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

Abstract

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.

Figure 1. Age-adjusted telomere lengths of some interstitial lung disease (ILD) patients are shorter than controls

Mean observed minus expected (age-adjusted) telomere length for controls (n=195), patient spouses (n=46) and individuals from familial pulmonary fibrosis kindreds who carry an inherited telomerase (TERT or TERC) mutation (n=106). The ILD patients were subdivided by etiology: idiopathic pulmonary fibrosis (IPF, n=149) and non-IPF patients which include those with connective-tissue disease associated ILD (CT-ILD, n=126), idiopathic interstitial pneumonias other than usual interstitial pneumonia (Other IIPs, n=17), hypersensitivity pneumonitis (n=30), drug-related or radiation-associated ILD (Exposures, n=10), sarcoidosis (n=22) and ILD from other causes (Other, n=16). Approximate age-adjusted prediction bands (percentiles) were calculated from the linear regression model.

Figure 2. Shorter telomere lengths predict worse survival for IPF patients in three independent cohorts

Estimated survival functions for IPF patients from Dallas, Chicago and San Francisco stratified by telomere length quartiles for transplant-free survival.