TY - JOUR
T1 - Effect of telomere length on survival in patients with idiopathic pulmonary fibrosis
T2 - An observational cohort study with independent validation
AU - Stuart, Bridget D.
AU - Lee, Joyce S.
AU - Kozlitina, Julia
AU - Noth, Imre
AU - Devine, Megan S.
AU - Glazer, Craig S.
AU - Torres, Fernando
AU - Kaza, Vaidehi
AU - Girod, Carlos E.
AU - Jones, Kirk D.
AU - Elicker, Brett M.
AU - Ma, Shwu Fan
AU - Vij, Rekha
AU - Collard, Harold R.
AU - Wolters, Paul J.
AU - Garcia, Christine Kim
N1 - Funding Information:
We are grateful to all participating patients for their contributions to this research, to Hannah Bereuter for technical excellence in measuring telomere lengths, to Martha Kingman for help in patient recruitment, and to Helen H Hobbs for the control DNA samples. We are grateful for funding provided by the National Institutes of Health (NIH) K12 HD-068369 to BDS, the NIH and UCSF-CTI KL2TR000143 to JSL, P01 HL108794 to HRC and PJW, the Harroun Family Foundation and the Nina Ireland Lung Disease Program to HRC and PJW, NIH RC1 HL099619 to IN, and NIH R01 HL093096 and the UL1TR001105 to CKG.
PY - 2014/7
Y1 - 2014/7
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84903995680&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84903995680&partnerID=8YFLogxK
U2 - 10.1016/S2213-2600(14)70124-9
DO - 10.1016/S2213-2600(14)70124-9
M3 - Article
C2 - 24948432
AN - SCOPUS:84903995680
SN - 2213-2600
VL - 2
SP - 557
EP - 565
JO - The Lancet Respiratory Medicine
JF - The Lancet Respiratory Medicine
IS - 7
ER -