Telomerase mutations in smokers with severe emphysema

Susan E. Stanley, Julian Chen, Joshua D. Podlevsky, Jonathan K. Alder, Nadia N. Hansel, Rasika A. Mathias, Xiaodong Qi, Nicholas M. Rafaels, Robert A. Wise, Edwin K. Silverman, Kathleen C. Barnes, Mary Armanios

Research output: Contribution to journalArticle

73 Citations (Scopus)

Abstract

Mutations in the essential telomerase genes TERT and TR cause familial pulmonary fibrosis; however, in telomerase-null mice, short telomeres predispose to emphysema after chronic cigarette smoke exposure. Here, we tested whether telomerase mutations are a risk factor for human emphysema by examining their frequency in smokers with chronic obstructive pulmonary disease (COPD). Across two independent cohorts, we found 3 of 292 severe COPD cases carried deleterious mutations in TERT (1%). This prevalence is comparable to the frequency of alpha-1 antitrypsin deficiency documented in this population. The TERT mutations compromised telomerase catalytic activity, and mutation carriers had short telomeres. Telomerase mutation carriers with emphysema were predominantly female and had an increased incidence of pneumothorax. In families, emphysema showed an autosomal dominant inheritance pattern, along with pulmonary fibrosis and other telomere syndrome features, but manifested only in smokers. Our findings identify germline mutations in telomerase as a Mendelian risk factor for COPD susceptibility that clusters in autosomal dominant families with telomere-mediated disease including pulmonary fibrosis.

Original languageEnglish (US)
Pages (from-to)563-570
Number of pages8
JournalJournal of Clinical Investigation
Volume125
Issue number2
DOIs
StatePublished - Feb 2 2015

Fingerprint

Telomerase
Emphysema
Telomere
Mutation
Pulmonary Fibrosis
Chronic Obstructive Pulmonary Disease
alpha 1-Antitrypsin Deficiency
Inheritance Patterns
Germ-Line Mutation
Essential Genes
Disease Susceptibility
Pneumothorax
Smoke
Tobacco Products
Incidence
Population

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Stanley, S. E., Chen, J., Podlevsky, J. D., Alder, J. K., Hansel, N. N., Mathias, R. A., ... Armanios, M. (2015). Telomerase mutations in smokers with severe emphysema. Journal of Clinical Investigation, 125(2), 563-570. https://doi.org/10.1172/JCI78554

Telomerase mutations in smokers with severe emphysema. / Stanley, Susan E.; Chen, Julian; Podlevsky, Joshua D.; Alder, Jonathan K.; Hansel, Nadia N.; Mathias, Rasika A.; Qi, Xiaodong; Rafaels, Nicholas M.; Wise, Robert A.; Silverman, Edwin K.; Barnes, Kathleen C.; Armanios, Mary.

In: Journal of Clinical Investigation, Vol. 125, No. 2, 02.02.2015, p. 563-570.

Research output: Contribution to journalArticle

Stanley, SE, Chen, J, Podlevsky, JD, Alder, JK, Hansel, NN, Mathias, RA, Qi, X, Rafaels, NM, Wise, RA, Silverman, EK, Barnes, KC & Armanios, M 2015, 'Telomerase mutations in smokers with severe emphysema', Journal of Clinical Investigation, vol. 125, no. 2, pp. 563-570. https://doi.org/10.1172/JCI78554
Stanley SE, Chen J, Podlevsky JD, Alder JK, Hansel NN, Mathias RA et al. Telomerase mutations in smokers with severe emphysema. Journal of Clinical Investigation. 2015 Feb 2;125(2):563-570. https://doi.org/10.1172/JCI78554
Stanley, Susan E. ; Chen, Julian ; Podlevsky, Joshua D. ; Alder, Jonathan K. ; Hansel, Nadia N. ; Mathias, Rasika A. ; Qi, Xiaodong ; Rafaels, Nicholas M. ; Wise, Robert A. ; Silverman, Edwin K. ; Barnes, Kathleen C. ; Armanios, Mary. / Telomerase mutations in smokers with severe emphysema. In: Journal of Clinical Investigation. 2015 ; Vol. 125, No. 2. pp. 563-570.
@article{3f729ff65b974263ad33b00b4d611723,
title = "Telomerase mutations in smokers with severe emphysema",
abstract = "Mutations in the essential telomerase genes TERT and TR cause familial pulmonary fibrosis; however, in telomerase-null mice, short telomeres predispose to emphysema after chronic cigarette smoke exposure. Here, we tested whether telomerase mutations are a risk factor for human emphysema by examining their frequency in smokers with chronic obstructive pulmonary disease (COPD). Across two independent cohorts, we found 3 of 292 severe COPD cases carried deleterious mutations in TERT (1{\%}). This prevalence is comparable to the frequency of alpha-1 antitrypsin deficiency documented in this population. The TERT mutations compromised telomerase catalytic activity, and mutation carriers had short telomeres. Telomerase mutation carriers with emphysema were predominantly female and had an increased incidence of pneumothorax. In families, emphysema showed an autosomal dominant inheritance pattern, along with pulmonary fibrosis and other telomere syndrome features, but manifested only in smokers. Our findings identify germline mutations in telomerase as a Mendelian risk factor for COPD susceptibility that clusters in autosomal dominant families with telomere-mediated disease including pulmonary fibrosis.",
author = "Stanley, {Susan E.} and Julian Chen and Podlevsky, {Joshua D.} and Alder, {Jonathan K.} and Hansel, {Nadia N.} and Mathias, {Rasika A.} and Xiaodong Qi and Rafaels, {Nicholas M.} and Wise, {Robert A.} and Silverman, {Edwin K.} and Barnes, {Kathleen C.} and Mary Armanios",
year = "2015",
month = "2",
day = "2",
doi = "10.1172/JCI78554",
language = "English (US)",
volume = "125",
pages = "563--570",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "2",

}

TY - JOUR

T1 - Telomerase mutations in smokers with severe emphysema

AU - Stanley, Susan E.

AU - Chen, Julian

AU - Podlevsky, Joshua D.

AU - Alder, Jonathan K.

AU - Hansel, Nadia N.

AU - Mathias, Rasika A.

AU - Qi, Xiaodong

AU - Rafaels, Nicholas M.

AU - Wise, Robert A.

AU - Silverman, Edwin K.

AU - Barnes, Kathleen C.

AU - Armanios, Mary

PY - 2015/2/2

Y1 - 2015/2/2

N2 - Mutations in the essential telomerase genes TERT and TR cause familial pulmonary fibrosis; however, in telomerase-null mice, short telomeres predispose to emphysema after chronic cigarette smoke exposure. Here, we tested whether telomerase mutations are a risk factor for human emphysema by examining their frequency in smokers with chronic obstructive pulmonary disease (COPD). Across two independent cohorts, we found 3 of 292 severe COPD cases carried deleterious mutations in TERT (1%). This prevalence is comparable to the frequency of alpha-1 antitrypsin deficiency documented in this population. The TERT mutations compromised telomerase catalytic activity, and mutation carriers had short telomeres. Telomerase mutation carriers with emphysema were predominantly female and had an increased incidence of pneumothorax. In families, emphysema showed an autosomal dominant inheritance pattern, along with pulmonary fibrosis and other telomere syndrome features, but manifested only in smokers. Our findings identify germline mutations in telomerase as a Mendelian risk factor for COPD susceptibility that clusters in autosomal dominant families with telomere-mediated disease including pulmonary fibrosis.

AB - Mutations in the essential telomerase genes TERT and TR cause familial pulmonary fibrosis; however, in telomerase-null mice, short telomeres predispose to emphysema after chronic cigarette smoke exposure. Here, we tested whether telomerase mutations are a risk factor for human emphysema by examining their frequency in smokers with chronic obstructive pulmonary disease (COPD). Across two independent cohorts, we found 3 of 292 severe COPD cases carried deleterious mutations in TERT (1%). This prevalence is comparable to the frequency of alpha-1 antitrypsin deficiency documented in this population. The TERT mutations compromised telomerase catalytic activity, and mutation carriers had short telomeres. Telomerase mutation carriers with emphysema were predominantly female and had an increased incidence of pneumothorax. In families, emphysema showed an autosomal dominant inheritance pattern, along with pulmonary fibrosis and other telomere syndrome features, but manifested only in smokers. Our findings identify germline mutations in telomerase as a Mendelian risk factor for COPD susceptibility that clusters in autosomal dominant families with telomere-mediated disease including pulmonary fibrosis.

UR - http://www.scopus.com/inward/record.url?scp=84961291345&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84961291345&partnerID=8YFLogxK

U2 - 10.1172/JCI78554

DO - 10.1172/JCI78554

M3 - Article

VL - 125

SP - 563

EP - 570

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

IS - 2

ER -