, Volume 191, Issue 2, pp 199–205 | Cite as

TGF-β1 T869C Polymorphism May Affect Susceptibility to Idiopathic Pulmonary Fibrosis and Disease Severity

  • Ji Young Son
  • Song Yee Kim
  • Sang Ho Cho
  • Hyo Sub Shim
  • Ji-Ye Jung
  • Eun Young Kim
  • Ju Eun Lim
  • Byung Hoon Park
  • Young Ae Kang
  • Young Sam Kim
  • Se Kyu Kim
  • Joon Chang
  • Moo Suk ParkEmail author



Transforming growth factor-β1 (TGF-β1) is a key cytokine that plays a critical role in idiopathic pulmonary fibrosis (IPF). The genotypes of T869C polymorphism may be associated with the susceptibility to fibrotic lung disease.


We investigated a single-nucleotide polymorphism at exon 1 nucleotide position 29 (T → C) of the TGF-β1 gene. Eighty-five healthy controls and 85 subjects with surgically confirmed IPF were investigated using polymerase chain reaction and restriction enzyme fragment length polymorphism techniques.


The IPF patients consisted of 55 men and 30 women. The mean age was 61 ± 8 years. Fifty-one (60 %) of the 85 IPF patients were smokers and 34 were nonsmokers. The distribution of genotypes between IPF patients and controls was significantly different (IPF: TT 43.5 % and TC or CC 56.5 %; controls: TT 27.1 % and TC or CC 72.9 %, p = 0.037). TT genotype was significantly associated with decreased PaO2 and increased D(A–a)O2 upon initial diagnosis (p = 0.006 and 0.009, respectively). There was a positive association between TT genotype and IPF development (odds ratio [OR] = 2.1, 95 % confidence interval [CI] = 1.1–4.0, p = 0.028).


This study suggests that the TGF-β1 gene T869C polymorphism may affect susceptibility to IPF in Koreans. Larger studies are required to confirm the genetic association of TGF-β1 gene polymorphism and IPF.


Pulmonary fibrosis Idiopathic Transforming growth factor-β1 Polymorphism 



This study was supported by a faculty research Grant (6-2005-0010) from the Department of Internal Medicine, Yonsei University, College of Medicine.

Conflict of interest

The authors have no conflicts of interest to declare.


  1. 1.
    Selman M, King TE, Pardo A (2001) Idiopathic pulmonary fibrosis: prevailing and evolving hypotheses about its pathogenesis and implications for therapy. Ann Intern Med 134(2):136–151PubMedGoogle Scholar
  2. 2.
    Blobe GC, Schiemann WP, Lodish HF (2000) Role of transforming growth factor beta in human disease. N Engl J Med 342(18):1350–1358PubMedCrossRefGoogle Scholar
  3. 3.
    Border WA, Noble NA (1994) Transforming growth factor beta in tissue fibrosis. N Engl J Med 331(19):1286–1292PubMedCrossRefGoogle Scholar
  4. 4.
    Awad MR, El-Gamel A, Hasleton P, Turner DM, Sinnott PJ, Hutchinson IV (1998) Genotypic variation in the transforming growth factor-beta1 gene: association with transforming growth factor-beta1 production, fibrotic lung disease, and graft fibrosis after lung transplantation. Transplantation 66(8):1014–1020PubMedCrossRefGoogle Scholar
  5. 5.
    Cambien F, Ricard S, Troesch A, Mallet C, Generenaz L, Evans A, Arveiler D, Luc G, Ruidavets JB, Poirier O (1996) Polymorphisms of the transforming growth factor-beta 1 gene in relation to myocardial infarction and blood pressure. The Etude Cas-Temoin de l’Infarctus du Myocarde (ECTIM) Study. Hypertension 28(5):881–887PubMedCrossRefGoogle Scholar
  6. 6.
    Grainger DJ, Heathcote K, Chiano M, Snieder H, Kemp PR, Metcalfe JC, Carter ND, Spector TD (1999) Genetic control of the circulating concentration of transforming growth factor type beta1. Hum Mol Genet 8(1):93–97PubMedCrossRefGoogle Scholar
  7. 7.
    Perrey C, Pravica V, Sinnott PJ, Hutchinson IV (1998) Genotyping for polymorphisms in interferon-gamma, interleukin-10, transforming growth factor-beta 1 and tumour necrosis factor-alpha genes: a technical report. Transpl Immunol 6(3):193–197PubMedCrossRefGoogle Scholar
  8. 8.
    Arkwright PD, Laurie S, Super M, Pravica V, Schwarz MJ, Webb AK, Hutchinson IV (2000) TGF-beta(1) genotype and accelerated decline in lung function of patients with cystic fibrosis. Thorax 55(6):459–462PubMedCrossRefGoogle Scholar
  9. 9.
    Xaubet A, Marin-Arguedas A, Lario S, Ancochea J, Morell F, Ruiz-Manzano J, Rodriguez-Becerra E, Rodriguez-Arias JM, Inigo P, Sanz S, Campistol JM, Mullol J, Picado C (2003) Transforming growth factor-beta1 gene polymorphisms are associated with disease progression in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 168(4):431–435PubMedCrossRefGoogle Scholar
  10. 10.
    American Thoracic Society (ATS), European Respiratory Society (ERS) (2002) American Thoracic Society/European Respiratory Society International Multidisciplinary consensus classification of the idiopathic interstitial pneumonias. This joint statement of the American Thoracic Society (ATS), and the European Respiratory Society (ERS) was adopted by the ATS board of directors, June 2001 and by the ERS Executive Committee, June 2001. Am J Respir Crit Care Med 165(2):277–304Google Scholar
  11. 11.
    El-Gamel A, Awad M, Sim E, Hasleton P, Yonan N, Egan J, Deiraniya A, Hutchinson IV (1998) Transforming growth factor-beta1 and lung allograft fibrosis. Eur J Cardiothorac Surg 13(4):424–430PubMedCrossRefGoogle Scholar
  12. 12.
    Raghu G, Collard HR, Egan JJ, Martinez FJ, Behr J, Brown KK, Colby TV, Cordier JF, Flaherty KR, Lasky JA, Lynch DA, Ryu JH, Swigris JJ, Wells AU, Ancochea J, Bouros D, Carvalho C, Costabel U, Ebina M, Hansell DM, Johkoh T, Kim DS, King TE Jr, Kondoh Y, Myers J, Muller NL, Nicholson AG, Richeldi L, Selman M, Dudden RF, Griss BS, Protzko SL, Schunemann HJ (2011) An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med 183(6):788–824PubMedCrossRefGoogle Scholar
  13. 13.
    Franko AJ, Sharplin J, Ghahary A, Barcellos-Hoff MH (1997) Immunohistochemical localization of transforming growth factor beta and tumor necrosis factor alpha in the lungs of fibrosis-prone and “non-fibrosing” mice during the latent period and early phase after irradiation. Radiat Res 147(2):245–256PubMedCrossRefGoogle Scholar
  14. 14.
    Phan SH, Kunkel SL (1992) Lung cytokine production in bleomycin-induced pulmonary fibrosis. Exp Lung Res 18(1):29–43PubMedCrossRefGoogle Scholar
  15. 15.
    Yamada Y, Miyauchi A, Goto J, Takagi Y, Okuizumi H, Kanematsu M, Hase M, Takai H, Harada A, Ikeda K (1998) Association of a polymorphism of the transforming growth factor-beta1 gene with genetic susceptibility to osteoporosis in postmenopausal Japanese women. J Bone Miner Res 13(10):1569–1576PubMedCrossRefGoogle Scholar
  16. 16.
    Li B, Khanna A, Sharma V, Singh T, Suthanthiran M, August P (1999) TGF-beta1 DNA polymorphisms, protein levels, and blood pressure. Hypertension 33(1 Pt 2):271–275PubMedCrossRefGoogle Scholar
  17. 17.
    Bayer EM, Herr W, Kanzler S, Waldmann C, Meyer Zum Buschenfelde KH, Dienes HP, Lohse AW (1998) Transforming growth factor-beta1 in autoimmune hepatitis: correlation of liver tissue expression and serum levels with disease activity. J Hepatol 28(5):803–811PubMedCrossRefGoogle Scholar
  18. 18.
    Qi Z, Atsuchi N, Ooshima A, Takeshita A, Ueno H (1999) Blockade of type beta transforming growth factor signaling prevents liver fibrosis and dysfunction in the rat. Proc Natl Acad Sci USA 96(5):2345–2349PubMedCrossRefGoogle Scholar
  19. 19.
    Kanzler S, Lohse AW, Keil A, Henninger J, Dienes HP, Schirmacher P, Rose-John S, zum Buschenfelde KH, Blessing M (1999) TGF-beta1 in liver fibrosis: an inducible transgenic mouse model to study liver fibrogenesis. Am J Physiol 276(4 Pt 1):G1059–G1068PubMedGoogle Scholar
  20. 20.
    Sanderson N, Factor V, Nagy P, Kopp J, Kondaiah P, Wakefield L, Roberts AB, Sporn MB, Thorgeirsson SS (1995) Hepatic expression of mature transforming growth factor beta 1 in transgenic mice results in multiple tissue lesions. Proc Natl Acad Sci USA 92(7):2572–2576PubMedCrossRefGoogle Scholar
  21. 21.
    Kopp JB, Factor VM, Mozes M, Nagy P, Sanderson N, Bottinger EP, Klotman PE, Thorgeirsson SS (1996) Transgenic mice with increased plasma levels of TGF-beta 1 develop progressive renal disease. Lab Invest 74(6):991–1003PubMedGoogle Scholar
  22. 22.
    Santana A, Saxena B, Noble NA, Gold LI, Marshall BC (1995) Increased expression of transforming growth factor beta isoforms (beta 1, beta 2, beta 3) in bleomycin-induced pulmonary fibrosis. Am J Respir Cell Mol Biol 13(1):34–44PubMedGoogle Scholar
  23. 23.
    Khalil N, O’Connor RN, Unruh HW, Warren PW, Flanders KC, Kemp A, Bereznay OH, Greenberg AH (1991) Increased production and immunohistochemical localization of transforming growth factor-beta in idiopathic pulmonary fibrosis. Am J Respir Cell Mol Biol 5(2):155–162PubMedGoogle Scholar
  24. 24.
    El-Gamel A, Awad MR, Hasleton PS, Yonan NA, Hutchinson JA, Campbell CS, Rahman AH, Deiraniya AK, Sinnott PJ, Hutchinson IV (1999) Transforming growth factor-beta (TGF-beta1) genotype and lung allograft fibrosis. J Heart Lung Transplant 18(6):517–523PubMedCrossRefGoogle Scholar
  25. 25.
    Zeki AA, Schivo M, Chan AL, Hardin KA, Kenyon NJ, Albertson TE, Rosenquist GL, Louie S (2010) Geoepidemiology of COPD and idiopathic pulmonary fibrosis. J Autoimmun 34(3):J327–J338PubMedCrossRefGoogle Scholar
  26. 26.
    Kang HG, Chae MH, Park JM, Kim EJ, Park JH, Kam S, Cha SI, Kim CH, Park RW, Park SH, Kim YL, Kim IS, Jung TH, Park JY (2006) Polymorphisms in TGF-beta1 gene and the risk of lung cancer. Lung Cancer 52(1):1–7PubMedCrossRefGoogle Scholar
  27. 27.
    Bravo MJ, Colmenero JD, Queipo-Ortuno MI, Alonso A, Caballero A (2008) TGF-beta1 and IL-6 gene polymorphism in Spanish brucellosis patients. Cytokine 44(1):18–21PubMedCrossRefGoogle Scholar
  28. 28.
    Shah M, Revis D, Herrick S, Baillie R, Thorgeirson S, Ferguson M, Roberts A (1999) Role of elevated plasma transforming growth factor-beta1 levels in wound healing. Am J Pathol 154(4):1115–1124PubMedCrossRefGoogle Scholar
  29. 29.
    Yong SJ, Adlakha A, Limper AH (2001) Circulating transforming growth factor-beta(1): a potential marker of disease activity during idiopathic pulmonary fibrosis. Chest 120(1 Suppl):68S–70SPubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Ji Young Son
    • 1
  • Song Yee Kim
    • 1
  • Sang Ho Cho
    • 2
  • Hyo Sub Shim
    • 4
  • Ji-Ye Jung
    • 1
  • Eun Young Kim
    • 1
  • Ju Eun Lim
    • 1
  • Byung Hoon Park
    • 1
  • Young Ae Kang
    • 1
  • Young Sam Kim
    • 1
    • 3
  • Se Kyu Kim
    • 1
    • 3
  • Joon Chang
    • 1
    • 3
  • Moo Suk Park
    • 1
    • 3
    Email author
  1. 1.Division of Pulmonary, Department of Internal MedicineSeverance Hospital, Yonsei University College of MedicineSeoulKorea
  2. 2.Department of PathologyBundang CHA Hospital, CHA UniversitySeongnamKorea
  3. 3.The Institute of Chest DiseasesYonsei University College of MedicineSeoulKorea
  4. 4.Department of PathologySeverance Hospital, Yonsei University College of MedicineSeoulKorea

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