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Effect of telomere length on survival in patients with idiopathic pulmonary fibrosis: an observational cohort study with independent validation

https://doi.org/10.1016/S2213-2600(14)70124-9Get rights and content

Summary

Background

Short telomere lengths are found in a subset of patients with idiopathic pulmonary fibrosis, but their clinical significance is unknown. Our aim was to investigate whether patients with various blood leucocyte telomere lengths had different overall survival.

Methods

In this observational cohort study, we enrolled patients with interstitial lung disease from Dallas, TX (primary cohort), and from Chicago, IL, and San Francisco, CA (replication cohorts). We obtained genomic DNA samples from unrelated healthy controls in Dallas, TX, and spouses of patients were also enrolled as an independent control group. Telomere lengths were measured in genomic DNA samples isolated from peripheral blood obtained at the time of the initial enrolment assessment. The primary endpoint was transplant-free survival (ie, time to death or lung transplantation) in the Dallas cohort. Findings were validated in the two independent idiopathic pulmonary fibrosis cohorts (Chicago and San Francisco).

Findings

370 patients were enrolled into the Dallas cohort between June 17, 2003, and Aug 25, 2011. The 149 patients with idiopathic pulmonary fibrosis had shorter telomere lengths than did the 195 healthy controls (mean age-adjusted log-transformed ratio of telomere to single copy gene was −0·16 [SD 0·23] vs 0·00 [0·18]; p<0·0001); however, telomere lengths of the Dallas patients with idiopathic pulmonary fibrosis (1·33 [SD 0·25]) were similar to the 221 patients with other interstitial lung disease diagnoses (1·46 [0·24]) after adjusting for age, sex, and ethnicity (p=0·47). Telomere length was independently associated with transplant-free survival time for patients with idiopathic pulmonary fibrosis (HR 0·22 [95% CI 0·08–0·63]; p=0·0048), but not for patients with interstitial lung disease diagnoses other than idiopathic pulmonary fibrosis (HR 0·73 [0·16–3·41]; p=0·69). The association between telomere length and survival in patients with idiopathic pulmonary fibrosis was independent of age, sex, forced vital capacity, or diffusing capacity of carbon monoxide, and was replicated in the two independent idiopathic pulmonary fibrosis replication cohorts (Chicago cohort, HR 0·11 [0·03–0·39], p=0·00066; San Francisco cohort, HR 0·25 [0·07–0·87], p=0·029).

Interpretation

Shorter leucocyte telomere lengths are associated with worse survival in idiopathic pulmonary fibrosis. Additional studies will be needed to establish clinically relevant thresholds for telomere length and how this biomarker might affect risk stratification of patients with idiopathic pulmonary fibrosis.

Funding

US National Heart, Lung, and Blood Institute, National Center for Advancing Translational Sciences, Harroun Family Foundation, and Nina Ireland Lung Disease Program.

Introduction

Idiopathic pulmonary fibrosis is a chronic, fibrotic lung disease usually affecting adults older than 50 years. Countries such as Canada, and the European Union, have approved pirfenidone for the treatment of idiopathic pulmonary fibrosis; however, no therapies have been approved for this disorder in the USA. The natural history of this disease is progressive with a highly variable rate of decline in lung function.1, 2, 3 The cause of idiopathic pulmonary fibrosis is unknown, but recent investigations have implicated telomere shortening in the pathogenesis of the disease.4, 5

Telomeres are specialised nucleoprotein structures that protect chromosomal ends. Mutations in the genes encoding telomerase—the multisubunit enzyme that extends telomere lengths—have been reported in patients with idiopathic pulmonary fibrosis.6, 7 Heterozygous telomerase mutations, mainly those in the gene encoding the protein component of telomerase (TERT), are found in about 15% of kindreds with familial pulmonary fibrosis and 3% of patients with sporadic idiopathic pulmonary fibrosis with no known family history of disease.7, 8 Pulmonary fibrosis associated with TERT mutations is progressive and lethal with a mean survival of 3 years after diagnosis.8 Compared with the other disorders of telomere dysfunction caused by a single gene defect (such as dyskeratosis congenita, aplastic anaemia, and liver cirrhosis), idiopathic pulmonary fibrosis is the most common manifestation of telomere-mediated disease.9 Telomere lengths of the offspring of telomerase mutation carriers can be affected by epigenetic inheritance of short telomere lengths independent of mutant alleles.8, 10 Additionally, genome-wide association studies of pulmonary fibrosis have identified susceptibility loci near TERT,11, 12 TERC,12 and OBFC1,12 implicating common variants in genes that are associated with telomere length in the general population13 as contributors to the development of pulmonary fibrosis.

Peripheral blood telomere lengths have been reported to be shorter in patients with idiopathic pulmonary fibrosis than in age-matched controls, suggesting that they might be a marker of increased disease susceptibility.4, 5 Non-genetic contributions to telomere shortening relevant to lung disease include exposure to oxidative damage and cigarette smoking.14, 15, 16 At present, the clinical significance of telomere lengths in patients with idiopathic pulmonary fibrosis and other forms of interstitial lung disease are unknown.

We aimed to test the hypothesis that telomere length is associated with survival in patients with idiopathic pulmonary fibrosis and those with non-idiopathic pulmonary fibrosis interstitial lung disease.

Section snippets

Study design and participants

In this observational cohort study, patients with interstitial lung disease were enrolled from a large academic medical centre in Dallas, TX (the primary cohort of patients), and patients with idiopathic pulmonary fibrosis were enrolled in Chicago, IL and San Francisco, CA (replication cohorts). Genomic DNA samples from healthy control participants aged 19–89 years, which had been used in previous studies,4, 8 were obtained from a cohort of unrelated, multiethnic individuals from Dallas, TX.

Results

The primary (Dallas) cohort consisted of 370 patients (149 with idiopathic pulmonary fibrosis) enrolled between June 17, 2003, and Aug 25, 2011; the replication cohorts consisted of 139 patients with idiopathic pulmonary fibrosis from Chicago enrolled between Sept 1, 2005, and Jan 31, 2012, and 54 patients with idiopathic pulmonary fibrosis from San Francisco enrolled between Oct 14, 2005, and July 8, 2011. The Dallas patients with idiopathic pulmonary fibrosis were older and were more likely

Discussion

Although short telomere lengths have been identified in patients with pulmonary fibrosis with rare loss-of-function telomerase mutations6, 7 and have been implicated in disease pathogenesis, our study is the first to our knowledge to show an independent association between telomere length and survival in patients with idiopathic pulmonary fibrosis (panel). We found that the mean telomere length in patients with idiopathic pulmonary fibrosis and those with non-idiopathic pulmonary fibrosis is

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