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Telomerase mutations in smokers with severe emphysema.
- Source :
-
The Journal of clinical investigation [J Clin Invest] 2015 Feb; Vol. 125 (2), pp. 563-70. Date of Electronic Publication: 2014 Dec 22. - Publication Year :
- 2015
-
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.
- Subjects :
- Adult
Animals
Female
Humans
Incidence
Male
Mice
Middle Aged
Mutation
Pneumothorax enzymology
Pneumothorax epidemiology
Pneumothorax genetics
Pneumothorax pathology
Prevalence
Pulmonary Fibrosis enzymology
Pulmonary Fibrosis epidemiology
Pulmonary Fibrosis genetics
Pulmonary Fibrosis pathology
Sex Factors
Telomere enzymology
Telomere genetics
Telomere pathology
alpha 1-Antitrypsin genetics
alpha 1-Antitrypsin metabolism
Chromosome Disorders enzymology
Chromosome Disorders epidemiology
Chromosome Disorders genetics
Chromosome Disorders pathology
Pulmonary Emphysema enzymology
Pulmonary Emphysema epidemiology
Pulmonary Emphysema genetics
Pulmonary Emphysema pathology
Registries
Sex Characteristics
Smoking epidemiology
Smoking genetics
Smoking metabolism
Smoking pathology
Telomerase genetics
Telomerase metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1558-8238
- Volume :
- 125
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- The Journal of clinical investigation
- Publication Type :
- Academic Journal
- Accession number :
- 25562321
- Full Text :
- https://doi.org/10.1172/JCI78554