We identified a common variant in the putative promoter of MUC5B that is associated with the development of familial interstitial pneumonia and idiopathic pulmonary fibrosis. Linkage, fine mapping, selective resequencing of MUC2 and MUC5AC, and a genetic analysis of the gel-forming mucin region at the p-terminus of chromosome 11 resulted in the identification of a SNP (rs35705950) in the putative MUC5B promoter that is strongly associated with both MUC5B expression in the lung among unaffected subjects and the development of familial interstitial pneumonia and idiopathic pulmonary fibrosis. Moreover, subjects with idiopathic pulmonary fibrosis had significantly higher levels of expression of MUC5B in the lungs than did controls, and the MUC5B protein was expressed in lesions of idiopathic pulmonary fibrosis. On the basis of our findings, the population attributable risk of familial interstitial pneumonia or idiopathic pulmonary fibrosis for this promoter polymorphism is likely to be substantial. In aggregate, our findings suggest that dysregulated MUC5B expression in the lung may be involved in the pathogenesis of pulmonary fibrosis.
The prevailing opinion is that idiopathic pulmonary fibrosis develops as a result of excessive, sequential lung injury or aberrant wound healing.21
Although the mechanisms that account for excessive lung injury or aberrant repair in persons with the SNP in the putative MUC5B
promoter remain unknown, our findings point to at least three possibilities. First, on the basis of the relationship between the SNP and excess production of MUC5B, we hypothesize that too much MUC5B impairs mucosal host defense, results in excessive lung injury from inhaled substances, and over time leads to the development of idiopathic interstitial pneumonia. In addition to the MUC5B
promoter SNP, common exposures and basic biologic processes can influence either the expression of the gene or the clearance of the protein. For instance, MUC5B
expression can be enhanced in the lung by cigarette smoke,17,22
or epigenetic changes that alter DNA methylation or chromatin structure.29
In addition, clearance of lung mucus is dependent on effective ciliary motion, adequate hydration of the periciliary liquid layer, and an intact cough.26
However, regardless of whether excess MUC5B in the air space is caused by overexpression or impaired clearance, our findings raise the possibility that excess concentrations of MUC5B compromise mucosal host defense, reducing lung clearance of inhaled particles, dissolved chemicals, and microorganisms. Given the importance of environmental exposures (e.g., exposure to asbestos and silica) in the development of other forms of interstitial lung disease, it is logical to speculate that common inhaled particles, such as those associated with cigarette smoke or air pollution, might cause exaggerated interstitial injury in persons who have defects in mucosal host defense.
Second, excess MUC5B in the respiratory bronchioles may interfere with alveolar repair. It has been established that alveolar injury results in the collapse of bronchoalveolar units and that this focal lung injury is repaired through re-epithelialization of the alveolus by type II alveolar epithelial cells.30,31
Thus, an alternative hypothesis is that MUC5B impedes alveolar repair, either by interfering with the interaction between the type II alveolar epithelial cells and the underlying matrix or by interfering with the surface-tension properties of surfactant. Either the failure to re-epithelialize the basal lamina of the alveolus or the presence of suboptimal surfactant activity could enhance ongoing alveolar collapse and fibrosis of adjacent bronchoalveolar units and eventually lead to the development of idiopathic interstitial pneumonia.
Third, the lesions of idiopathic pulmonary fibrosis are spatially heterogeneous,21
suggesting that the disorder is multifocal, originating in individual bronchoalveolar units. Since the rs35705950 SNP occurs in the putative promoter region of MUC5B
and is predicted to disrupt transcription-factor binding sites, one must consider ectopic production of MUC5B in cells or locations that cause injury to the bronchoalveolar unit. Although all three mechanisms are plausible and may act alone or together to contribute to the development of idiopathic interstitial pneumonia in persons with the MUC5B
promoter SNP, further research is needed to define the mechanisms involved in MUC5B
-associated interstitial lung disease and to address the possibility that unscreened genetic variants (especially in the inaccessible repetitive mucin regions) in linkage disequilibrium with the MUC5B
promoter SNP affect the function of other lung mucins.
Our results could potentially alter the clinical approach to idiopathic interstitial pneumonia. The implication of secreted airway mucins in the pathogenesis of pulmonary fibrosis suggests that the air space plays a role in the development of idiopathic interstitial pneumonia. Although identification of rs35705950 in the putative MUC5B promoter can be used to target persons at risk for the development of idiopathic interstitial pneumonia (especially those who are members of families subject to idiopathic interstitial pneumonia), our observation that the biologic features of mucins may be important etiologic factors in this disease could reorient the focus of pathogenic and therapeutic studies in interstitial lung disease to lung mucins, the air space, and the bronchoalveolar unit. In addition, the genetic causes of idiopathic interstitial pneumonia — MUC5B, surfactant protein C, surfactant protein A2, and two telomerase genes — could provide insight into the particular clinical manifestations of this complex disease process and consequently lead to earlier detection, more predictable prognosis, and personalized therapeutic strategies.