Telomere Length in Interstitial Lung Diseases

doi:10.1378/chest.14-3078

Chest

Volume 148, Issue 4, October 2015, Pages 1011-1018

https://doi.org/10.1378/chest.14-3078 Get rights and content

BACKGROUND

Interstitial lung disease (ILD) is a heterogeneous group of rare diseases that primarily affect the pulmonary interstitium. Studies have implicated a role for telomere length (TL) maintenance in ILD, particularly in idiopathic interstitial pneumonia (IIP). Here, we measure TL in a wide spectrum of sporadic and familial cohorts of ILD and compare TL between patient cohorts and control subjects.

METHODS

A multiplex quantitative polymerase chain reaction method was used to measure TL in 173 healthy subjects and 359 patients with various ILDs, including familial interstitial pneumonia (FIP). The FIP cohort was divided into patients carrying TERT mutations, patients carrying SFTPA2 or SFTPC mutations, and patients without a proven mutation (FIP-no mutation).

RESULTS

TL in all cases of ILD was significantly shorter compared with those of control subjects (P range: .038 to < .0001). Furthermore, TL in patients with idiopathic pulmonary fibrosis (IPF) was significantly shorter than in patients with other IIPs (P = .002) and in patients with sarcoidosis (P < .0001). Within the FIP cohort, patients in the FIP-telomerase reverse transcriptase (TERT) group had the shortest telomeres (P < .0001), and those in the FIP-no mutation group had TL comparable to that of patients with IPF (P = .049). Remarkably, TL of patients with FIP-surfactant protein (SFTP) was significantly longer than in patients with IPF, but similar to that observed in patients with other sporadic IIPs.

CONCLUSIONS

The results show telomere shortening across all ILD diagnoses. The difference in TL between the FIP-TERT and FIP-SFTP groups indicates the distinction between acquired and innate telomere shortening. Short TL in the IPF and FIP-no mutation groups is indicative of an innate telomere-biology defect, while a stress-induced, acquired telomere shortening might be the underlying process for the other ILD diagnoses.

Section snippets

Results

Relative TL was determined in control subjects and patients diagnosed with the following ILDs: sarcoidosis, HP, CTD-ILD, iNSIP, SR-ILD, COP, IPF, and FIP (Table 1).

Discussion

This study shows that telomeres of patients with ILD are shorter compared with those of healthy control subjects. However, the degree of difference in TL differs significantly between the different ILD diagnoses and particularly within the IIP subgroup. Within familial disease, TL correlates with the underlying genetic cause. This is a large study on TL and ILD, including eight different ILD diagnoses and 532 subjects, and is the first study, to our knowledge, to separately analyze different

Acknowledgments

Author contributions: R. S., C. H. M. v. M., and J. C. G. had full access to all of the data in the study, and take responsibility for the integrity of the data and the accuracy of the data analysis, including and especially any adverse effects. R. S. served as principal author. R. S., C. H. M. v. M., K. M. K., J. J. v. d. V., and J. C. G. contributed to the study concept and design; K. M. K. and J. J. v. d. V. contributed to data collection; R. S., C. H. M. v. M., K. M. K., J. J. v. d. V., P.

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Differences in disease behaviour and genotypes are described in Asian and Western interstitial lung disease (ILD) cohorts. Short leukocyte telomere length (LTL) correlates with poor outcomes in Western ILD cohorts but its significance in Asian populations is unknown. We aim to characterise the burden and clinical implications of short LTL in Singaporean ILD patients.
Patients diagnosed with ILD at Singapore General Hospital were prospectively recruited and compared against 36 healthy controls. The primary outcome was transplant-free survival. Genomic DNA from peripheral blood was extracted and LTL measured using quantitative polymerase chain reaction assay (qPCR).
Amongst 165 patients, 37% had short LTL. There was a higher proportion of combined pulmonary fibrosis and emphysema (CPFE) patients with short LTL (n = 21, 34.4% vs n = 16, 15.4%; p < 0.001). Short LTL patients had reduced survival at 12-, 24- and 36-months and median survival of 24 months (p < 0.001) which remained significant following adjustment for smoking, GAP Stage and radiological UIP pattern (Hazard Ratio (HR), 2.74; 95%CI:1.46, 5.11; p = 0.002). They had increased respiratory-related mortality and acute exacerbation incidences. Despite similar baseline lung function, short LTL patients had a faster decline in absolute forced vital capacity (FVC) of −105.3 (95% CI: 151.4, −59.1) mL/year compared to −58.2 (95% CI: 82.9, −33.6) mL/year (p < 0.001) in normal LTL patients.
Short LTL correlated with increased mortality and faster lung function decline in our Singaporean ILD cohort with a magnitude similar to that in Western ILD cohorts. Further research is needed to integrate LTL assessment into clinical practice.
Persistent Pulmonary Fibrotic Sequelae in Patients With Telomere Shortening One Year After Severe COVID-19
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Associations between shortened telomeres and rheumatoid arthritis-associated interstitial lung disease among U.S. Veterans
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Shortened telomeres are associated with several different subtypes of interstitial lung disease (ILD), although studies of telomere length and ILD in rheumatoid arthritis (RA) are lacking.
Within the Veterans Affairs Rheumatoid Arthritis (VARA) registry, we performed cross-sectional and case-control studies of prevalent and incident ILD, respectively. We randomly selected a subset of RA patients with ILD and individually matched them to RA patients without ILD according to age, sex, and VARA enrollment date. Telomere length was measured on peripheral blood leukocytes collected at registry enrollment using quantitative PCR (T/S ratio). Short telomeres were defined as a T/S ratio in the lowest 10th percentile of the cohort.
Our cross-sectional study cohort was comprised of 54 RA-ILD patients and 92 RA-non-ILD patients. T/S ratios significantly differed between patients with and without prevalent ILD (1.56 [IQR 1.30, 1.78] vs. 1.96 [IQR 1.65, 2.27], p < 0.001). Similarly, prevalence of ILD was significantly higher in patients with short vs. normal-length telomeres (73.3% vs. 32.8%, p = 0.002). Short telomeres were independently associated with an increased odds of prevalent ILD compared to normal-length telomeres (adjusted OR 6.60, 95% CI 1.78–24.51, p = 0.005). In our case-control analysis, comprised of 22 incident RA-ILD cases and 36 RA-non-ILD controls, short telomeres were not associated with incident RA-ILD (adjusted OR 0.90, 95% CI 0.06–13.4, p = 0.94).
Short telomeres were strongly associated with prevalent but not incident ILD among patients with RA. Additional studies are needed to better understand telomere length dynamics among RA patients with and without ILD.
Telomeres and lung
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L’étude génétique des formes familiales de pneumopathie interstitielle diffuse (PID) a permis de mettre en évidence dans approximativement 30 % des familles des variants pathogènes constitutionnels des gènes de la maintenance des télomères (TRG « Telomere Related Genes » : TERT, TERC, RTEL1, PARN, DKC1, TINF2, NAF1, NOP10,NHP2,ACD,ZCCHC8). Les patients symptomatiques sur le plan pulmonaire et porteurs de variants pathogènes mono-alléliques dans les TRG peuvent aussi présenter des atteintes extra-pulmonaires (immuno-hématologiques, hépatiques et/ou cutanéo-muqueuses) avec ou sans histoire de fibrose pulmonaire familiale. Des mutations dans les TRG peuvent être associées à une fibrose pulmonaire idiopathique (FPI), mais aussi à d’autres PID fibrosantes, inclassables ou secondaires, comme les formes associées aux connectivites ou les pneumopathies d’hypersensibilité (PHS). Chez un patient atteint de FPI, la présence d’une mutation dans un TRG pourrait être associée à un déclin plus rapide de la capacité vitale forcée (CVF), ainsi qu’à un moins bon pronostic après la transplantation pulmonaire, bien que les traitements usuels de PID puissent aussi être proposés. Enfin, les patients et leurs apparentés doivent limiter les expositions toxiques environnementales, et pouvoir bénéficier d’un conseil génétique et d’un test pré-symptomatique.
Genetic studies of familial forms of interstitial lung disease (ILD) have led to the discovery of telomere-related gene (TRG) mutations (TERT, TERC, RTEL1, PARN, DKC1, TINF2, NAF1, NOP10, NHP2, ACD, ZCCH8) in approximately 30% of familial ILD forms. ILD patients with TRG mutation are also subject to extra-pulmonary (immune-hematological, hepatic and/or mucosal-cutaneous) manifestations. TRG mutations may be associated not only with idiopathic pulmonary fibrosis (IPF), but also with non-IPF ILDs, including idiopathic and secondary ILDs, such as hypersensitivity pneumonitis (HP). The presence of TRG mutation may also be associated with an accelerated decline of forced vital capacity (FVC) or poorer prognosis after lung transplantation, notwithstanding which, usual ILD treatments may be proposed. Lastly, patients and their relatives are called upon to reduce their exposure to environmental lung toxicity, and are likely to derive benefit from specific genetic counseling and pre-symptomatic genetic testing.
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Short telomeres are recognized as risk factor for idiopathic pulmonary fibrosis (IPF). We aimed to assess the role of telomere length (TL) in fibrotic-Interstitial Lung Diseases (f-ILDs) associated with a usual interstitial pneumonia (UIP) pattern as well as in IPF acute exacerbation (IPF-AE).
TL was measured from peripheral white blood cells using a multiplex quantitative polymerase chain reaction in consecutive patients with f-ILDs, all presenting UIP pattern in the high-resolution chest-computed-tomography and compared to age-matched healthy controls.
Seventy-nine individuals were included (mean age 69.77 ± 0.72 years); 24 stable IPF, 18 IPF-AE, 10 combined pulmonary fibrosis and emphysema, 7 Rheumatoid arthritis-UIP-ILDs and 20 controls. TL in all patients was significantly shorter compared to controls [mean T/S ratio (SE) 0.77 (±0.05) vs 2.26 (±0.36), p < 0.001] as well as separately in each one of f-ILD subgroups. IPF-AE patients presented significantly shorter TL compared to stable IPF (p = 0.029). Patients with IPF and shorter than the median TL (0−0.72) showed reduced overall survival (p = 0.004). T/S < 0.72 was associated with increased risk for IPF-AE (OR = 30.787, 95% CI: 2.153, 440.183, p = 0.012) independent of age, gender, smoking and lung function impairment. A protective effect of TL was observed, as it was inversely associated with risk of death both in UIP-f-ILDs (HR = 0.174, 95%CI: 0.036, 0.846, p = 0.030) and IPF patients (HR = 0.096, 95%CI: 0.011, 0.849, p = 0.035).
Shorter TL characterizes different UIP f-ILDs. Although no difference was observed in TL among diverse UIP subgroups, IPF-AE presented shorter TL compared to stable IPF. Reduced overall survival and higher hazard ratio of death are associated with shorter TL in IPF.

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FUNDING/SUPPORT: Funding for this study was received from the St. Antonius Research Fund and the Pender Foundation.

Part of this study was presented at the International World Association for Sarcoidosis and Other Granulomatous Disorders (WASOG) Conference on Diffuse Parenchymal Lung Diseases, June 6-7, 2013, Paris, France, and the Pittsburgh-Munich International Lung Conference, October 23-24, 2014, Pittsburgh, PA.

originally published Online First May 14, 2015.

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Chest

Original ResearchDiffuse Lung DiseaseTelomere Length in Interstitial Lung Diseases

BACKGROUND

METHODS

RESULTS

CONCLUSIONS

Section snippets

Results

Discussion

Acknowledgments

Chest

Chest

Mutat Res

Am J Hum Genet

Transl Res

Lancet Respir Med

Blood

Lancet

Mech Ageing Dev

Clinical advances in the diagnosis and therapy of the interstitial lung diseases

Am J Respir Crit Care Med

Am J Respir Crit Care Med

Update on the diagnosis and classification of ILD

Curr Opin Pulm Med

Short telomeres are a risk factor for idiopathic pulmonary fibrosis

Proc Natl Acad Sci U S A

An analysis of telomere length in sarcoidosis

J Gerontol A Biol Sci Med Sci

Telomere shortening in familial and sporadic pulmonary fibrosis

Am J Respir Crit Care Med

Telomere biology and telomere diseases: implications for practice and research

Hematology Am Soc Hematol Educ Program

Telomerase mutations in families with idiopathic pulmonary fibrosis

N Engl J Med

Adult-onset pulmonary fibrosis caused by mutations in telomerase

Proc Natl Acad Sci U S A.

Rare variants in RTEL1 are associated with familial interstitial pneumonia

Am J Respir Crit Care Med

Telomere length in circulating leukocytes is associated with lung function and disease

Eur Respir J

Is chronic asthma associated with shorter leukocyte telomere length at midlife?

Am J Respir Crit Care Med

Original Research
Diffuse Lung Disease
Telomere Length in Interstitial Lung Diseases