C71-25 Gene Modulators of Muc5b-driven Lung Fibrosis

Abstract Rationale 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, suggesting the presence of additional genetic modifiers. Methods We identified the loci and genes that control bleomycin-induced MUC5B protein expression and contribute to bleomycin-induced lung fibrosis at different stages in DO population using QTL mapping and evaluated the relevance of candidate genes to human IPF with available human IPF data. Results At the early stage of bleomycin exposure, we identify the mucin-locus, including Muc5ac, Muc5b, Muc2 genes, regulating MUC5B protein abundance. At the later stages of the response to bleomycin, when fibrosis is more established, MUC5B protein is no longer a dominant signal; instead, we identify ten distinct QTLs associated with measures of lung fibrosis. Among the candidate genes, Oat emerges as a strong modifier that may act in concert with Muc5b to drive fibrotic remodeling, while others such as Rcan2 and Glb1l2 may contribute through distinct or Muc5b-dependent mechanisms. Together, these results suggest that the pathogenic consequences of the Muc5b promoter variant are shaped by additional genetic factors that act in a stage- and cell-type specific manner. Conclusions Our findings highlight the temporal and spatial complexity of genetic regulation of fibrotic lung disease, and indicate that the Muc5b locus appears to be involved in the early response to bleomycin, or more generally environmental challenges, by increasing the concentration of MUC5B, while other independent genomic responses appear to be involved in the progression of lung fibrosis. This abstract is funded by: R01HL149836