Skip to main content
SpringerLink
Log in

Association of Tumor Necrosis Factor-α-863C/A Gene Polymorphism with Chronic Obstructive Pulmonary Disease

  • Published:
Lung Aims and scope Submit manuscript

Abstract

The aim of this study was to investigate genetic effects on the pathogenesis of chronic obstructive pulmonary disease (COPD). The study was conducted as a prospective case–control study in a medical center in southern Taiwan. The patient group consisted of 145 male patients with smoking-related COPD and a control group of 139 resistant smokers from July 2004 to September 2009. We compared allele and genotype frequencies of three tag single nucleotide polymorphisms (SNP) of the TNF-α gene promoter region at −308, −863, and −1031 in all subjects. We also analyzed the influence of each genetic variant on pulmonary function parameters, body mass index (BMI), serum TNF-α levels, and outcomes among heavy smokers with or without COPD. COPD patients had a significantly lower A allele frequency (9.7 vs. 15.1%, OR = 0.6, p = 0.048, false discovery rate q = 0.144) and a significantly lower A carrier genotype frequency (19.3 vs. 30.2%, OR = 0.52, p = 0.042, q = 0.135) than resistant smokers. The −863 CA genotype was associated with a better FEV1/FVC ratio (79 vs. 71.5%, p = 0.034), and higher BMI (24.9 vs. 23.6 kg/m2, p = 0.048). In addition, COPD patients with the −1031 C carrier genotype had higher serum TNF-α levels (20.9 vs. 16.2 pg/ml, p = 0.01). BMI (hazard ratio = 0.84, 95% CI = 0.74–0.96, p = 0.008) was the only independent predictor for mortality. The TNF-α −863 A allele may confer a degree of resistance to the susceptibility to and muscle wasting of COPD among heavy smokers.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Keatings VM, Collins PD, Scott DM, Barnes PJ (1996) Differences in interleukin-8 and tumor necrosis factor-alpha in induced sputum from patients with chronic obstructive pulmonary disease or asthma. Am J Respir Crit Care Med 153:530–534

    PubMed  CAS  Google Scholar 

  2. Mueller R, Chanez P, Campbell AM, Bousquet J, Heusser C, Bullock GR (1996) Different cytokine patterns in bronchial biopsies in asthma and chronic bronchitis. Respir Med 90:79–85

    Article  PubMed  CAS  Google Scholar 

  3. Keatings VM, Barnes PJ (1997) Granulocyte activation markers in induced sputum: comparison between chronic obstructive pulmonary disease, asthma, and normal subjects. Am J Respir Crit Care Med 155:449–453

    PubMed  CAS  Google Scholar 

  4. Aaron SD, Angel JB, Lunau M, Wright K, Fex C, Le Saux N, Dales RE (2001) Granulocyte inflammatory markers and airway infection during acute exacerbation of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 163:349–355

    PubMed  CAS  Google Scholar 

  5. Yang SR, Chida AS, Bauter MR, Shafiq N, Seweryniak K, Maggirwar SB, Kilty I, Rahman I (2006) Cigarette smoke induces proinflammatory cytokine release by activation of NF-kappaB and posttranslational modifications of histone deacetylase in macrophages. Am J Physiol Lung Cell Mol Physiol 291:L46–L57

    Article  PubMed  CAS  Google Scholar 

  6. Løkke A, Lange P, Scharling H, Fabricius P, Vestbo J (2006) Developing COPD: a 25 year follow up study of the general population. Thorax 61:935–939

    Article  PubMed  Google Scholar 

  7. Barrett JC, Fry B, Maller J, Daly MJ (2005) Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21(2):263–265

    Article  PubMed  CAS  Google Scholar 

  8. The International HapMap Consortium (2005) A haplotype map of the human genome. Nature 437:1299–1320

    Article  CAS  Google Scholar 

  9. Huang SL, Su CH, Chang SC (1997) Tumor necrosis factor-alpha gene polymorphism in chronic bronchitis. Am J Respir Crit Care Med 156:1436–1439

    PubMed  CAS  Google Scholar 

  10. Sakao S, Tatsumi K, Igari H, Shino Y, Shirasawa H, Kuriyama T (2001) Association of tumor necrosis factor alpha gene promoter polymorphism with the presence of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 163:420–422

    PubMed  CAS  Google Scholar 

  11. Gingo MR, Silveira LJ, Miller YE, Friedlander AL, Cosgrove GP, Chan ED, Maier LA, Bowler RP (2008) Tumour necrosis factor gene polymorphisms are associated with COPD. Eur Respir J 31:1005–1012

    Article  PubMed  CAS  Google Scholar 

  12. Higham MA, Pride NB, Alikhan A, Morrell NW (2000) Tumour necrosis factor-alpha gene promoter polymorphism in chronic obstructive pulmonary disease. Eur Respir J 15:281–284

    Article  PubMed  CAS  Google Scholar 

  13. Patuzzo C, Gile LS, Zorzetto M, Trabetti E, Malerba G, Pignatti PF, Luisetti M (2000) Tumor necrosis factor gene complex in COPD and disseminated bronchiectasis. Chest 117:1353–1358

    Article  PubMed  CAS  Google Scholar 

  14. Keatings VM, Cave SJ, Henry MJ, Morgan K, O’Connor CM, FitzGerald MX, Kalsheker N (2000) A polymorphism in the tumor necrosis factor-alpha gene promoter region may predispose to a poor prognosis in COPD. Chest 118:971–975

    Article  PubMed  CAS  Google Scholar 

  15. Teramoto S, Ishii T (2001) No association of tumor necrosis factor-alpha gene polymorphism and COPD in Caucasian smokers and Japanese smokers. Chest 119:315–316

    Article  PubMed  CAS  Google Scholar 

  16. Ferrarotti I, Zorzetto M, Beccaria M, Gile LS, Porta R, Ambrosino N, Pignatti PF, Cerveri I, Pozzi E, Luisetti M (2003) Tumour necrosis factor family genes in a phenotype of COPD associated with emphysema. Eur Respir J 21:444–449

    Article  PubMed  CAS  Google Scholar 

  17. Chierakul N, Wongwisutikul P, Vejbaesya S, Chotvilaiwan K (2005) Tumor necrosis factor-alpha gene promoter polymorphism is not associated with smoking-related COPD in Thailand. Respirology 10:36–39

    Article  PubMed  Google Scholar 

  18. Hersh CP, Demeo DL, Lange C, Litonjua AA, Reilly JJ, Kwiatkowski D, Laird N, Sylvia JS, Sparrow D, Speizer FE, Weiss ST, Silverman EK (2005) Attempted replication of reported chronic obstructive pulmonary disease candidate gene associations. Am J Respir Cell Mol Biol 33:71–78

    Article  PubMed  CAS  Google Scholar 

  19. Brogger J, Steen VM, Eiken HG, Gulsvik A, Bakke P (2006) Genetic association between COPD and polymorphisms in TNF, ADRB2 and EPHX1. Eur Respir J 27:682–688

    Article  PubMed  CAS  Google Scholar 

  20. Papatheodorou A, Latsi P, Vrettou C, Dimakou A, Chroneou A, Makrythanasis P, Kaliakatsos M, Orfanidou D, Roussos C, Kanavakis E, Tzetis M (2007) Development of a novel microarray methodology for the study of SNPs in the promoter region of the TNF-alpha gene: their association with obstructive pulmonary disease in Greek patients. Clin Biochem 40:843–850

    Article  PubMed  CAS  Google Scholar 

  21. Buist AS, Anzueto A, Calverley P, deGuia TS, Fukuchi Y, Jenkins C, Khaltaev N, Kiley J, Kocabas A, López MV, Nizankowska-Mogilnicka E, Rabe KF, Roisin RR, Molen TVD, Weel CV (2006) Global strategy for the diagnosis, management, and prevention of copd - 2006 update. Am J Respir Crit Care Med 176:532–555

    Google Scholar 

  22. Skoog T, van’t Hooft FM, Kallin B, Jovinge S, Boquist S, Nilsson J, Eriksson P, Hamsten A (1999) A common functional polymorphism (C– > A substitution at position -863) in the promoter region of the tumour necrosis factor-alpha (TNF-alpha) gene associated with reduced circulating levels of TNF-alpha. Hum Mol Genet 8:1443–1449

    Article  PubMed  CAS  Google Scholar 

  23. American Thoracic Society (1995) Standardization of Spirometry, 1994 Update. Am J Respir Crit Care Med 152:1107–1136

    Google Scholar 

  24. Storey JD, Tibshirani R (2003) Statistical significance for genomewide studies. Proc Natl Acad Sci USA 100(16):9440–9445

    Article  PubMed  CAS  Google Scholar 

  25. Sharma S, Sharma A, Kumar S, Sharma SK, Ghosh B (2006) Association of TNF haplotypes with asthma, serum IgE levels, and correlation with serum TNF-alpha levels. Am J Respir Cell Mol Biol 35:488–495

    Article  PubMed  CAS  Google Scholar 

  26. Higuchi T, Seki N, Kamizono S, Yamada A, Kimura A, Kato H, Itoh K (1998) Polymorphism of the 5’-flanking region of the human tumor necrosis factor (TNF)-alpha gene in Japanese. Tissue Antigens 51:605–612

    Article  PubMed  CAS  Google Scholar 

  27. Uglialoro AM, Turbay D, Pesavento PA, Delgado JC, McKenzie FE, Gribben JG, Hartl D, Yunis EJ, Goldfeld AE (1998) Identification of three new single nucleotide polymorphisms in the human tumor necrosis factor-alpha gene promoter. Tissue Antigens 52:359–367

    Article  PubMed  CAS  Google Scholar 

  28. Kaijzel EL, Bayley JP, van Krugten MV, Smith L, van de Linde P, Bakker AM, Breedveld FC, Huizinga TW, Verweij CL (2001) Allele-specific quantification of tumor necrosis factor alpha (TNF) transcription and the role of promoter polymorphisms in rheumatoid arthritis patients and healthy individuals. Genes Immun 2:135–144

    Article  PubMed  CAS  Google Scholar 

  29. Ramos EM, Lin MT, Larson EB, Maezawa I, Tseng LH, Edwards KL, Schellenberg GD, Hansen JA, Kukull WA, Jin LW (2006) Tumor necrosis factor alpha and interleukin 10 promoter region polymorphisms and risk of late-onset Alzheimer disease. Arch Neurol 63:1165–1169

    Article  PubMed  Google Scholar 

  30. Akman A, Sallakci N, Coskun M, Bacanli A, Yavuzer U, Alpsoy E, Yegin O (2006) TNF-alpha gene 1031 T/C polymorphism in Turkish patients with Behcet’s disease. Br J Dermatol 155:350–356

    Article  PubMed  CAS  Google Scholar 

  31. Matsushita M, Tsuchiya N, Nakayama T, Ohashi J, Shibue T, Shiota M, Oka T, Yamane A, Tokunaga K (1999) Allele typing of human TNFA 5’-flanking region using polymerase chain reaction-preferential homoduplex formation assay (PCR-PHFA): linkage disequilibrium with HLA class I and class II genes in Japanese. Tissue Antigens 54:478–484

    Article  PubMed  CAS  Google Scholar 

  32. Tanaka G, Sandford AJ, Burkett K, Connett JE, Anthonisen NR, Pare PD, He JQ (2007) Tumour necrosis factor and lymphotoxin A polymorphisms and lung function in smokers. Eur Respir J 29:34–41

    Article  PubMed  CAS  Google Scholar 

  33. Wilson AG, Symons JA, McDowell TL, McDevitt HO, Duff GW (1997) Effects of a polymorphism in the human tumor necrosis factor alpha promoter on transcriptional activation. Proc Natl Acad Sci U S A 94:3195–3199

    Article  PubMed  CAS  Google Scholar 

  34. Pociot F, Briant L, Jongeneel CV, Molvig J, Worsaae H, Abbal M, Thomsen M, Nerup J, Cambon-Thomsen A (1993) Association of tumor necrosis factor (TNF) and class II major histocompatibility complex alleles with the secretion of TNF-alpha and TNF-beta by human mononuclear cells: a possible link to insulin-dependent diabetes mellitus. Eur J Immunol 23:224–231

    Article  PubMed  CAS  Google Scholar 

  35. Sakao S, Tatsumi K, Igari H, Watanabe R, Shino Y, Shirasawa H, Kuriyama T (2002) Association of tumor necrosis factor-alpha gene promoter polymorphism with low attenuation areas on high-resolution CT in patients with COPD. Chest 122:416–420

    Article  PubMed  CAS  Google Scholar 

  36. Matheson MC, Ellis JA, Raven J, Walters EH, Abramson MJ (2006) Association of IL8, CXCR2 and TNF-alpha polymorphisms and airway disease. J Hum Genet 51:196–203

    Article  PubMed  CAS  Google Scholar 

  37. Schols AM, Slangen J, Volovics L, Wouters EF (1998) Weight loss is a reversible factor in the prognosis of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 157:1791–1797

    PubMed  CAS  Google Scholar 

  38. Di Francia M, Barbier D, Mege JL, Orehek J (1994) Tumor necrosis factor-alpha levels and weight loss in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 150:1453–1455

    PubMed  CAS  Google Scholar 

  39. Langen RC, Schols AM, Kelders MC, Wouters EF, Janssen-Heininger YM (2001) Inflammatory cytokines inhibit myogenic differentiation through activation of nuclear factor-kappaB. FASEB J 15:1169–1180

    Article  PubMed  CAS  Google Scholar 

  40. Young RP, Hopkins R, Black PN, Eddy C, Wu L, Gamble GD, Mills GD, Garrett JE, Eaton TE, Rees MI (2006) Functional variants of antioxidant genes in smokers with COPD and in those with normal lung function. Thorax 61:394–399

    Article  PubMed  CAS  Google Scholar 

  41. Suissa S, Ernst P, Hudson M (2008) TNF-alpha antagonists and the prevention of hospitalisation for chronic obstructive pulmonary disease. Pulm Pharmacol Ther 21:234–238

    Article  PubMed  CAS  Google Scholar 

  42. Rennard SI, Fogarty C, Kelsen S, Long W, Ramsdell J, Allison J, Mahler D, Saadeh C, Siler T, Snell P, Korenblat P, Smith W, Kaye M, Mandel M, Andrews C, Prabhu R, Donohue JF, Watt R, Lo KH, Schlenker-Herceg R, Barnathan ES, Murray J (2007) The safety and efficacy of infliximab in moderate to severe chronic obstructive pulmonary disease. Am J Respir Crit Care Med 175:926–934s

    Article  PubMed  CAS  Google Scholar 

Download references

Disclosures

All authors have no conflicts of interest or financial ties to disclose. The authors alone are responsible for the contents of this article.

Author information

Authors and Affiliations

  1. Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan, ROC

    Yung-Che Chen, Shih-Feng Liu, Chien-Hung Chin, Chao-Chien Wu, Yi-Hsi Wang, Yu-Hsiu Chung, Tung-Ying Chao & Meng-Chih Lin

  2. Department of Respiratory Care, Chang Gung Institute of Technology, Chia-Yi, Taiwan, ROC

    Meng-Chih Lin

  3. Division of Rheumatology, Department of Internal Medicine, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Chang Gung University College of Medicine, Kaohsiung, Taiwan, ROC

    Chung-Jen Chen

  4. Department of Biological Sciences, National Sun-Yat Sen University, Kaohsiung, Taiwan, ROC

    Hsueh-Wen Chang

Authors
  1. Yung-Che Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shih-Feng Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chien-Hung Chin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Chao-Chien Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Chung-Jen Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hsueh-Wen Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yi-Hsi Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yu-Hsiu Chung
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Tung-Ying Chao
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Meng-Chih Lin
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Meng-Chih Lin.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Chen, YC., Liu, SF., Chin, CH. et al. Association of Tumor Necrosis Factor-α-863C/A Gene Polymorphism with Chronic Obstructive Pulmonary Disease. Lung 188, 339–347 (2010). https://doi.org/10.1007/s00408-010-9236-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00408-010-9236-5

Keywords

Search

Navigation