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Observational Study
. 2017 Aug;5(8):639-647.
doi: 10.1016/S2213-2600(17)30216-3. Epub 2017 Jun 22.

The MUC5B promoter polymorphism and telomere length in patients with chronic hypersensitivity pneumonitis: an observational cohort-control study

Brett Ley  1 , Chad A Newton  2 , Isabel Arnould  3 , Brett M Elicker  4 , Travis S Henry  4 , Eric Vittinghoff  5 , Jeffrey A Golden  3 , Kirk D Jones  6 , Kiran Batra  7 , Jose Torrealba  8 , Christine Kim Garcia  2 , Paul J Wolters  3
Affiliations
Observational Study

The MUC5B promoter polymorphism and telomere length in patients with chronic hypersensitivity pneumonitis: an observational cohort-control study

Brett Ley et al. Lancet Respir Med. 2017 Aug.

Abstract

Background: Patients with hypersensitivity pneumonitis are at risk of developing pulmonary fibrosis, which is associated with reduced survival. In families with multiple affected members, individuals might be diagnosed as having idiopathic pulmonary fibrosis (IPF) or chronic (fibrotic) hypersensitivity pneumonitis, which suggests these disorders share risk factors. We aimed to test whether the genomic risk factors associated with the development and progression of IPF are also associated with the development of fibrosis and reduced survival in people with chronic hypersensitivity pneumonitis.

Methods: We did an observational study of two independent cohorts of patients with chronic hypersensitivity pneumonitis, one from the University of California San Francisco, CA, USA (UCSF), and one from the University of Texas Southwestern, TX, USA (UTSW). We measured two common single-nucleotide polymorphisms associated with IPF (MUC5B rs35705950 and TOLLIP rs5743890) and telomere length in peripheral blood leucocytes, and assessed their associations with chronic hypersensitivity pneumonitis risk, survival, and clinical, radiographic, and pathological features. We compared findings with those in patients with IPF from the UCSF and UTSW cohorts, and healthy controls from the European population of the 1000 Genomes Project Phase 3, version 1.

Findings: The cohorts included 145 patients from UCSF and 72 from UTSW. The minor allele frequency (MAF) was greater for MUC5B rs35705950 in patients with chronic hypersensitivity pneumonitis than in healthy controls (24·4% in UCSF and 32·3% in UTSW vs 10·7%, both p<0·0001), but not for TOLLIP rs5743890. The MAFs were similar to those for IPF (UCSF 33·3%, p=0·09; UTSW 32·0%, p=0·95). In the combined UCSF and UTSW chronic hypersensitivity pneumonitis cohort, we saw associations between extent of radiographic fibrosis and MUC5B rs35705950 minor alleles (adjusted odds ratio [OR] 1·91, 95% CI 1·02-3·59, p=0·045) and short telomere length (adjusted OR per unit change in mean natural logarithm-transformed ratio of telomere repeat copy number to single gene copy number 0·23, 0·09-0·59, p=0·002). Telomere length less than the tenth percentile for age was also significantly associated with reduced survival (log-rank p=0·006).

Interpretation: The associations between MUC5B rs35705950 and short telomere length with extent of fibrosis, histopathological features of usual interstitial pneumonia, and reduced survival in patients with chronic hypersensitivity pneumonitis suggest shared pathobiology with IPF, and might help to stratify risk.

Funding: National Institutes of Health and Nina Ireland Program for Lung Health.

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Conflict of interest statement

Conflict of Interest Statements: None of the authors report conflicts of interest relevant to this study. Dr. Ley reports a speaking fee from Genentech. Dr. Wolters reports grants from Medimmune, personal fees from Roche, and grants from Genentech. Dr. Garcia reports personal fees from Pliant Therapeutics involving activities outside the submitted work.

Figures

Figure 1
Figure 1
Telomere length distribution (observed – expected for age) and mucin 5B (MUC5B) single nucleotide polymorphism rs35705950 grouped by extent of fibrosis on HRCT in the combined cohort of patients with chronic hypersensitivity pneumonitis
Figure 2
Figure 2
Survival (A) and transplant–free survival (B) in the combined cohort of patients with chronic hypersensitivity pneumonitis with peripheral blood leukocyte telomere less than or greater than the 10th percentile for age
Figure 2
Figure 2
Survival (A) and transplant–free survival (B) in the combined cohort of patients with chronic hypersensitivity pneumonitis with peripheral blood leukocyte telomere less than or greater than the 10th percentile for age
See this image and copyright information in PMC

Comment in

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