Genetics

 

Evidence for a genetic basis of IIP is substantial.

  • Interstitial lung disease (ILD) has been associated with pleiotropic genetic disorders,

  • At least 3% of cases of idiopathic interstitial pneumonia (IIP) have a first degree relative with a similar illness. 

  • Rare mutations in genes that maintain telomere length (TERT and TERC) have been reported to be associated with the development of Familial interstitial pneumonia (FIP), defined as 2 cases of IIP in one family and the most common form of IIP, idiopathic pulmonary fibrosis (IPF).

  • Four families with FIP have been shown to have disease-associated mutations in surfactant protein C (SFTPC) or SFTPA2.

Autosomal Dominant Inheritance

 

Approximately 40% of families with FIP have discordant types of IIP among family members, suggesting that IIP may be caused by common gene variants that are altered phenotypically by environmental exposures. In fact, FIP and IPF can be influenced by environmental exposures.

 

 

 

 

Role of genetics in the development of pulmonary fibrosis

Diagram of gene structure? or other?

 

 

 

 

 

 

Although the genes associated with familial pulmonary fibrosis (FPF) are not known, the following is known:

  • TERT and TERC: Mutations have been reported in about 10% of individuals with FPF and fewer than 1% of sporadic cases of idiopathic PF.1,2

  • SFTPC: Mutations in the gene encoding surfactant protein C (SFTPC) are associated with the development of an inflammatory form of IIP in one family3 and what appears to be both idiopathic pulmonary fibrosis (IPF) and NSIP in another large family4.  In sporadic cases of IPF, surfactant protein C mutations appear to be rare5.

  • SP-A1: In a Mexican cohort, mutations in the genes encoding surfactant protein A1 and surfactant protein B have been shown to be associated with IPF in nonsmoking and smoking populations, respectively6.

  • Polymorphisms of various cytokines (IL-1RA, TNF-alpha, and IL-6) have been reported to be associated with the development of IPF7.

  • ELMOD2 was identified as a candidate gene for FPF in a genomic screen of six multiplex families from southeastern Finland8.



Genetic Disorders that can develop pulmonary fibrosis

 

Pulmonary fibrosis has also been observed in genetic disorders with pleiotropic presentation:

  • Hermansky-Pudlak syndrome9 

  • Neurofibromatosis10 

  • Tuberous sclerosis11,12

  • Neimann-Pick disease13

  • Gaucher's disease14

  • Dyskeratosis congenita15

  • Familial hypocalciuric hypercalcemia16

 

 

References

  1. Armanios MY et al., Telomerase mutations in families with idiopathic pulmonary fibrosis. N Engl J Med 356; 1317-1326 (2007). 

  2. Tsakiri KD et al., Adult-onset pulmonary fibrosis caused by mutations in telomerase.  Proc Natl Acad Sci USA 104: 7552-7557 (2007).

  3. Nogee et al., A mutation in the surfactant protein C gene associated with familial interstitial lung disease.  N Engl J Med 344(8)573-579 (2001).

  4. Thomas 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. 165:1322-1328 (2002).

  5. Lawson et al., Genetic mutations in surfactant protein C are rare cause of spradic cases of IPF.  Thorax 59: 977-980 (2004). 

  6. Selman et al., Surfactant protein A and B genetic variants predispose to idiopathic pulmonary fibrosis.  Hum Genet 113: 542-550 (2003).

  7. Whyte 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. 79: 162: 755-780 (2000).

  8. Hodgson et al., ELMOD2 is a candidate gene for familial idiopathic pulmonary fibrosis.  Am J Hum Genet. 79: 149-154 (2006).  

  9. DePinho et al., The Hermansky-Pudlak syndrome.  Report of three cases and review of pathophysiology and management considerations.  Medicine (Baltimore). 64: 192-202 (1985). 

  10. Riccardi et al., Neurofibromitosis.  N Engl J Med. 305:1617-1627 (1981). 

  11. Malik et al., Involvement of the lungs in tuberous sclerosis.  Chest 58:538-540 (1970).

  12. Harris et al., The pathophysiology of the lungs in tuberous sclerosis.  A case report and literature review.  Am Rev Respir Dis. 100: 379-387 (1969).  

  13. Terry et al., Adult lipidosis resembling Niemann-Pick's disease.  Am J Pathol., 30: 263-285 (1954).

  14. Schneider et al., Severe pulmonary involvement in adult Gaucher disease.  Report of three cases and review of the literature.  Am J Med. 63: 475-480 (1977).

  15. Armanios et al., Haploinsufficiency of telomerase reverse transcriptase leads to anticipation in autosomal dominant dyskeratosis congenital. Proc Natl Acad Sci USA 102: 15960-15964 (2005).

  16. Auwerx et al., Coexistence of hypocalciuric hypercalcaemia and interstitial lung disease in a family: a cross-sectional study. Eur J Clin Invest. 15: 6-14 (1985).