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

Bridget D. Stuart, Joyce S. Lee, Julia Kozlitina, Imre Noth, Megan S. Devine, Craig S. Glazer, Fernando Torres, Vaidehi Kaza, Carlos E. Girod, Kirk D. Jones, Brett M. Elicker, Shwu Fan Ma, Rekha Vij, Harold R. Collard, Paul J. Wolters, Christine Kim Garcia

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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.

Original languageEnglish (US)
Pages (from-to)557-565
Number of pages9
JournalThe Lancet Respiratory Medicine
Volume2
Issue number7
DOIs
StatePublished - 2014

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Idiopathic Pulmonary Fibrosis
Telomere
Observational Studies
Cohort Studies
Survival
San Francisco
Interstitial Lung Diseases
Leukocytes
National Heart, Lung, and Blood Institute (U.S.)
Transplants
Lung Transplantation
DNA
Vital Capacity
Carbon Monoxide
Spouses
Ireland
Lung Diseases
Biomarkers

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine

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Effect of telomere length on survival in patients with idiopathic pulmonary fibrosis : An observational cohort study with independent validation. / Stuart, Bridget D.; Lee, Joyce S.; Kozlitina, Julia; Noth, Imre; Devine, Megan S.; Glazer, Craig S.; Torres, Fernando; Kaza, Vaidehi; Girod, Carlos E.; Jones, Kirk D.; Elicker, Brett M.; Ma, Shwu Fan; Vij, Rekha; Collard, Harold R.; Wolters, Paul J.; Garcia, Christine Kim.

In: The Lancet Respiratory Medicine, Vol. 2, No. 7, 2014, p. 557-565.

Research output: Contribution to journalArticle

Stuart, Bridget D. ; Lee, Joyce S. ; Kozlitina, Julia ; Noth, Imre ; Devine, Megan S. ; Glazer, Craig S. ; Torres, Fernando ; Kaza, Vaidehi ; Girod, Carlos E. ; Jones, Kirk D. ; Elicker, Brett M. ; Ma, Shwu Fan ; Vij, Rekha ; Collard, Harold R. ; Wolters, Paul J. ; Garcia, Christine Kim. / Effect of telomere length on survival in patients with idiopathic pulmonary fibrosis : An observational cohort study with independent validation. In: The Lancet Respiratory Medicine. 2014 ; Vol. 2, No. 7. pp. 557-565.
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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.",
author = "Stuart, {Bridget D.} and Lee, {Joyce S.} and Julia Kozlitina and Imre Noth and Devine, {Megan S.} and Glazer, {Craig S.} and Fernando Torres and Vaidehi Kaza and Girod, {Carlos E.} and Jones, {Kirk D.} and Elicker, {Brett M.} and Ma, {Shwu Fan} and Rekha Vij and Collard, {Harold R.} and Wolters, {Paul J.} and Garcia, {Christine Kim}",
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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

PY - 2014

Y1 - 2014

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.

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