The MUC5B IPF risk variant promotes a distal airway secretory phenotype and loss of alveolar markers

The dominant risk factor for the development of idiopathic pulmonary fibrosis (IPF) is a common variant in the promoter region of the airway mucin MUC5B, variant rs35705950. The MUC5B promoter variant enhances MUC5B expression in the terminal respiratory bronchiole, where it is normally absent. We pursued a spatial gene expression approach to understand how the MUC5B variant influences IPF in age-matched unaffected and IPF lung tissue specimens. We used the Nanostring Digital Spatial Profiler platform to analyze transcriptional profiles from 310 separate lung regions from 75 age-matched donors who were either unaffected (21) or had IPF (54). Formalin-fixed, paraffin-embedded tissues were obtained from the Lung Tissue Research Consortum or from patients undergoing lung transplant at the University of Colorado (Colorado Multi-Institutional Review Board protocol #15-1147). Acquired regions fell into one of five categories: Airway, alveolus, transition zones characterized by fibroblastic foci, dense fibrosis, or honeycomb cysts guided by our pathologist (C.D.C.). Specimens were genotyped for the IPF risk variant in the promoter for the MUC5B gene, rs35705950 G;T, with 7 control specimens and 31 IPF specimens containing at least one copy of the variant allele. *************************************************************** Due to this being human subjects data, we are not including raw data files. ***************************************************************