TY - JOUR
T1 - Telomerase and the genetics of emphysema susceptibility
T2 - Implications for pathogenesis paradigms and patient care
AU - Stanley, Susan E.
AU - Merck, Samantha J.
AU - Armanios, Mary
N1 - Funding Information:
Supported by National Institutes of Health grants RO1 CA160433 (S.E.S. and M.A.), RO1 HL119476 (S.E.S. and M.A.), and T32 HL007534 (S.J.M.), and by the Commonwealth Foundation (S.E.S., S.J.M., and M.A.).
Publisher Copyright:
Copyright © 2016 by the American Thoracic Society.
PY - 2016/12
Y1 - 2016/12
N2 - In the past five decades, alpha-1 antitrypsin deficiency has been the only known genetic cause of emphysema, yet it explains the genetics in only 1-2% of severe cases. Recently, mutations in telomerase genes were found to induce susceptibility to young-onset, severe, and familial emphysema at a frequency comparable to that of alpha-1 antitrypsin deficiency. Telomerase mutation carriers with emphysema report a family history of idiopathic pulmonary fibrosis, and both lung phenotypes show autosomal dominant inheritance within families. The data so far point to a strong gene-environment interaction that determines the lung disease type. In never-smokers, pulmonary fibrosis predominates, while smokers, especially females, are at risk for developing emphysema alone or in combination with pulmonary fibrosis. The telomere-mediated emphysema phenotype appears to have clinically recognizable features that are distinct from alpha-1 antitrypsin deficiency, and patients are prone to developing short telomere syndrome comorbidities that influence clinical outcomes. In animal models, telomere dysfunction causes alveolar epithelial stem cell senescence, which is sufficient to drive lung remodeling and recruit inflammation. Here, we review the implications of these discoveries for understanding emphysema biology as well as for patient care.
AB - In the past five decades, alpha-1 antitrypsin deficiency has been the only known genetic cause of emphysema, yet it explains the genetics in only 1-2% of severe cases. Recently, mutations in telomerase genes were found to induce susceptibility to young-onset, severe, and familial emphysema at a frequency comparable to that of alpha-1 antitrypsin deficiency. Telomerase mutation carriers with emphysema report a family history of idiopathic pulmonary fibrosis, and both lung phenotypes show autosomal dominant inheritance within families. The data so far point to a strong gene-environment interaction that determines the lung disease type. In never-smokers, pulmonary fibrosis predominates, while smokers, especially females, are at risk for developing emphysema alone or in combination with pulmonary fibrosis. The telomere-mediated emphysema phenotype appears to have clinically recognizable features that are distinct from alpha-1 antitrypsin deficiency, and patients are prone to developing short telomere syndrome comorbidities that influence clinical outcomes. In animal models, telomere dysfunction causes alveolar epithelial stem cell senescence, which is sufficient to drive lung remodeling and recruit inflammation. Here, we review the implications of these discoveries for understanding emphysema biology as well as for patient care.
KW - Aging
KW - Alpha-1 antitrypsin deficiency
KW - Hepatopulmonary syndrome
KW - Idiopathic pulmonary fibrosis
KW - Senescence
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U2 - 10.1513/AnnalsATS.201609-718AW
DO - 10.1513/AnnalsATS.201609-718AW
M3 - Article
C2 - 28005428
AN - SCOPUS:85008384636
SN - 2325-6621
VL - 13
SP - S447-S451
JO - Annals of the American Thoracic Society
JF - Annals of the American Thoracic Society
ER -