title: Telomerase and the Genetics of Emphysema Susceptibility. Implications for Pathogenesis Paradigms and Patient Care.
abstract: 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.
authors.affiliation: 1 Medical Scientist Training Program.|2 Department of Oncology.
authors.forename: Susan E
authors.initials: SE
authors.lastname: Stanley
authors.affiliation: 2 Department of Oncology.|3 Division of Pulmonary and Critical Care Medicine.
authors.forename: Samantha J
authors.initials: SJ
authors.lastname: Merck
authors.affiliation: 2 Department of Oncology.|4 Sidney Kimmel Comprehensive Cancer Center, and.|5 McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Mary
authors.identifier: 0000-0002-7105-1847
authors.initials: M
authors.lastname: Armanios
mesh_terms: D059647:Gene-Environment Interaction; D020022:Genetic Predisposition to Disease; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000453:epidemiology / Q000235:genetics*; D011656:Pulmonary Emphysema / Q000453:epidemiology / Q000235:genetics*; D012737:Sex Factors; D012907:Smoking / Q000453:epidemiology*; D019098:Telomerase / Q000235:genetics*; D000073869:Tobacco Smoking; D019896:alpha 1-Antitrypsin Deficiency / Q000235:genetics
chemical_list: D019098:Telomerase
keywords: aging; alpha-1 antitrypsin deficiency; hepatopulmonary syndrome; idiopathic pulmonary fibrosis; senescence