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Semin Respir Crit Care Med 2003; 24(2): 205-212
DOI: 10.1055/s-2003-39019
Copyright © 2003 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.: +1(212) 584-4662

Genetics of Pulmonary Fibrosis

R. M. du Bois, I. Kangesan, S. Veeraraghavan
  • Interstitial Lung Disease Unit and Clinical Genomics Group, Royal Brompton Hospital, London, United Kingdom
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Publication History

Publication Date:
07 May 2003 (online)

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ABSTRACT

Identifying genetic determinants of pulmonary fibrosis is 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 diffuse lung diseases of children that may progress to fibrosis are quite different from those of adults. Defining clinical phenotype is an absolute prerequisite to precise identification of genetic determinants, and this is at least part of the reason why we understand relatively little of these genetic determinants to date.

In children, a number of mutations have been identified, particularly with regard to surfactant protein. In adults, families with idiopathic pulmonary fibrosis are being collected but there are no genetic data on these at this point. In sporadic disease, associations have been reported in early phase genes with disease predisposition and also, importantly, with disease severity: future studies will inevitably incorporate issues of severity of disease in analyses.

KEYWORDS

Genetics - diffuse lung disease - idiopathic pulmonary fibrosis

REFERENCES

  • 1 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 . 2002;  165 277-304
    PubMedGoogle Scholar
  • 2 Wright J A, Pennington J E. Familial lymphoid interstitial pneumonitis.  J Pediatr . 1987;  111 638
    PubMedGoogle Scholar
  • 3 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
    PubMedGoogle Scholar
  • 4 Tal A, Maor E, Bar-Ziv J, Gorodischer R. Fatal desquamative interstitial pneumonia in three infants siblings.  J Pediatr . 1984;  104 873-876
    PubMedGoogle Scholar
  • 5 Canakis A M, Cutz E, Manson D, O'Brodovich H. Pulmonary interstitial glycogenosis: a new variant of neonatal interstitial lung disease.  Am J Respir Crit Care Med . 2002;  165 1557-1565
    CrossrefPubMedGoogle Scholar
  • 6 Fan L L, Langston C. Pediatric interstitial lung disease: children are not small adults.  Am J Respir Crit Care Med . 2002;  165 1466-1467
    CrossrefPubMedGoogle Scholar
  • 7 Low R B. Bronchoalveolar lavage lipids in idiopathic pulmonary fibrosis.  Chest . 1989;  95 3-5
    PubMedGoogle Scholar
  • 8 Wilsher M L, Hughes D A, Haslam P L. Immunoregulatory properties of pulmonary surfactant: influence of variations in the phospholipid profile.  Clin Exp Immunol . 1988;  73 117-122
    PubMedGoogle Scholar
  • 9 Hughes D A, Haslam P L. Changes in phosphatidylglycerol in bronchoalveolar lavage fluids from patients with cryptogenic fibrosing alveolitis.  Chest . 1989;  95 82-89
    PubMedGoogle Scholar
  • 10 Amin R S, Wert S E, Baughman R P. et al . Surfactant protein deficiency in familial interstitial lung disease.  J Pediatr . 2001;  139 85-92
    CrossrefPubMedGoogle Scholar
  • 11 Karinch A M, deMello D E, Floros J. Effect of genotype on the levels of surfactant protein A mRNA and on the SP-A2 splice variants in adult humans.  Biochem J . 1997;  321(pt 1) 39-47
    PubMedGoogle Scholar
  • 12 Diangelo S, Lin Z, Wang G. et al . Novel, nonradioactive, simple and multiplex PCR-cRFLP methods for genotyping human SP-A and SP-D marker alleles.  Dis Markers . 1999;  15 269-281
    PubMedGoogle Scholar
  • 13 Lin Z, deMello D E, Batanian J R. et al . Aberrant SP-B mRNA in lung tissue of patients with congenital alveolar proteinosis (CAP).  Clin Genet . 2000;  57 359-369
    CrossrefPubMedGoogle Scholar
  • 14 Floros J, Veletza S V, Kotikalapudi P. et al . Dinucleotide repeats in the human surfactant protein-B gene and respiratory-distress syndrome.  Biochem J . 1995;  305(pt 2) 583-590
    CrossrefPubMedGoogle Scholar
  • 15 Lin Z, deMello D E, Wallot M, Floros J. An SP-B gene mutation responsible for SP-B deficiency in fatal congenital alveolar proteinosis: evidence for a mutation hotspot in exon 4.  Mol Genet Metab . 1998;  64 25-35
    CrossrefPubMedGoogle Scholar
  • 16 Nogee L M, Wert S E, Proffit S A, Hull W M, Whitsett J A. Allelic heterogeneity in hereditary surfactant protein B (SP-B) deficiency.  Am J Respir Crit Care Med . 2000;  161(3 pt 1) 973-981
    CrossrefPubMedGoogle Scholar
  • 17 Nogee L M, Dunbar III E A, Wert S E, Askin F, Hamvas A, Whitsett J A. A mutation in the surfactant protein C gene associated with familial interstitial lung disease.  N Engl J Med . 2001;  344 573-579
    CrossrefPubMedGoogle Scholar
  • 18 Glasser S W, Korfhagen T R, Perme C M, Pilot-Matias T J, Kister S E, Whitsett J A. Two SP-C genes encoding human pulmonary surfactant proteolipid.  J Biol Chem . 1988;  263 10326-10331
    PubMedGoogle Scholar
  • 19 Nogee L M, Dunbar III E A, Wert S E, Askin F, Hamvas A, Whitsett J A. A mutation in the surfactant protein C gene associated with familial interstitial lung disease.  N Engl J Med . 2001;  344 573-579
    CrossrefPubMedGoogle Scholar
  • 20 Nogee L M, Dunbar III E A, Wert S, Askin F, Hamvas A, Whitsett J A. Mutations in the surfactant protein C gene associated with interstitial lung disease.  Chest . 2002;  121(suppl 3) S20-S21
    CrossrefPubMedGoogle Scholar
  • 21 Marshall R P, Puddicombe A, Cookson W O, Laurent G J. Adult familial cryptogenic fibrosing alveolitis in the United Kingdom.  Thorax . 2000;  55 143-146
    CrossrefPubMedGoogle Scholar
  • 22 Bitterman P B, Rennard S I, Keogh B A. Familial idiopathic pulmonary fibrosis: evidence of lung inflammation in unaffected family members.  N Engl J Med . 1986;  314 1343-1347
    CrossrefPubMedGoogle Scholar
  • 23 Peabody J W, Peabody Jr W J, Hayes E W, Hayes Jr W E. Idiopathic pulmonary fibrosis: its occurrence in identical twin sisters.  Dis Chest . 1950;  18 330-344
    PubMedGoogle Scholar
  • 24 Bonanni P P, Frymoyer J W, Jacox R F. A family study of idiopathic pulmonary fibrosis: a possible dysproteinemic and genetically determined disease.  Am J Med . 1965;  39 411-421
    CrossrefPubMedGoogle Scholar
  • 25 Marney A, Lane K B, Phillips III A J, Riley D J, Loyd J E. Idiopathic pulmonary fibrosis can be an autosomal dominant trait in some families.  Chest . 2001;  120(suppl 1) S30
    PubMedGoogle Scholar
  • 26 Wahidi M M, Speer M C, Steele M P, Brown K K, Schwarz M I, Schwartz D A. Familial pulmonary fibrosis in the United States.  Chest . 2002;  121(suppl 3) S30
    CrossrefPubMedGoogle Scholar
  • 27 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
    CrossrefPubMedGoogle Scholar
  • 28 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
    CrossrefPubMedGoogle Scholar
  • 29 Brantly M, Avila N A, Shotelersuk V, Lucero C, Huizing M, Gahl W A. Pulmonary function and high-resolution CT findings in patients with an inherited form of pulmonary fibrosis, Hermansky-Pudlak syndrome, due to mutations in HPS-1.  Chest . 2000;  117 129-136
    CrossrefPubMedGoogle Scholar
  • 30 Gahl W A, Brantly M, Kaiser-Kupfer M I. et al . Genetic defects and clinical characteristics of patients with a form of oculocutaneous albinism (Hermansky-Pudlak syndrome).  N Engl J Med . 1998;  338 1258-1264
    CrossrefPubMedGoogle Scholar
  • 31 Huizing M, Gahl W A. Disorders of vesicles of lysosomal lineage: the Hermansky-Pudlak syndromes.  Curr Mol Med . 2002;  2 451-467
    PubMedGoogle Scholar
  • 32 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(3 pt 1) 1115-1119
    PubMedGoogle Scholar
  • 33 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
    PubMedGoogle Scholar
  • 34 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
    CrossrefPubMedGoogle Scholar
  • 35 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
    CrossrefPubMedGoogle Scholar
  • 36 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
    CrossrefPubMedGoogle Scholar
  • 37 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
    CrossrefPubMedGoogle Scholar
  • 38 Pantelidis P, Fanning G C, Wells A U, Welsh K I, du Bois M R. 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
    CrossrefPubMedGoogle Scholar
  • 39 Bouros D, Wells A U, Nicholson A G. et al . Histopathologic subsets of fibrosing alveolitis in patients with systemic sclerosis and their relationship to outcome.  Am J Respir Crit Care Med . 2002;  165 1581-1586
    CrossrefPubMedGoogle Scholar
  • 40 Gilchrist F C, Bunn C, Foley P J. et al . Class II HLA associations with autoantibodies in scleroderma: a highly significant role for HLA-DP.  Genes Immun . 2001;  2 76-81
    CrossrefPubMedGoogle Scholar
  • 41 Arnett F C. HLA and autoimmunity in scleroderma (systemic sclerosis) [review].  Int Rev Immunol . 1995;  12 107-128
    PubMedGoogle Scholar
  • 42 Kuwana M, Medsger Jr A T, 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
    CrossrefPubMedGoogle Scholar
  • 43 Avila J J, Lympany P A, Pantelidis P, Welsh K I, Black C M, du Bois M R. Fibronectin gene polymorphisms associated with fibrosing alveolitis in systemic sclerosis.  Am J Respir Cell Mol Biol . 1999;  20 106-112
    PubMedGoogle Scholar
  • 44 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
    CrossrefPubMedGoogle Scholar