The MUC5B promoter polymorphism and telomere length in patients with chronic hypersensitivity pneumonitis

BACKGROUND: Patients with hypersensitivity pneumonitis (HP) may develop lung fibrosis, which is associated with reduced survival. Families with pulmonary fibrosis can present with members diagnosed with idiopathic pulmonary fibrosis (IPF) or chronic HP (cHP), suggesting that fibrotic HP may share risk factors with IPF. METHODS: In an observational study of two independent cohorts of patients with cHP (UCSF n=145, UTSW n=72), we measured two common single nucleotide polymorphisms associated with IPF (MUC5B rs35705950 & TOLLIP rs5743890) and peripheral blood leukocyte telomere length and evaluated their associations with cHP disease, survival, and clinical-radiograph-pathologic features. FINDINGS: The frequency of the MUC5B minor allele, but not the TOLLIP minor allele, was significantly increased in cHP patients in both cohorts (UCSF MAF 24.4% & UTSW MAF 32.3%) compared to healthy controls (MAF 10.7%; p-values for comparison = <0.0001 for both cohorts) and similar to IPF (UCSF MAF 33.3% & UTSW MAF 32.0%, p-values for comparison=0.10 & 0.95, respectively). The MUC5B minor allele (adjusted OR 1.91, p=0.045) and shorter telomere length (adjusted OR 0.23, p=0.002) were associated with extent of radiographic fibrosis and other measures of lung remodeling and fibrosis in the combined cHP cohorts. Shorter telomere length had a significant association (adjusted HR 0.18, p=0.001) with reduced survival in the combined cHP cohorts. INTERPRETATION: The MUC5B promoter polymorphism rs35705950 and shorter telomere length are associated with extent of fibrosis in cHP. Shorter telomere length is associated with histopathology findings typical of usual interstitial pneumonia and reduced survival in cHP. FUNDING: NIH grants KL2TR001870, T32HL098040, UL1TR001105, R01HL093096, and the Nina Ireland Program for Lung Health.