Skip to main content

The Genetics of Pulmonary Fibrosis

  • Chapter
  • First Online:
Idiopathic Pulmonary Fibrosis

Part of the book series: Respiratory Medicine ((RM,volume 9))

  • 2061 Accesses

Abstract

The past two decades have been marked by a dramatic increase in the knowledge of the genetics of human disease. The field of interstitial lung disease (ILD) genetics has expanded as well. Much of the early understanding of ILD genetics came from rare Mendelian disorders that were associated with premature onset of disease. Other information came from single-gene multisystem disorders in which lung disease was variably present. More recently, the major advances in ILD genetics have come from focused analysis of familial pulmonary fibrosis. These rare families with multiple members affected by ILD have provided critical new insight into the possible mechanism of sporadic as well as inherited disease. Both linkage studies and large-scale, genome-wide association studies (GWAS) have identified genetic loci implicated in susceptibility to idiopathic pulmonary fibrosis (IPF). The next two decades will surely produce not only new risk alleles but also a more extensive understanding of genetics based on patient molecular phenotyping. In addition, epigenetics remains an area of potential discovery.

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

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 109.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 139.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Devine MS, Garcia CK. Genetic interstitial lung disease. Clin Chest Med. 2012;33(1):95–110.

    Article  PubMed  Google Scholar 

  2. Tomassetti S, Carloni A, Chilosi M, Maffè A, Ungari S, Sverzellati N, et al. Pulmonary features of Birt-Hogg-Dube syndrome: cystic lesions and pulmonary histiocytoma. Respir Med. 2011;105(5):768–74.

    Article  PubMed  CAS  Google Scholar 

  3. Furuya M, Tanaka R, Koga S, Yatabe Y, Gotoda H, Takagi S, et al. Pulmonary cysts of Birt-Hogg-Dube syndrome: a clinicopathologic and immunohistochemical study of 9 families. Am J Surg Pathol. 2012;36(4):589–600.

    Article  PubMed  Google Scholar 

  4. Mason PJ, Bessler M. The genetics of dyskeratosis congenita. Cancer Genet. 2011;204(12):635–45.

    Article  PubMed  CAS  Google Scholar 

  5. Dokal I. Dyskeratosis congenita. Hematology Am Soc Hematol Educ Program. 2011;2011:480–6.

    Article  PubMed  Google Scholar 

  6. Garcia CK. Idiopathic pulmonary fibrosis: update on genetic discoveries. Proc Am Thorac Soc. 2011;8(2):158–62.

    Article  PubMed  CAS  Google Scholar 

  7. Armanios MY, Chen JJ, Cogan JD, Alder JK, Ingersoll RG, Markin C, et al. Telomerase mutations in families with idiopathic pulmonary fibrosis. N Engl J Med. 2007;356(13):1317–26.

    Article  PubMed  CAS  Google Scholar 

  8. Moyzis RK, Buckingham JM, Cram LS, Dani M, Deaven LL, Jones MD, et al. A highly conserved repetitive DNA sequence, (TTAGGG)n, present at the telomeres of human chromosomes. Proc Natl Acad Sci USA. 1988;85(18):6622–6.

    Article  PubMed  CAS  Google Scholar 

  9. Morin GB. The human telomere terminal transferase enzyme is a ribonucleoprotein that synthesizes TTAGGG repeats. Cell. 1989;59(3):521–9.

    Article  PubMed  CAS  Google Scholar 

  10. Diaz de Leon A, Cronkhite JT, Yilmaz C, Brewington C, Wang R, Xing C, et al. Subclinical lung disease, macrocytosis, and premature graying in kindreds with telomerase (TERT) mutations. Chest. 2011;140(3):753–63.

    Article  PubMed  CAS  Google Scholar 

  11. Calado RT, Young NS. Telomere diseases. N Engl J Med. 2009;361(24):2353–65.

    Article  PubMed  CAS  Google Scholar 

  12. Wurfel MM, Raghu G. Genetics of pulmonary fibrosis. Semin Respir Crit Care Med. 2002;23(2):177–87.

    Article  PubMed  Google Scholar 

  13. Ward BK, Magno AL, Walsh JP, Ratajczak T. The role of the calcium-sensing receptor in human disease. Clin Biochem. 2012;45(12):943–53.

    Article  PubMed  CAS  Google Scholar 

  14. Demedts M, Lissens W, Wuyts W, Matthijs G, Thomeer M, Bouillon R. A new missense mutation in the CASR gene in familial interstitial lung disease with hypocalciuric hypercalcemia and defective granulocyte function. Am J Respir Crit Care Med. 2008;177(5):558–9.

    Article  PubMed  Google Scholar 

  15. Lawson WE, Grant SW, Ambrosini V, Womble KE, Dawson EP, Lane KB, et al. Genetic mutations in surfactant protein C are a rare cause of sporadic cases of IPF. Thorax. 2004;59(11):977–80.

    Article  PubMed  CAS  Google Scholar 

  16. Pastores GM, Hughes DA. Gaucher disease. In: Pagon RA, Bird TD, Dolan CR, Stephens K, Adam MP, editors. GeneReviews. Seattle, WA: University of Washington; 1993.

    Google Scholar 

  17. Lo SM, Liu J, Chen F, Pastores GM, Knowles J, Boxer M, et al. Pulmonary vascular disease in Gaucher disease: clinical spectrum, determinants of phenotype and long-term outcomes of therapy. J Inherit Metab Dis. 2011;34(3):643–50.

    Article  PubMed  Google Scholar 

  18. Grutters JC, du Bois RM. Genetics of fibrosing lung diseases. Eur Respir J. 2005;25(5):915–27.

    Article  PubMed  CAS  Google Scholar 

  19. Pierson DM, Ionescu D, Qing G, Yonan AM, Parkinson K, Colby TC, et al. Pulmonary fibrosis in hermansky-pudlak syndrome. A case report and review. Respiration. 2006;73(3):382–95.

    Article  PubMed  Google Scholar 

  20. Woellner C, Gertz EM, Schaffer AA, Lagos M, Perro M, Glocker EO, et al. Mutations in STAT3 and diagnostic guidelines for hyper-IgE syndrome. J Allergy Clin Immunol. 2010;125(2):424–32.e8.

    Article  PubMed  CAS  Google Scholar 

  21. Grimbacher B, Schaffer AA, Holland SM, Davis J, Gallin JI, Malech HL, et al. Genetic linkage of hyper-IgE syndrome to chromosome 4. Am J Hum Genet. 1999;65(3):735–44.

    Article  PubMed  CAS  Google Scholar 

  22. Ogier de Baulny H, Schiff M, Dionisi-Vici C. Lysinuric protein intolerance (LPI): a multi organ disease by far more complex than a classic urea cycle disorder. Mol Genet Metab. 2012;106(1):12–7.

    Article  PubMed  CAS  Google Scholar 

  23. Palmeri S, Tarugi P, Sicurelli F, Buccoliero R, Malandrini A, De Santi MM, et al. Lung involvement in Niemann-Pick disease type C1: improvement with bronchoalveolar lavage. Neurol Sci. 2005;26(3):171–3.

    Article  PubMed  CAS  Google Scholar 

  24. Minai OA, Sullivan EJ, Stoller JK. Pulmonary involvement in Niemann-Pick disease: case report and literature review. Respir Med. 2000;94(12):1241–51.

    Article  PubMed  CAS  Google Scholar 

  25. Katsenos S, Nikolopoulou M, Rallis E, Constantopoulos SH. Chronic eosinophilic pneumonia associated with neurofibromatosis type 1: an unusual complication. J Med Invest. 2009;56(1–2):64–9.

    Article  PubMed  Google Scholar 

  26. Hirsch NP, Murphy A, Radcliffe JJ. Neurofibromatosis: clinical presentations and anaesthetic implications. Br J Anaesth. 2001;86(4):555–64.

    Article  PubMed  CAS  Google Scholar 

  27. Malik SK, Pardee N, Martin CJ. Involvement of the lungs in tuberous sclerosis. Chest. 1970;58(5):538–40.

    Article  PubMed  CAS  Google Scholar 

  28. Hohman DW, Noghrehkar D, Ratnayake S. Lymphangioleiomyomatosis: a review. Eur J Intern Med. 2008;19(5):319–24.

    Article  PubMed  Google Scholar 

  29. Chibbar R, Shih F, Baga M, Torlakovic E, Ramlall K, Skomro R, et al. Nonspecific interstitial pneumonia and usual interstitial pneumonia with mutation in surfactant protein C in familial pulmonary fibrosis. Mod Pathol. 2004;17(8):973–80.

    Article  PubMed  CAS  Google Scholar 

  30. Guillot L, Epaud R, Thouvenin G, Jonard L, Mohsni A, Couderc R, et al. New surfactant protein C gene mutations associated with diffuse lung disease. J Med Genet. 2009;46(7):490–4.

    Article  PubMed  CAS  Google Scholar 

  31. Maitra M, Wang Y, Gerard RD, Mendelson CR, Garcia CK. Surfactant protein A2 mutations associated with pulmonary fibrosis lead to protein instability and endoplasmic reticulum stress. J Biol Chem. 2010;285(29):22103–13.

    Article  PubMed  CAS  Google Scholar 

  32. Nogee LM, Dunbar 3rd AE, Wert SE, Askin F, Hamvas A, Whitsett JA. A mutation in the surfactant protein C gene associated with familial interstitial lung disease. N Engl J Med. 2001;344(8):573–9.

    Article  PubMed  CAS  Google Scholar 

  33. Seibold MA, Wise AL, Speer MC, Steele MP, Brown KK, Loyd JE, et al. A common MUC5B promoter polymorphism and pulmonary fibrosis. N Engl J Med. 2011;364(16):1503–12.

    Article  PubMed  CAS  Google Scholar 

  34. Thomas AQ, Lane K, Phillips 3rd J, et al. Heterozygosity for a surfactant protein C gene mutation associated with usual interstitial pneumonitis and cellular nonspecific interstitial pneumonitis in one kindred. Am J Respir Crit Care Med. 2002;165(9):1322–8.

    Article  PubMed  Google Scholar 

  35. van Moorsel CH, van Oosterhout MF, Barlo NP, de Jong PA, van der Vis JJ, Ruven HJ, et al. Surfactant protein C mutations are the basis of a significant portion of adult familial pulmonary fibrosis in a dutch cohort. Am J Respir Crit Care Med. 2010;182(11):1419–25.

    Article  PubMed  Google Scholar 

  36. Verleden GM, du Bois RM, Bouros D, Drent M, Millar A, Müller-Quernheim J, et al. Genetic predisposition and pathogenetic mechanisms of interstitial lung diseases of unknown origin. Eur Respir J Suppl. 2001;32:17s–29.

    PubMed  CAS  Google Scholar 

  37. Wang Y, Kuan PJ, Xing C, Cronkhite JT, Torres F, Rosenblatt RL, et al. Genetic defects in surfactant protein A2 are associated with pulmonary fibrosis and lung cancer. Am J Hum Genet. 2009;84(1):52–9.

    Article  PubMed  CAS  Google Scholar 

  38. Zhang Y, Noth I, Garcia JG, Kaminski N. A variant in the promoter of MUC5B and idiopathic pulmonary fibrosis. N Engl J Med. 2011;364(16):1576–7.

    Article  PubMed  CAS  Google Scholar 

  39. Ono S, Tanaka T, Ishida M, Kinoshita A, Fukuoka J, Takaki M, et al. Surfactant protein C G100S mutation causes familial pulmonary fibrosis in Japanese kindred. Eur Respir J. 2011;38(4):861–9.

    Article  PubMed  CAS  Google Scholar 

  40. Lawson WE, Loyd JE, Degryse AL. Genetics in pulmonary fibrosis–familial cases provide clues to the pathogenesis of idiopathic pulmonary fibrosis. Am J Med Sci. 2011;341(6):439–43.

    Article  PubMed  Google Scholar 

  41. King Jr TE, Pardo A, Selman M. Idiopathic pulmonary fibrosis. Lancet. 2011;378(9807):1949–61.

    Article  PubMed  Google Scholar 

  42. Raghu G, Weycker D, Edelsberg J, Bradford WZ, Oster G. Incidence and prevalence of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med. 2006;174(7):810–6.

    Article  PubMed  Google Scholar 

  43. Tsakiri KD, Cronkhite JT, Kuan PJ, Xing C, Raghu G, Weissler JC, et al. Adult-onset pulmonary fibrosis caused by mutations in telomerase. Proc Natl Acad Sci USA. 2007;104(18):7552–7.

    Article  PubMed  CAS  Google Scholar 

  44. Alder JK, Chen JJ, Lancaster L, Danoff S, Su SC, Cogan JD, et al. Short telomeres are a risk factor for idiopathic pulmonary fibrosis. Proc Natl Acad Sci USA. 2008;105(35):13051–6.

    Article  PubMed  CAS  Google Scholar 

  45. Cronkhite JT, Xing C, Raghu G, Chin KM, Torres F, Rosenblatt RL, et al. Telomere shortening in familial and sporadic pulmonary fibrosis. Am J Respir Crit Care Med. 2008;178(7):729–37.

    Article  PubMed  CAS  Google Scholar 

  46. Armanios M, Alder JK, Parry EM, Karim B, Strong MA, Greider CW. Short telomeres are sufficient to cause the degenerative defects associated with aging. Am J Hum Genet. 2009;85(6):823–32.

    Article  PubMed  CAS  Google Scholar 

  47. Hamvas A, Cole FS, Nogee LM. Genetic disorders of surfactant proteins. Neonatology. 2007;91(4):311–7.

    Article  PubMed  CAS  Google Scholar 

  48. Beers MF, Mulugeta S. Surfactant protein C biosynthesis and its emerging role in conformational lung disease. Annu Rev Physiol. 2005;67:663–96.

    Article  PubMed  CAS  Google Scholar 

  49. Bullard JE, Nogee LM. Heterozygosity for ABCA3 mutations modifies the severity of lung disease associated with a surfactant protein C gene (SFTPC) mutation. Pediatr Res. 2007;62(2):176–9.

    Article  PubMed  CAS  Google Scholar 

  50. Tal A, Maor E, Bar-Ziv J, Gorodischer R. Fatal desquamative interstitial pneumonia in three infants siblings. J Pediatr. 1984;104(6):873–6.

    Article  PubMed  CAS  Google Scholar 

  51. Tsukahara M, Yoshii H, Imamura T, Kamei T, Koga M, Furukawa S. Desquamative interstitial pneumonia in sibs. Am J Med Genet. 1995;59(4):431–4.

    Article  PubMed  CAS  Google Scholar 

  52. Oak SR, Murray L, Herath A, Sleeman M, Anderson I, Joshi AD, et al. A micro RNA processing defect in rapidly progressing idiopathic pulmonary fibrosis. PLoS One. 2011;6(6):e21253.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Sonye K. Danoff M.D., Ph.D. .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2014 Springer Science+Business Media New York

About this chapter

Cite this chapter

Danoff, S.K., Johnson, C. (2014). The Genetics of Pulmonary Fibrosis. In: Meyer, K., Nathan, S. (eds) Idiopathic Pulmonary Fibrosis. Respiratory Medicine, vol 9. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-62703-682-5_9

Download citation

  • DOI: https://doi.org/10.1007/978-1-62703-682-5_9

  • Published:

  • Publisher Name: Humana Press, Totowa, NJ

  • Print ISBN: 978-1-62703-681-8

  • Online ISBN: 978-1-62703-682-5

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics