Chest
Volume 117, Issue 5, May 2000, Pages 1353-1358
Journal home page for Chest

Clinical Investigations
COPD
Tumor Necrosis Factor Gene Complex in COPD and Disseminated Bronchiectasis

https://doi.org/10.1378/chest.117.5.1353Get rights and content

Background

Tumor necrosis factor (TNF) is a potent proinflammatory cytokine with increased levels in the sputum of COPD subjects. Two biallelic TNF gene complex polymorphisms have been described: LtαNcoI, in the first intron of the lymphotoxin α (previously referred to as TNF-β) gene, and TNF-308, in the promoter region of the TNF-α gene. Higher levels of TNF production are associated with allele 1 of LtαNcoI (LtαNcoI*1) and with allele 2 of TNF-308 (TNF-308*2).

Study objectives

To study the frequencies of the two TNF gene complex polymorphisms in patients with COPD and bronchiectasis.

Design

Association study.

Subjects and methods

We studied the frequencies of these polymorphisms in 66 subjects with COPD and in 23 subjects with disseminated bronchiectasis and compared them to the frequencies in 98 healthy control subjects and 45 subjects with nonobstructive pulmonary disease. Genomic DNA samples were extracted, and TNF-α and LtαNcoI polymorphisms were detected after polymerase chain reaction by restriction digestion.

Results

We found the following frequencies: the TNF-308*2 allele was detected in 11% of COPD individuals, 15% of bronchiectasis patients, 10% of healthy control subjects, and 18% of subjects with nonobstructive pulmonary disease. The LtαNcoI*1 allele was detected in 28% of COPD individuals, 30% of bronchiectasis patients, 29% of healthy control subjects, and 29% of subjects with nonobstructive pulmonary disease. We found evidence of linkage disequilibrium between the two loci (Δ = 0.068).

Conclusions

We conclude that the TNF gene complex, at least in Caucasoid individuals and for the considered polymorphisms, does not seem to play a major role as genetic risk factor in COPD and bronchiectasis.

Section snippets

Subjects

The investigation was designed as an association study, consisting of unrelated individuals recruited from the same geographic area (Pavia, Northern Italy). In such a strategy, frequencies of known mutations/polymorphisms of a given gene are compared in different groups of individuals.3 All subjects investigated were white Caucasoids of Italian descent.

Obstructed Group 1:

Sixty-six consecutive patients (60 male and 6 female patients) with COPD. The diagnosis of COPD was made according to American Thoracic Society

Results

With reference to the TNF-308 polymorphism, allele frequencies of TNF-308*1 and TNF-308*2 were 0.881 and 0.119, respectively (number of alleles counted overall, 464). Table 2 reports the frequencies in the different groups of individuals studied. Frequencies of the TNF-308*2 allele in COPD and bronchiectasis patients were 11% and 15%, respectively, whereas in nonobstructive pulmonary disease patients and healthy control subjects, they were 18% and 10%, respectively. None of the comparisons was

Discussion

Investigation of the genetic component of multifactorial disorders such as COPD is a scientific priority.18 Based on the knowledge, albeit limited, of the biochemical basis of COPD, a number of putative candidate genes for this disease may be postulated, and, among them, the TNF gene complex may play a role.1, 3 The current hypothesis of the pathogenesis of COPD, and, to a lesser extent, of disseminated bronchiectasis, deals with an imbalance between proteinases and their naturally occurring

References (29)

  • R Mueller et al.

    Different cytokine patterns in bronchial biopsies in asthma and chronic bronchitis

    Respir Med

    (1996)
  • NJ Makhatadze

    Tumour necrosis factor locus: genetic organisation and biological implications

    Hum Immunol

    (1998)
  • AJ Sandford et al.

    Genetic risk factors for chronic obstructive pulmonary disease

    Eur Respir J

    (1997)
  • EK Silverman et al.

    Genetic epidemiology of severe, early-onset chronic obstructive pulmonary disease: risk to relatives for airflow obstruction and chronic bronchitis

    Am J Respir Crit Care Med

    (1998)
  • PJ Barnes

    Molecular genetics of chronic obstructive pulmonary disease

    Thorax

    (1999)
  • VM Keatings et al.

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

    Am J Respir Crit Care Med

    (1996)
  • MC Carroll et al.

    Linkage map of the human histocompatibility complex including the tumor necrosis factor genes

    Proc Natl Acad Sci USA USA

    (1987)
  • G Messer et al.

    Polymorphic structure of the Tumour Necrosis Factor (TNF) locus: an NcoI polymorphism in the first intron of the human TNF-β gene correlates with a variant amino acid in position 26 and a reduced level of TNF-β production

    J Exp Med

    (1991)
  • AG Wilson et al.

    Effects of a polymorphism in the human tumor necrosis factor α promoter on transcriptional activity

    Proc Natl Acad Sci USA

    (1997)
  • S-L Huang et al.

    Tumor necrosis factor-α gene polymorphism in chronic bronchitis

    Am J Respir Crit Care Med

    (1997)
  • JA Nadel

    Obstructive diseases: general principles and diagnostic approach

  • M Gaga et al.

    Increases in CD4+ T lymphocytes, macrophages, neutrophils and interleukin 8 positive cells in the airways of patients with bronchiectasis

    Thorax

    (1998)
  • M Luisetti et al.

    Genetics of chronic obstructive pulmonary disease and disseminated bronchiectasis

    Monaldi Arch Chest Dis

    (1998)
  • F Verra et al.

    Inherited factors in diffuse bronchiectasis in the adult: a prospective study

    Eur Respir J

    (1991)
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    This work was supported by MURST, Italian CNR target project Biotechnologies, Consorzio Studi Universitari Verona, Ministero della Sanità–IRCCS Policlinico San Matteo grant 681RFM94/01 and Ministero della Sanità CF projects law 584/93.

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