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    Telomere length and genetic variant associations with interstitial lung disease progression and survival. Newton Chad A,Oldham Justin M,Ley Brett,Anand Vikram,Adegunsoye Ayodeji,Liu Gabrielle,Batra Kiran,Torrealba Jose,Kozlitina Julia,Glazer Craig,Strek Mary E,Wolters Paul J,Noth Imre,Garcia Christine Kim The European respiratory journal Leukocyte telomere length (LTL), rs35705950 and rs5743890 have been associated with idiopathic pulmonary fibrosis (IPF).In this observational cohort study, we assessed the associations between these genomic markers and outcomes of survival and rate of disease progression in patients with interstitial pneumonia with autoimmune features (IPAF, n=250) and connective tissue disease-associated interstitial lung disease (CTD-ILD, n=248). IPF (n=499) was used as a comparator.The LTL of IPAF and CTD-ILD patients (mean age-adjusted log-transformed T/S of -0.05±0.29 and -0.04±0.25, respectively) is longer than that of IPF patients (-0.17±0.32). For IPAF patients, LTL <10th percentile is associated with faster lung function decline compared to LTL ≥10th percentile (-6.43% per year -0.86% per year; p<0.0001) and worse transplant-free survival (hazard ratio 2.97, 95% CI 1.70-5.20; p=0.00014). The rs35705950 minor allele frequency (MAF) is greater for IPAF patients (23.2, 95% CI 18.8-28.2; p<0.0001) than controls and is associated with worse transplant-free IPAF survival (hazard ratio 1.92, 95% CI 1.18-3.13; p=0.0091). Rheumatoid arthritis (RA)-associated ILD (RA-ILD) has a shorter LTL than non-RA CTD-ILD (-0.14±0.27 -0.01±0.23; p=0.00055) and higher MAF (34.6, 95% CI 24.4-46.3 14.1, 95% CI 9.8-20.0; p=0.00025). Neither LTL nor are associated with transplant-free CTD-ILD survival.LTL and MAF have different associations with lung function progression and survival for IPAF and CTD-ILD. 10.1183/13993003.01641-2018
    Rare Protein-Altering Telomere-related Gene Variants in Patients with Chronic Hypersensitivity Pneumonitis. Ley Brett,Torgerson Dara G,Oldham Justin M,Adegunsoye Ayodeji,Liu Shuo,Li Jie,Elicker Brett M,Henry Travis S,Golden Jeffrey A,Jones Kirk D,Dressen Amy,Yaspan Brian L,Arron Joseph R,Noth Imre,Hoffmann Thomas J,Wolters Paul J American journal of respiratory and critical care medicine Rare genetic variants in telomere-related genes have been identified in familial, idiopathic, and rheumatoid arthritis-associated pulmonary fibrosis. Short peripheral blood leukocyte (PBL) telomere length predicts poor outcomes in chronic hypersensitivity pneumonitis (CHP). Determine the prevalence and clinical relevance of rare protein-altering variants in telomere-related genes in patients with CHP. Next-generation sequences from two CHP cohorts were analyzed to identify variants in (telomerase reverse transcriptase), (telomerase RNA component), (dyskerin pseudouridine synthase 1), (regulator of telomere elongation helicase 1), (poly[A]-specific RNase), and (TERF1-interacting nuclear factor 2). To qualify, variants were required to have a minor allele frequency less than 0.005 and be predicted to be damaging to protein function. Variant status (binary variable) was used in statistical association tests, including Cox proportional hazard models for transplant-free survival. PBL telomere length was measured using quantitative PCR. Qualifying variants were identified in 16 of 144 patients (11.1%; 95% confidence interval [CI], 6.5-17.4) in the discovery cohort and 17 of 209 patients (8.1%; 95% CI, 4.8-12.7) in the replication cohort. Age- and ancestry-adjusted PBL telomere length was significantly shorter in the presence of a variant in both cohorts (discovery: -561 bp; 95% CI, -933 to -190;  = 0.003; replication: -612 bp; 95% CI, -870 to -354;  = 5.30 × 10). Variant status was significantly associated with transplant-free survival in both cohorts (discovery: age-, sex-, and ancestry-adjusted hazard ratio, 3.73; 95% CI, 1.92-7.28;  = 0.0001; replication: hazard ratio, 2.72; 95% CI, 1.26-5.88;  = 0.011). A substantial proportion of patients diagnosed with CHP have rare, protein-altering variants in telomere-related genes, which are associated with short peripheral blood telomere length and significantly reduced transplant-free survival. 10.1164/rccm.201902-0360OC
    The MUC5B promoter polymorphism and telomere length in patients with chronic hypersensitivity pneumonitis: an observational cohort-control study. Ley Brett,Newton Chad A,Arnould Isabel,Elicker Brett M,Henry Travis S,Vittinghoff Eric,Golden Jeffrey A,Jones Kirk D,Batra Kiran,Torrealba Jose,Garcia Christine Kim,Wolters Paul J The Lancet. Respiratory medicine BACKGROUND:Patients with hypersensitivity pneumonitis are at risk of developing pulmonary fibrosis, which is associated with reduced survival. In families with multiple affected members, individuals might be diagnosed as having idiopathic pulmonary fibrosis (IPF) or chronic (fibrotic) hypersensitivity pneumonitis, which suggests these disorders share risk factors. We aimed to test whether the genomic risk factors associated with the development and progression of IPF are also associated with the development of fibrosis and reduced survival in people with chronic hypersensitivity pneumonitis. METHODS:We did an observational study of two independent cohorts of patients with chronic hypersensitivity pneumonitis, one from the University of California San Francisco, CA, USA (UCSF), and one from the University of Texas Southwestern, TX, USA (UTSW). We measured two common single-nucleotide polymorphisms associated with IPF (MUC5B rs35705950 and TOLLIP rs5743890) and telomere length in peripheral blood leucocytes, and assessed their associations with chronic hypersensitivity pneumonitis risk, survival, and clinical, radiographic, and pathological features. We compared findings with those in patients with IPF from the UCSF and UTSW cohorts, and healthy controls from the European population of the 1000 Genomes Project Phase 3, version 1. FINDINGS:The cohorts included 145 patients from UCSF and 72 from UTSW. The minor allele frequency (MAF) was greater for MUC5B rs35705950 in patients with chronic hypersensitivity pneumonitis than in healthy controls (24·4% in UCSF and 32·3% in UTSW vs 10·7%, both p<0·0001), but not for TOLLIP rs5743890. The MAFs were similar to those for IPF (UCSF 33·3%, p=0·09; UTSW 32·0%, p=0·95). In the combined UCSF and UTSW chronic hypersensitivity pneumonitis cohort, we saw associations between extent of radiographic fibrosis and MUC5B rs35705950 minor alleles (adjusted odds ratio [OR] 1·91, 95% CI 1·02-3·59, p=0·045) and short telomere length (adjusted OR per unit change in mean natural logarithm-transformed ratio of telomere repeat copy number to single gene copy number 0·23, 0·09-0·59, p=0·002). Telomere length less than the tenth percentile for age was also significantly associated with reduced survival (log-rank p=0·006). INTERPRETATION:The associations between MUC5B rs35705950 and short telomere length with extent of fibrosis, histopathological features of usual interstitial pneumonia, and reduced survival in patients with chronic hypersensitivity pneumonitis suggest shared pathobiology with IPF, and might help to stratify risk. FUNDING:National Institutes of Health and Nina Ireland Program for Lung Health. 10.1016/S2213-2600(17)30216-3
    Is chronic asthma associated with shorter leukocyte telomere length at midlife? Belsky Daniel W,Shalev Idan,Sears Malcolm R,Hancox Robert J,Lee Harrington Hona,Houts Renate,Moffitt Terrie E,Sugden Karen,Williams Benjamin,Poulton Richie,Caspi Avshalom American journal of respiratory and critical care medicine RATIONALE:Asthma is prospectively associated with age-related chronic diseases and mortality, suggesting the hypothesis that asthma may relate to a general, multisystem phenotype of accelerated aging. OBJECTIVES:To test whether chronic asthma is associated with a proposed biomarker of accelerated aging, leukocyte telomere length. METHODS:Asthma was ascertained prospectively in the Dunedin Multidisciplinary Health and Development Study cohort (n = 1,037) at nine in-person assessments spanning ages 9-38 years. Leukocyte telomere length was measured at ages 26 and 38 years. Asthma was classified as life-course-persistent, childhood-onset not meeting criteria for persistence, and adolescent/adult-onset. We tested associations between asthma and leukocyte telomere length using regression models. We tested for confounding of asthma-leukocyte telomere length associations using covariate adjustment. We tested serum C-reactive protein and white blood cell counts as potential mediators of asthma-leukocyte telomere length associations. MEASUREMENTS AND MAIN RESULTS:Study members with life-course-persistent asthma had shorter leukocyte telomere length as compared with sex- and age-matched peers with no reported asthma. In contrast, leukocyte telomere length in study members with childhood-onset and adolescent/adult-onset asthma was not different from leukocyte telomere length in peers with no reported asthma. Adjustment for life histories of obesity and smoking did not change results. Study members with life-course-persistent asthma had elevated blood eosinophil counts. Blood eosinophil count mediated 29% of the life-course-persistent asthma-leukocyte telomere length association. CONCLUSIONS:Life-course-persistent asthma is related to a proposed biomarker of accelerated aging, possibly via systemic eosinophilic inflammation. Life histories of asthma can inform studies of aging. 10.1164/rccm.201402-0370OC
    Telomere length, COPD and emphysema as risk factors for lung cancer. de-Torres Juan P,Sanchez-Salcedo Pablo,Bastarrika Gorka,Alcaide Ana B,Pío Rubén,Pajares María Jose,Campo Arantza,Berto Juan,Montuenga Luis,Del Mar Ocon Maria,Monente Carmen,Celli Bartolome R,Zulueta Javier J The European respiratory journal 10.1183/13993003.01521-2016
    Accelerated telomere attrition in children and teenagers with α1-antitrypsin deficiency. Escribano Amparo,Pastor Sara,Reula Ana,Castillo Silvia,Vicente Silvia,Sanz Francisco,Casas Francisco,Torres María,Fernández-Fabrellas Estrella,Codoñer-Franch Pilar,Dasí Francisco The European respiratory journal Numerous studies have shown that oxidative stress accelerates telomere shortening in several lung pathologies. Since oxidative stress is involved in the pathophysiology of α1-antitrypsin deficiency (AATD), we hypothesised that telomere shortening would be accelerated in AATD patients. This study aimed to assess telomere length in AATD patients and to study its association with α1-antitrypsin phenotypes.Telomere length, telomerase activity, telomerase reverse transcriptase (hTERT) expression and biomarkers of oxidative stress were measured in 62 children and teenagers (aged 2-18 years) diagnosed with AATD and 18 controls (aged 3-16 years).Our results show that intermediate-risk (MZ; SZ) and high-risk (ZZ) AATD patients have significantly shorter telomeres and increased oxidative stress than controls. Correlation studies indicate that telomere length was related to oxidative stress markers in AATD patients. Multiple hypothesis testing revealed an association between telomere length, telomerase activity, hTERT expression and AATD phenotypes; high-risk patients showed shorter telomeres, lower hTERT expression and decreased telomerase activity than intermediate-risk and low-risk patients.AATD patients show evidence of increased oxidative stress leading to telomere attrition. An association between telomere and α1-antitrypsin phenotypes is observed suggesting that telomere length could be a promising biomarker for AATD disease progression. 10.1183/13993003.00176-2016
    MUC5B and short telomere length in hypersensitivity pneumonitis. Zhang Yingze The Lancet. Respiratory medicine 10.1016/S2213-2600(17)30210-2
    Telomere Length and Use of Immunosuppressive Medications in Idiopathic Pulmonary Fibrosis. Newton Chad A,Zhang David,Oldham Justin M,Kozlitina Julia,Ma Shwu-Fan,Martinez Fernando J,Raghu Ganesh,Noth Imre,Garcia Christine Kim American journal of respiratory and critical care medicine Immunosuppression was associated with adverse events for patients with idiopathic pulmonary fibrosis (IPF) in the PANTHER-IPF (Evaluating the Effectiveness of Prednisone, Azathioprine and -Acetylcysteine in Patients with IPF) clinical trial. The reason why some patients with IPF experience harm is unknown. To determine whether age-adjusted leukocyte telomere length (LTL) was associated with the harmful effect of immunosuppression in patients with IPF. LTL was measured from available DNA samples from PANTHER-IPF (interim analysis,  = 79; final analysis,  = 118). Replication cohorts included ACE-IPF (Anticoagulant Effectiveness in Idiopathic Pulmonary Fibrosis) ( = 101) and an independent observational cohort (University of Texas Southwestern Medical Center-IPF,  = 170). LTL-stratified and medication-stratified survival analyses were performed using multivariable Cox regression models for composite endpoint-free survival. Of the subjects enrolled in the PANTHER-IPF and ACE-IPF, 62% (49/79) and 56% (28/50) had an LTL less than the 10th percentile of normal, respectively. In PANTHER-IPF, exposure to prednisone/azathioprine/-acetylcysteine was associated with a higher composite endpoint of death, lung transplantation, hospitalization, or FVC decline for those with an LTL less than the 10th percentile (hazard ratio, 2.84; 95% confidence interval, 1.02-7.87;  = 0.045). This finding was replicated in the placebo arm of ACE-IPF for those exposed to immunosuppression (hazard ratio, 7.18; 95% confidence interval, 1.52-33.84;  = 0.013). A propensity-matched University of Texas Southwestern Medical Center IPF cohort showed a similar association between immunosuppression and composite endpoints (death, lung transplantation, or FVC decline) for those with an LTL less than the 10th percentile (hazard ratio, 3.79; 95% confidence interval, 1.73-8.30;  = 0.00085). An interaction was found between immunosuppression and LTL for the combined PANTHER-IPF and ACE-IPF clinical trials ( = 0.048), and the University of Texas Southwestern Medical Center IPF cohort ( = 0.00049). LTL is a biomarker that may identify patients with IPF at risk for poor outcomes when exposed to immunosuppression. 10.1164/rccm.201809-1646OC