title: 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).
  
  
  RESULTS
  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).
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  US National Heart, Lung, and Blood Institute, National Center for Advancing Translational Sciences, Harroun Family Foundation, and Nina Ireland Lung Disease Program.
authors.affiliation: University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Bridget D
authors.initials: BD
authors.lastname: Stuart
authors.affiliation: University of California San Francisco, San Francisco, CA, USA.
authors.forename: Joyce S
authors.initials: JS
authors.lastname: Lee
authors.affiliation: University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Julia
authors.initials: J
authors.lastname: Kozlitina
authors.affiliation: University of Chicago, Chicago, IL, USA.
authors.forename: Imre
authors.initials: I
authors.lastname: Noth
authors.affiliation: University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Megan S
authors.initials: MS
authors.lastname: Devine
authors.affiliation: University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Craig S
authors.initials: CS
authors.lastname: Glazer
authors.affiliation: University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Fernando
authors.initials: F
authors.lastname: Torres
authors.affiliation: University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Vaidehi
authors.initials: V
authors.lastname: Kaza
authors.affiliation: University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: Carlos E
authors.initials: CE
authors.lastname: Girod
authors.affiliation: University of California San Francisco, San Francisco, CA, USA.
authors.forename: Kirk D
authors.initials: KD
authors.lastname: Jones
authors.affiliation: University of California San Francisco, San Francisco, CA, USA.
authors.forename: Brett M
authors.initials: BM
authors.lastname: Elicker
authors.affiliation: University of Chicago, Chicago, IL, USA.
authors.forename: Shwu-Fan
authors.initials: SF
authors.lastname: Ma
authors.affiliation: University of Chicago, Chicago, IL, USA.
authors.forename: Rekha
authors.initials: R
authors.lastname: Vij
authors.affiliation: University of California San Francisco, San Francisco, CA, USA.
authors.forename: Harold R
authors.initials: HR
authors.lastname: Collard
authors.affiliation: University of California San Francisco, San Francisco, CA, USA.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Wolters
authors.affiliation: University of Texas Southwestern Medical Center, Dallas, TX, USA. Electronic address: christine.garcia@utsouthwestern.edu.
authors.forename: Christine Kim
authors.initials: CK
authors.lastname: Garcia
mesh_terms: D000328:Adult; D000368:Aged; D015415:Biomarkers; D002641:Chicago / Q000453:epidemiology; D015331:Cohort Studies; D004247:DNA / Q000032:analysis*; D005260:Female; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000235:genetics* / Q000401:mortality*; D007962:Leukocytes; D008297:Male; D008875:Middle Aged; D018570:Risk Assessment; D012495:San Francisco / Q000453:epidemiology; D015996:Survival Rate; D059506:Telomere Shortening; D013781:Texas / Q000453:epidemiology
chemical_list: D015415:Biomarkers; D004247:DNA