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The fibrosing IIPs are characterised by progressive scarring of the alveolar interstitium, which leads to significant morbidity and mortality. Idiopathic pulmonary fibrosis (IPF) is the most common and most severe form of IIP with a median survival of 3 years, limited treatment options and an increasing prevalence. The strongest and most replicated risk factor for IPF is the promoter variant located in a highly conserved region of the genome ~3 kilobases upstream of the airway mucin MUC5B transcription start site.1 The MUC5B variant rs35705950 has a regulatory role and is associated with increased RNA expression in whole lung tissue in IPF and controls.2 In mice, transgenic overexpression of Muc5b leads to increased lung fibrosis and decreased mucociliary clearance, supporting the functional role of this airway mucin in lung fibrosis.3 However, studies of the MUC5B function in human disease have been limited.
The short communication by Stock et al 4 is a follow-up to a previous publication by this group in which they characterised MUC5B protein expression in distal airways and honeycomb lesions in a set of surgical lung biopsies of IPF, scleroderma-associated NSIP (SSc-NSIP) and idiopathic NSIP (I-NSIP) lung tissue,5 showing that the primary site of MUC5B overexpression was in the distal airway and that this was specific to IPF. Nakano et al at the same time reported that increased MUC5B expression in the distal airway was associated with the MUC5B promoter variant.6 Stock et al have now validated the observation by Nakano et al and, for the first time, show that the effect of the alternate T allele is present in IPF distal airway and honeycomb cysts but not in SSc-NSIP, I-NSIP nor in histologically normal control lung tissue. Importantly, the MUC5B promoter variant is not associated with increased risk of these other IIPs.1 Moreover, Stock et al demonstrate that individuals with the T allele and higher MUC5B have less severe disease, as assessed by the Composite Physiological Index (CPI).
The main significance of the present study is the replication of previous findings in a larger number of samples and expansion of the variant analysis to other fibrosing IIPs and control tissue, demonstrating specificity to IPF. Stock and Nakano both quantified MUC5B in randomly selected regions of the lung sections to avoid bias. Ideally the entire lung sections will be analysed in the future to further reduce any potential bias. While results of the analysis of the MUC5B T allele association with disease severity are intriguing, we view them as preliminary because CPI, although validated against CT,7 is not a commonly used measure of disease severity. Given the controversy of the protective role of the MUC5B variant in survival,8 9 it will be important to validate these results in larger cohorts with multiple measures of diseases severity. Nevertheless, the work by Stock et al 4 provides important further evidence for the functional significance of the MUC5B promoter variant to IPF.
Footnotes
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests IVY is a consultant for Eleven P15.
Patient consent for publication Not required.
Provenance and peer review Commissioned; externally peer reviewed.
Data availability statement No data are available. Not applicable to commentary article.