measurements andresults:

Conclusions:

Section snippets

Materials and Methods

Results

Discussion

ACKNOWLEDGMENT

Lancet

Mol Immunol

Morbidity and mortality from chronic obstructive pulmonary disease

Am Rev Respir Dis

Intraluminal airways inflammation in chronic bronchitis: characterization and correlation with clinical parameters

Am Rev Respir Dis

Differences in interleukin-8 and tumor necrosis factor-α in induced sputum from patients with chronic obstructive pulmonary disease and asthma

Am J Respir Crit Care Med

TNFα alters human bronchial reactivity and induces inflammatory cell influx

Am Rev Respir Dis

Extracellular proteolysis of fibronectin by neutrophils: characterization and the effects of recombinant cytokines

Am J Respir Cell Mol Biol

New perspectives on basic mechanisms in lung disease: 6. Proteinase imbalance; its role in lung disease

Thorax

Inhibition of alveolar macrophage production of TNFα by acute in vivo and in vitro exposure to cigarette smoke

Respiration

Clinical Investigations
COPD
A Polymorphism in the Tumor Necrosis Factor-α Gene Promoter Region May Predispose to a Poor Prognosis in COPD