Download PDF
Semin Respir Crit Care Med 2006; 27(6): 581-588
DOI: 10.1055/s-2006-957330
Copyright © 2006 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

Genetic Factors in Pulmonary Fibrotic Disorders

Roland M. du Bois1
  • 1Department of Respiratory Medicine, Royal Brompton Hospital and Imperial College, London, United Kingdom
Further Information

Publication History

Publication Date:
29 December 2006 (online)

    Permissions and Reprints

ABSTRACT

Identifying genetic determinants of pulmonary fibrotic disorders remains at an early stage of evolution. It is now well-recognized that “pulmonary fibrosis” covers a broad range of lung diseases, including most topically the idiopathic interstitial pneumonias that have been classified recently. Additionally, it is recognized that the fibrosing lung disorders that are seen in the rheumatological diseases, notably systemic sclerosis, are quite different from those of the idiopathic variety. Defining clinical phenotype is an important prerequisite to the identification of genetic determinants associated with individual diseases, but it is important to acknowledge that there may be determinants of global lung fibrosis and that other factors drive diseases down specific, more individual disease pathways. Current association studies are encouraging but far from conclusive for a variety of reasons, including small numbers, poor controls, and curious candidate selection. The results of the ongoing multicenter familial linkage study in the United States should provide several candidate genes that will spur further studies of sporadic disease in, it is hoped, a more internationally coordinated effort.

KEYWORDS

Genetics - polymorphism - familial - idiopathic pulmonary fibrosis - pulmonary fibrosis - systemic sclerosis

REFERENCES

  • 1 Wright J A, Pennington J E. Familial lymphoid interstitial pneumonitis.  J Pediatr. 1987;  111 638
    PubMedSearch in Google Scholar
  • 2 Buchino J J, Keenan W J, Algren J T, Bove K E. Familial desquamative interstitial pneumonitis occurring in infants.  Am J Med Genet Suppl. 1987;  3 285-291
    PubMedSearch in Google Scholar
  • 3 Tal A, Maor E, Bar-Ziv J, Gorodischer R. Fatal desquamative interstitial pneumonia in three infants siblings.  J Pediatr. 1984;  104 873-876
    PubMedSearch in Google Scholar
  • 4 Fan L L, Langston C. Pediatric diffuse lung disease: children are not small adults.  Am J Respir Crit Care Med. 2002;  165 1466-1467
    CrossrefPubMedSearch in Google Scholar
  • 5 Loyd J E. Pulmonary fibrosis in families.  Am J Respir Cell Mol Biol. 2003;  29 S47-S50
    PubMedSearch in Google Scholar
  • 6 Marney A, Lane K B, Phillips III J A, Riley D J, Loyd J E. Idiopathic pulmonary fibrosis can be an autosomal dominant trait in some families.  Chest. 2001;  120(Suppl 1) 56S
    CrossrefPubMedSearch in Google Scholar
  • 7 Hodgson U, Laitinen T, Tukiainen P. Nationwide prevalence of sporadic and familial idiopathic pulmonary fibrosis: evidence of founder effect among multiplex families in Finland.  Thorax. 2002;  57 338-342
    CrossrefPubMedSearch in Google Scholar
  • 8 Steele M P, Speer M C, Loyd J E et al.. Clinical and pathologic features of familial interstitial pneumonia.  Am J Respir Crit Care Med. 2005;  172 1146-1152
    CrossrefPubMedSearch in Google Scholar
  • 9 Nogee L M, Dunbar III A E, Wert S E, Askin F, Hamvas A, Whitsett J A. A mutation in the surfactant protein C gene associated with familial diffuse lung disease.  N Engl J Med. 2001;  344 573-579
    CrossrefPubMedSearch in Google Scholar
  • 10 Nogee L M, Dunbar III A E, Wert S, Askin F, Hamvas A, Whitsett J A. Mutations in the surfactant protein C gene associated with diffuse lung disease.  Chest. 2002;  121(Suppl 3) 20S-21S
    CrossrefPubMedSearch in Google Scholar
  • 11 Cameron H S, Somaschini M, Carrera P et al.. A common mutation in the surfactant protein C gene associated with lung disease.  J Pediatr. 2005;  146 370-375
    CrossrefPubMedSearch in Google Scholar
  • 12 Thomas A Q, Lane K, Phillips III 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 1322-1328
    CrossrefPubMedSearch in Google Scholar
  • 13 Tredano M, Griese M, Brasch F et al.. Mutation of SFTPC in infantile pulmonary alveolar proteinosis with or without fibrosing lung disease.  Am J Med Genet A. 2004;  126 18-26
    PubMedSearch in Google Scholar
  • 14 Hodgson U, Pulkkinen V, Dixon M et al.. ELMOD2 is a candidate gene for familial idiopathic pulmonary fibrosis.  Am J Hum Genet. 2006;  79 149-154
    CrossrefPubMedSearch in Google Scholar
  • 15 Morgan N V, Pasha S, Johnson C A et al.. A germline mutation in BLOC1S3/reduced pigmentation causes a novel variant of Hermansky-Pudlak syndrome (HPS8).  Am J Hum Genet. 2006;  78 160-166
    CrossrefPubMedSearch in Google Scholar
  • 16 Vassilakis D A, Sourvinos G, Spandidos D A, Siafakas N M, Bouros D. Frequent genetic alterations at the microsatellite level in cytologic sputum samples of patients with idiopathic pulmonary fibrosis.  Am J Respir Crit Care Med. 2000;  162 1115-1119
    PubMedSearch in Google Scholar
  • 17 Mori M, Kida H, Morishita H et al.. Microsatellite instability in transforming growth factor-beta 1 type II receptor gene in alveolar lining epithelial cells of idiopathic pulmonary fibrosis.  Am J Respir Cell Mol Biol. 2001;  24 398-404
    PubMedSearch in Google Scholar
  • 18 Kunitake R, Kuwano K, Miyazaki H et al.. Expression of p53, p21 (Waf1/Cip1/Sdi1) and Fas antigen in collagen vascular and granulomatous lung diseases.  Eur Respir J. 1998;  12 920-925
    CrossrefPubMedSearch in Google Scholar
  • 19 Hojo S, Fujita J, Yamadori I et al.. Heterogeneous point mutations of the p53 gene in pulmonary fibrosis.  Eur Respir J. 1998;  12 1404-1408
    CrossrefPubMedSearch in Google Scholar
  • 20 Selman M, Lin H M, Montano M et al.. Surfactant protein A and B genetic variants predispose to idiopathic pulmonary fibrosis.  Hum Genet. 2003;  113 542-550
    CrossrefPubMedSearch in Google Scholar
  • 21 Lawson W E, Grant S W, Ambrosini V et al.. Genetic mutations in surfactant protein C are a rare cause of sporadic cases of IPF.  Thorax. 2004;  59 977-980
    CrossrefPubMedSearch in Google Scholar
  • 22 Whyte M, Hubbard R, Meliconi R et al.. Increased risk of fibrosing alveolitis associated with interleukin-1 receptor antagonist and tumor necrosis factor-alpha gene polymorphisms.  Am J Respir Crit Care Med. 2000;  162(2 Pt 1) 755-758
    CrossrefPubMedSearch in Google Scholar
  • 23 Hutyrova B, Pantelidis P, Drabek J et al.. Interleukin-1 gene cluster polymorphisms in sarcoidosis and idiopathic pulmonary fibrosis.  Am J Respir Crit Care Med. 2002;  165 148-151
    CrossrefPubMedSearch in Google Scholar
  • 24 Riha R L, Yang I A, Rabnott G C, Tunnicliffe A M, Fong K M, Zimmerman P V. Cytokine gene polymorphisms in idiopathic pulmonary fibrosis.  Intern Med J. 2004;  34 126-129
    CrossrefPubMedSearch in Google Scholar
  • 25 Renzoni E, Lympany P, Sestini P et al.. Distribution of novel polymorphisms of the interleukin-8 and CXC receptor 1 and 2 genes in systemic sclerosis and cryptogenic fibrosing alveolitis.  Arthritis Rheum. 2000;  43 1633-1640
    CrossrefPubMedSearch in Google Scholar
  • 26 Whittington H A, Freeburn R W, Godinho S I, Egan J, Haider Y, Millar A B. Analysis of an IL-10 polymorphism in idiopathic pulmonary fibrosis.  Genes Immun. 2003;  4 258-264
    CrossrefPubMedSearch in Google Scholar
  • 27 Vasakova M, Striz I, Slavcev A, Jandova S, Kolesar L, Sulc J. Th1/Th2 cytokine gene polymorphisms in patients with idiopathic pulmonary fibrosis.  Tissue Antigens. 2006;  67 229-232
    CrossrefPubMedSearch in Google Scholar
  • 28 Pantelidis P, Fanning G C, Wells A U, Welsh K I, du Bois R M. Analysis of tumor necrosis factor-alpha, lymphotoxin-alpha, tumor necrosis factor receptor II, and interleukin-6 polymorphisms in patients with idiopathic pulmonary fibrosis.  Am J Respir Crit Care Med. 2001;  163 1432-1436
    CrossrefPubMedSearch in Google Scholar
  • 29 Zorzetto M, Bombieri C, Ferrarotti I et al.. Complement receptor 1 gene polymorphisms in sarcoidosis.  Am J Respir Cell Mol Biol. 2002;  27 17-23
    PubMedSearch in Google Scholar
  • 30 Hodgson U, Tukiainen P, Laitinen T. The polymorphism C5507G of complement receptor 1 does not explain idiopathic pulmonary fibrosis among the Finns.  Respir Med. 2005;  99 265-267
    Search in Google Scholar
  • 31 Zorzetto M, Ferrarotti I, Campo I et al.. NOD2/CARD15 gene polymorphisms in idiopathic pulmonary fibrosis.  Sarcoidosis Vasc Diffuse Lung Dis. 2005;  22 180-185
    PubMedSearch in Google Scholar
  • 32 Xaubet A, Marin-Arguedas A, Lario S et al.. Transforming growth factor-beta1 gene polymorphisms are associated with disease progression in idiopathic pulmonary fibrosis.  Am J Respir Crit Care Med. 2003;  168 431-435
    CrossrefPubMedSearch in Google Scholar
  • 33 Kim K K, Flaherty K R, Long Q et al.. A plasminogen activator inhibitor-1 promoter polymorphism and idiopathic interstitial pneumonia.  Mol Med. 2003;  9 52-56
    PubMedSearch in Google Scholar
  • 34 Gilchrist F C, Bunn C, Foley P J et al.. Class II HLA associations with autoantibodies in systemic sclerosis: a highly significant role for HLA-DP.  Genes Immun. 2001;  2 76-81
    CrossrefPubMedSearch in Google Scholar
  • 35 Arnett F C. HLA and autoimmunity in systemic sclerosis (systemic sclerosis). [Review].  Int Rev Immunol. 1995;  12 107-128
    PubMedSearch in Google Scholar
  • 36 Kuwana M, Medsger Jr T A, Wright T M. T cell proliferative response induced by DNA topoisomerase I in patients with systemic sclerosis and healthy donors.  J Clin Invest. 1995;  96 586-596
    CrossrefPubMedSearch in Google Scholar
  • 37 Veeraraghavan S, Renzoni E A, Jeal H et al.. Mapping of the immunodominant T cell epitopes of the protein topoisomerase I.  Ann Rheum Dis. 2004;  63 982-987
    CrossrefPubMedSearch in Google Scholar
  • 38 Sato H, Lagan A L, Alexopoulou C, Welsh K I. The TNF-863 A allele strongly associates with anti-centromere antibody positivity in systemic sclerosis.  Arthritis Rheum. 2004;  50 558-564
    CrossrefPubMedSearch in Google Scholar
  • 39 Avila J J, Lympany P A, Pantelidis P, Welsh K I, Black C M, du Bois R M. Fibronectin gene polymorphisms associated with fibrosing alveolitis in systemic sclerosis.  Am J Respir Cell Mol Biol. 1999;  20 106-112
    PubMedSearch in Google Scholar
  • 40 Sugiura Y, Banno S, Matsumoto Y et al.. Transforming growth factor beta1 gene polymorphism in patients with systemic sclerosis.  J Rheumatol. 2003;  30 1520-1523
    PubMedSearch in Google Scholar
  • 41 Zhou X, Tan F K, Reveille J D et al.. Association of novel polymorphisms with the expression of SPARC in normal fibroblasts and with susceptibility to systemic sclerosis.  Arthritis Rheum. 2002;  46 2990-2999
    CrossrefPubMedSearch in Google Scholar
  • 42 Lagan A L, Pantelidis P, Renzoni E A et al.. Single-nucleotide polymorphisms in the SPARC gene are not associated with susceptibility to systemic sclerosis.  Rheumatology (Oxford). 2005;  44 197-201
    PubMedSearch in Google Scholar
  • 43 Tan F K, Wang N, Kuwana M et al.. Association of fibrillin 1 single-nucleotide polymorphism haplotypes with systemic sclerosis in Choctaw and Japanese populations.  Arthritis Rheum. 2001;  44 893-901
    CrossrefPubMedSearch in Google Scholar

Roland M du BoisM.D. 

Department of Respiratory Medicine, Royal Brompton Hospital

Sydney St., London SW3 6NP, UK

Email: r.dubois@rbh.nthames.nhs.uk