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

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Summary

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.

Introduction

Hypersensitivity pneumonitis is an inflammatory lung disease caused by exposure to various organic antigens via inhalation. Clinical presentation and natural history are heterogeneous and, therefore, the disease is most commonly classified with the temporal designations of acute, subacute, and chronic.1 Pulmonary fibrosis most clearly identifies patients with hypersensitivity pneumonitis that will be chronic and progressive and who will have a poor prognosis.2 The clinical presentation of fibrotic hypersensitivity pneumonitis is often similar to that for idiopathic pulmonary fibrosis (IPF), which is the most deadly form of idiopathic interstitial pneumonia and is associated with progressive pulmonary fibrosis and reduced survival.2, 3

The development of pulmonary fibrosis in hypersensitivity pneumonitis is thought to be due to persistent lung injury resulting from ongoing exposure to antigens and persistent inflammation. Epidemiological studies confirm that only a subset of individuals exposed to an inciting antigen develop hypersensitivity pneumonitis, which suggests a genetic contribution,4, 5, 6, 7 although no predisposing genomic factors have been identified.1 Several single-nucleotide polymorphisms (SNPs) have been associated with predisposition to IPF,8, 9, 10, 11, 12 two of which, MUC5B rs35705950 and TOLLIP rs5743890, have also been associated with altered survival risk in people with established disease.8, 9 Variants in genes associated with telomere maintenance have also been linked to IPF,11, 13, 14, 15, 16, 17, 18, 19 with short telomere lengths in peripheral blood leucocytes (PBLs) being associated with reduced survival.20 In families in which multiple members have pulmonary fibrosis, some might be diagnosed clinically as having chronic hypersensitivity pneumonitis, which suggests that telomere dysfunction could also be a risk factor for this disorder.13, 14, 15, 16, 17, 18, 19, 21

Research in context

Evidence before this study

We searched PubMed for studies published before Jan 14, 2017, with the search terms “MUC5B”, “TOLLIP”, “telomere length”, “hypersensitivity pneumonitis”, and “alveolitis, extrinsic allergic”. We found no studies reporting associations between the MUC5B rs35705950 or TOLLIP rs5743890 single-nucleotide polymorphisms and hypersensitivity pneumonitis. Two studies reported peripheral blood leucocyte telomere length in people with hypersensitivity pneumonitis, but did not assess associations with clinical features or outcomes.

Added value of this study

We found associations between MUC5B rs35705950 minor alleles and risk of chronic hypersensitivity pneumonitis and extent of fibrosis, but none with the TOLLIP rs5743890 single-nucleotide polymorphism. Additionally, short telomere length was associated with extent of fibrosis, histopathological features of usual interstitial pneumonia, and reduced survival in people with chronic hypersensitivity pneumonitis.

Implications of all the available evidence

MUC5B rs35705950 minor alleles and short telomere length in peripheral blood lymphocytes might be useful for risk stratification in patients with chronic hypersensitivity pneumonitis. Our findings also suggest shared pathobiology between idiopathic pulmonary fibrosis and chronic hypersensitivity pneumonitis.

We did an observational study to test the theory that the genomic risk factors associated with the development and progression of IPF—MUC5B rs35705950 and TOLLIP rs5743890 SNPs and PBL telomere length—are also associated with the development of fibrosis and reduced survival in people with chronic hypersensitivity pneumonitis. We specifically assessed associations between these factors and risk, radiographic and histopathological features of lung remodelling (eg, honeycombing and traction bronchiectasis) and fibrosis (eg, reticulation and fibroblast foci), and survival in patients with chronic hypersensitivity pneumonitis.

Section snippets

Study design and populations

We did an observational cohort study using data for two cohorts of patients with chronic hypersensitivity pneumonitis drawn from clinical registries at the University of California San Francisco, CA, USA (UCSF) and the University of Texas Southwestern, TX, USA (UTSW). These two cohorts comprised consecutive patients seen in interstitial lung disease clinics from October, 2001, to April, 2016, at UCSF and from August, 2005, to August, 2016, at UTSW. All diagnoses of chronic hypersensitivity

Results

The UCSF cohort included 145 patients and the UTSW cohort 72 patients with chronic hypersensitivity pneumonitis who were genotyped for the MUC5B rs35705950 and TOLLIP rs5743890 SNPs. Telomere length was measured in 129 (89%) of 145 UCSF patients and in all 72 UTSW patients. The baseline characteristics of patients are shown in table 1. Among patients with chronic hypersensitivity pneumonitis, the mean age was 62 (SD 11) years, 61% in the UCSF and 47% in the UTSW cohorts were women, and at least

Discussion

We investigated genomic factors in the development of pulmonary fibrosis and reduced survival in people with chronic hypersensitivity pneumonitis. Short PBL telomere length and the MUC5B promoter variant rs35705950, but not the TOLLIP variant rs5743890, were associated with pulmonary fibrosis. Short telomere length was also strongly associated with histopathological features typical of usual interstitial pneumonia and reduced survival. Before this study, the MUC5B rs35705950 SNP had been

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