A SNP altering the MUC5AC mucin structure is increased in idiopathic pulmonary fibrosis together with the MUC5B SNP.

BACKGROUND: The gel-forming mucins MUC5B and MUC5AC constitute the main structural components of mucus in the respiratory system where MUC5AC is known to form nets. The MUC5B (rs35705950) Single Nucleotide Polymorphism (SNP) has been shown to increase the risk for Idiopathic Pulmonary Fibrosis (IPF). The MUC5AC SNP rs878913005, common in European populations, results in an Arg1201Trp substitution, resulting in more stabilized secreted mucin nets. Here we investigate the association of rs878913005 with the development of IPF and the presence of the two mucins in IPF diagnostic honeycomb cysts. METHODS: We compared patient groups using whole genome sequences from the UK-Biobank for the SNPs in MUC5AC and MUC5B mucin genes. Lung tissue from IPF patients were immunostained for these mucins. RESULTS: The MUC5AC SNP shows a significant 1.49x increased frequency in IPF patients relative to controls (p < 0.0001) and an odds ratio of 2.09. The well-known IPF-associated SNP in the MUC5B promoter (rs35705950) has a stronger linkage to IPF when combined with the MUC5AC SNP. These two SNPs are located on the same chromosome and are in linkage disequilibrium (r2 = 0.10 in controls and up to r2 = 0.17 in IPF). Microscopic honeycomb cysts, typical for IPF, are filled with both the MUC5B and MUC5AC mucins with MUC5AC associated to the cysts' epithelial surface. CONCLUSION: A genetic variant with more stable MUC5AC nets in peripheral thin airways may increase the risk of IPF.