MUC5B and Idiopathic Pulmonary Fibrosis

Abstract

Idiopathic pulmonary fibrosis (IPF), a fatal disease that is a result of complex interactions between genetics and the environment, has limited treatment options. We have identified the MUC5B promoter polymorphism and other common genetic variants that in aggregate explain roughly one-third of disease risk. The MUC5B promoter polymorphism is the strongest and the most replicated genetic risk factor for IPF, appears to be protective and predictive in this disease, and is likely involved in disease pathogenesis through an increase in MUC5B expression in terminal bronchi and honeycombed cysts. Expression of MUC5B is also highly correlated with expression of cilium genes in IPF lung. Our work suggests that mucociliary dysfunction in the distal airway may play a role in the development of progressive fibroproliferative lung disease. In addition, our work has important implications for secondary prevention, early detection, and future early and personalized treatment based on genetic profiles.

Keywords: MUC5B; gene expression profile; mucociliary dysfunction; pulmonary fibrosis; genetic variant.

Figure 1.

Immunohistochemical staining for MUC5B protein (brown) in cystic structures in idiopathic pulmonary fibrosis (IPF) lung. Left: An area of IPF lung tissue containing histologically normal airway and honeycomb cysts. Middle and right: Honeycomb cysts, exclusively. In all three panels, honeycomb cysts are filled with mucus. Tissue was counterstained with hematoxylin.

Figure 2.

Gene expression profiling identifies two subtypes of idiopathic pulmonary fibrosis/usual interstitial pneumonia (IPF/UIP). mRNA profiles from 119 IPF/UIP lungs were subject to hierarchical clustering based on the expression of 472 transcripts that are differentially expressed at a 5% false discovery rate and with a greater than 2-fold change in IPF/UIP compared with control lung. The distance metric is Euclidean, with complete linkage across samples and Ward’s linkage across genes. Extent of honeycombing and fibroblastic foci in each sample as assessed by pathology is depicted by the color: yellow (unscored/not present), orange (rare), red (present). Reprinted by permission from Reference .