Heterozygous mutations in four telomere-related genes have been linked to pulmonary fibrosis, but little is known about similarities or differences of affected individuals. 115 patients with mutations in telomerase reverse transcriptase (TERT) (n=75), telomerase RNA component (TERC) (n=7), regulator of telomere elongation helicase 1 (RTEL1) (n=14) and poly(A)-specific ribonuclease (PARN) (n=19) were identified and clinical data were analysed. Approximately one-half (46%) had a multidisciplinary diagnosis of idiopathic pulmonary fibrosis (IPF); others had unclassifiable lung fibrosis (20%), chronic hypersensitivity pneumonitis (12%), pleuroparenchymal fibroelastosis (10%), interstitial pneumonia with autoimmune features (7%), an idiopathic interstitial pneumonia (4%) and connective tissue disease-related interstitial fibrosis (3%). Discordant interstitial lung disease diagnoses were found in affected individuals from 80% of families. Patients with TERC mutations were diagnosed at an earlier age than those with PARN mutations (51±11 years versus 64±8 years; p=0.03) and had a higher incidence of haematological comorbidities. The mean rate of forced vital capacity decline was 300 mL·year−1 and the median time to death or transplant was 2.87 years. There was no significant difference in time to death or transplant for patients across gene mutation groups or for patients with a diagnosis of IPF versus a non-IPF diagnosis. Genetic mutations in telomere related genes lead to a variety of interstitial lung disease (ILD) diagnoses that are universally progressive.

SUMMARY 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.

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Leukocyte telomere length (LTL), MUC5B rs35705950, and TOLLIP rs5743890 have been associated with idiopathic pulmonary fibrosis (IPF). In this observational cohort study, we assessed the associations between these genomic markers and outcomes of survival and rate of disease progression in patients with interstitial pneumonia with autoimmune features (IPAF, n=250) and connective tissue disease-associated interstitial lung disease (CTD-ILD, n=248). IPF (n=499) was used as a comparator. LTL of IPAF and CTD-ILD patients (mean age-adjusted log-transformed T/S of −0.05, [SD 0.29] and −0.04 [0.25], respectively) are longer than IPF (−0.17 [0.32]). For IPAF, LTL <10th percentile is associated with faster lung function decline compared to LTL ≥10th percentile (−6.43%/year versus −0.86%/year, p<0.0001) and worse transplant-free survival (HR 2.97 [95% CI 1.70–5.20], p=0.00014). The MUC5B rs35705950 minor allele frequency is greater for IPAF (23.2 [95% CI 18.8–28.2], p<0.0001) than controls and is associated with worse transplant-free IPAF survival (HR 1.92, [95% CI 1.18–3.13], p=0.0091). Rheumatoid arthritis-associated ILD (RA-ILD) has shorter LTL than non-RA CTD-ILD (−0.14 [SD 0.27] versus −0.01 [0.23], p=0.00055) and higher MUC5B minor allele frequency (34.6 [95% CI 24.4–46.3] versus 14.1 [9.8–20.0], p=0.00025). Neither LTL nor MUC5B are associated with transplant-free CTD-ILD survival. LTL and MUC5B minor allele frequency have different associations with lung function progression and survival for IPAF and CTD-ILD.

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