Editors' ChoicePulmonary fibrosis

Snipping Away at Pulmonary Fibrosis

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Science Translational Medicine  18 May 2011:
Vol. 3, Issue 83, pp. 83ec72
DOI: 10.1126/scitranslmed.3002638

Pulmonary fibrosis comprises a spectrum of diseases that result in a progressive and irreversible scarring of the lungs. Now, Seibold and colleagues identify a variant single-nucleotide polymorphism (SNP) associated with this incurable lung disease. The genetic variant, rs35705950, increases the production of MUC5B, a mucus glycoprotein expressed in the lungs that is essential to protect and lubricate the pulmonary epithelial surface.

Pulmonary fibrosis is a complex and devastating disease. Although scientists have identified genetic factors, including surfactant and telomerase mutations, as well as environmental contributors, the etiology of pulmonary fibrosis for most patients is largely unknown. In a genome-wide linkage analysis, the authors identify a common variant in the putative promoter of MUC5B that is associated with the development of idiopathic pulmonary fibrosis (IPF) and the related disease, familial interstitial pneumonia (FIP).

In this study, the researchers evaluated genetic variations in a region of chromosome 11p15 from individuals affected by IPF (492 patients) or FIP (83 patients), as well as from 322 healthy controls. The MUC5B variant was present in 38% of the patients with IPF and 34% of patients with familial FIP. Only 9% of the healthy controls had the variant. The association of the MUC5B promoter variant with IPF was independently confirmed by Zhang et al. and reported in the same issue. Seibold’s group report that individuals carrying one copy of the variant gene have approximately seven- to ninefold increased odds of developing fibrosis in their lungs compared with those without the genetic variant. Two copies of the variant confer 20-fold greater odds of developing lung fibrosis. The responsible MUC5B variant increased the production of mucin 5B protein in the lung, which the researchers hypothesize may impair the lung’s immune defense and result in lung injury.

Although the MUC5B genetic variant alone cannot predict disease risk for an individual, this discovery is important for physicians and scientists who study and treat patients with pulmonary fibrosis. The association between increased MUC5B and lung fibrosis suggests potential roles for excessive mucus production in impaired mucosal host defense, defective tissue repair, or possible direct injury to the lung. Unraveling the pathophysiological contributions of MUC5B to pulmonary fibrosis may lead to new ways of preventing and managing this incurable and devastating disease.

M. A. Seibold et al., A common MUC5B promoter polymorphism and pulmonary fibrosis. N. Engl. J. Med. 364, 1503–1512 (2011). [PubMed]

Y. Zhang et al., A variant in the promoter of MUC5B and idiopathic pulmonary fibrosis. N. Engl. J. Med. 364, 1576–1577 (2011). [PubMed]

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