Genes, other than Muc5b, are associated with bleomycin-induced lung injury

Abstract

The MUC5B promoter variant rs35705950 is the dominant risk factor for the development of idiopathic pulmonary fibrosis (IPF), yet its low penetrance remains unexplained. All eight founder strains of the Diversity Outbred (DO) mouse population carry the risk allele at the orthologous site, yet exhibited variable bleomycin-induced MUC5B expression and fibrosis severity. Herein, using the DO bleomycin model, we find that the Muc5b locus regulates MUC5B expression at 3 weeks, and at 10 weeks, several quantitative trait loci (QTLs) are associated with radiologic features of lung fibrosis, such as parenchymal consolidations. Cross-species integrations with human IPF studies reveal heterogeneous epithelial patterns and variable correlation with MUC5B among orthologous QTL genes, and expression of novel proteins in pathognomonic lesions of IPF. This study establishes a radiomics-genetics resource generated from DO mice subjected to bleomycin-induced lung injury, enabling systematic dissection of genetically driven heterogeneity in addition to MUC5B in lung imaging traits.