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Original Research: TransplantationShort Telomeres, Telomeropathy, and Subclinical Extrapulmonary Organ Damage in Patients With Interstitial Lung Disease
Section snippets
Subjects
In September 2011, the lung transplant program at Brigham and Women's Hospital established clinical guidelines designed to increase the index of suspicion for short telomeres and associated disease(s) in patients referred for consideration of candidacy. Here, we report the results of this intervention. All patients with ILD and two or more visits to the program were included in the study cohort. Patients with sarcoidosis or connective tissue disease (CTD)-associated ILD were excluded. Patients
Diagnosis of ILD and Clinical Information
A review of medical records including CT scanning and existing surgical lung biopsy results was used to determine the diagnosis of ILD. Hematology, chemistry, and pathology results were obtained through a review of the computerized medical records.
Telomere Length by Flow Fluorescence In Situ Hybridization
Telomere length analysis in peripheral blood lymphocytes was performed with a Clinical Laboratory Improvement Amendments-approved test performed at Repeat Diagnostics Laboratory, Vancouver, Canada.16, 17 The control population for this test consisted of 835 subjects identified only by age and sex; no other demographic or medical information was available.17 The age distribution of the control population was as follows: 0 to 40 years, 398; 41 to 50 years, 80; 51 to 70 years, 155; and > 70 years,
Sequencing and Mutation Analysis
Seven subjects consented to genetic testing. Sequencing and mutational analysis for TERT and TERC were performed in a Clinical Laboratory Improvement Amendments-approved laboratory.
Statistical Analysis
Results are expressed as mean ± SD for n number of samples. Analysis of difference between groups was conducted using an analysis of variance, t test, or Fisher exact test as appropriate. A two-sided P value < .05 was used for statistical significance. All analysis was done using GraphPad Prism software (GraphPad 5.0).
Results
From September 2011 until December 2013, 127 patients met our preestablished inclusion criteria of ILD without evidence of sarcoidosis or CTD and at least two visits to our lung transplant clinic (Fig 1, Table 1). Most patients (60.6') were diagnosed with IPF. Based on our predefined screening criteria, 30 patients (23.6') were suspected of having short telomeres, and 22 of 127 (17.3') patients underwent telomere length testing. Eight patients did not undergo telomere testing for the following
Discussion
We report significant subclinical marrow and liver abnormalities in our cohort of patients with ILD and short telomeres referred for lung transplantation. This group of patients showed important bone marrow abnormalities, in some cases in the absence of clinically significant changes in peripheral blood counts.
Others have shown that short telomere syndrome can present with lower RBC counts, leukopenia, thrombocytopenia, abnormal liver function, increased MCV, and early graying.14 We used these
Conclusions
In summary, our study shows that predetermined noninvasive testing can identify a subset of patients with ILD who should be tested for short telomeres. Further, seemingly mild peripheral blood abnormalities were associated with significant bone marrow pathology and regenerative changes on liver biopsy. These results increase our understanding of telomeropathies and have potentially important implications for patients with interstitial lung disease. A larger study is indicated to further examine
Acknowledgments
Author contributions: S. E.-C. is the guarantor of the paper and takes responsibility for the integrity of the work as a whole, from inception to published article. I. O. R., P. C. C., H. J. G., and S. E.-C. contributed to conception and design; G. G., Y. C., C. M., G. M. H., B. A. R., and S. E.-C. contributed to analysis and interpretation; and G. G., I. O. R., Y. C., C. M., P. C. C., B. A. R., H. J. G., and S. E.-C. contributed to drafting the manuscript for important intellectual content.
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Associations between shortened telomeres and rheumatoid arthritis-associated interstitial lung disease among U.S. Veterans
2022, Respiratory MedicineCitation Excerpt :To our knowledge, this is the largest study of an RA-specific cohort examining associations between telomere length and ILD. Broadly speaking, human telomere disease consists of a wide spectrum of disorders linked to neoplastic, pulmonary, hepatic, and bone marrow abnormalities [14,30]. Telomere erosion is a hallmark feature of immunosenescence and has been demonstrated in both lymphoid and myeloid cells in RA patients [31].
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2020, Blood AdvancesCitation Excerpt :Juge et al50 found germline P/LP RTEL1, PARN, or TERT variants in 11% of patients with rheumatoid arthritis–associated ILD. Conversely, ILD subtypes described in patients with P/LP variants in RTEL1, TERT, and TERC included autoimmune or inflammatory disease–associated subtypes as we saw in our cases.10,51,52 Although not diagnostic of overt autoimmune diseases, our findings of elevated antinuclear antibodies, Raynaud's syndrome, and lymphoplasmacytic infiltrates in lung and bone marrow biopsy specimens similar to those found in intestinal biopsy specimens in TBD cases by others53 in confirmed TBD carriers fit well with these reports.
Integrating Genomics Into Management of Fibrotic Interstitial Lung Disease
2019, ChestCitation Excerpt :Genetic abnormalities should be sought in patients with familial IPF.64 Experts recommend that patients with ILD who have a personal or family history of telomere-linked features should undergo genetic testing because these features are frequently present in patients with telomere-linked ILD.45,65 These include premature hair graying, aplastic anemia/myelodysplasia, thrombocytopenia, and unexplained portal hypertension (Figs 1, 2).45
Broadening the investigation—short telomeres and lung transplantation outcomes in pulmonary fibrosis
2017, Journal of Heart and Lung Transplantation
FOR EDITORIAL COMMENT SEE PAGE 1450
Drs Goldberg and El-Chemaly contributed equally to this manuscript.
FUNDING/SUPPORT: Dr El-Chemaly is funded by the National Institutes of Health (NIH) [Grant R21 HL119902-01] and the American Thoracic Society/American Lung Association foundation grant. Drs Hunninghake and Rosas are supported by the NIH [Grant R01 HL111024 to Dr Hunninghake and Grants U01HL105371 and P01HL114501 to Dr Rosas].
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