Telomerase mutations in smokers with severe emphysema

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

doi:10.1172/jci78554

Cited by 158 publications

(152 citation statements)

References 38 publications

(54 reference statements)

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“…Notably, the gene-environment interaction seems to be particularly evident in females (33). Among the small series of patients with telomeraseassociated emphysema heretofore reported, 90% are female even though the populations studied have been equally divided between males and females (33). Interestingly, this female predominance of severe disease among telomerase mutation carriers recapitulates a pattern previously documented in a Boston-based study of familial COPD in which 80% of probands younger than 53 years were female (6,34).…”

Section: Forms Of Emphysemasupporting

confidence: 78%

“…This pattern highlights a unique gene-environment interaction in which the lung disease phenotype is determined by an environmental exposure in the presence of the genetically determined short telomere defect ( Figure 1B). Notably, the gene-environment interaction seems to be particularly evident in females (33). Among the small series of patients with telomeraseassociated emphysema heretofore reported, 90% are female even though the populations studied have been equally divided between males and females (33).…”

Section: Forms Of Emphysemamentioning

confidence: 90%

“…The prevalence of telomerase mutations in patients with early-onset severe emphysema was recently reported to be comparable to alpha-1 antitrypsin deficiency across two cohorts (33). In the COPDGene and Lung Health Studies, the frequency of deleterious TERT mutations was 1% in severe, early-onset disease.…”

Section: Forms Of Emphysemamentioning

confidence: 97%

“…In the COPDGene and Lung Health Studies, the frequency of deleterious TERT mutations was 1% in severe, early-onset disease. Severe, early-onset disease was defined as Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 3 and 4 that occurs in individuals younger than 65 years; the COPDGene study included additional radiographic criteria for emphysema (33). Some of the mutations had been previously reported in families with pulmonary fibrosis (33).…”

Section: Forms Of Emphysemamentioning

confidence: 99%

“…Some of the mutations had been previously reported in families with pulmonary fibrosis (33). To date, three telomerase genes-TERT, TR, and NAF1-have been linked to familial emphysema risk (26,32,33). Notably, the pedigrees of mutation carriers show that their relatives, who also carry mutations, have pulmonary fibrosis ( Figure 1A) (33).…”

Section: Forms Of Emphysemamentioning

confidence: 99%

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Telomerase and the Genetics of Emphysema Susceptibility. Implications for Pathogenesis Paradigms and Patient Care

2016

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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.Keywords: aging; alpha-1 antitrypsin deficiency; senescence; idiopathic pulmonary fibrosis; hepatopulmonary syndrome

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Section: Forms Of Emphysemasupporting

confidence: 78%

Section: Forms Of Emphysemamentioning

confidence: 90%

Section: Forms Of Emphysemamentioning

confidence: 97%

Section: Forms Of Emphysemamentioning

confidence: 99%

Section: Forms Of Emphysemamentioning

confidence: 99%

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Telomerase and the Genetics of Emphysema Susceptibility. Implications for Pathogenesis Paradigms and Patient Care

2016

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TERT gene polymorphisms are associated with chronic obstructive pulmonary disease risk in the Chinese Li population

Ding

et al. 2019

Molec Gen & Gen Med

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Background Chronic obstructive pulmonary disease (COPD) is one of the leading causes of morbidity and mortality worldwide and is characterized by a partially reversible airflow limitation. Currently, many studies put forward that COPD is associated with both genetic and environmental factors. It has been reported that germline mutations in telomerase are risk factors for COPD susceptibility. In this study, we validated the association between TERT polymorphisms and COPD risk with a case–control study in the Chinese Li population. Methods A total of 279 COPD patients and 290 control individuals were recruited. We identified five single nucleotide polymorphisms (SNPs) in TERT that were associated with COPD. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated in logistic regression models after adjusting for age and gender to assess the association. Results In the genetic model analysis, we found the “C/T‐T/T” genotype of rs10069690 in TERT was associated with an increased COPD risk in the dominant model (p = 0.046); the rs2853677 in TERT was significantly associated with increased COPD risk based on the codominant model (“A/G” genotype, p = 0.033), dominant model (A/G‐G/G genotype, p = 0.0091), and log‐additive model (p = 0.023). The rs2853676 in TERT could increase the risk of COPD in the dominant model (“C/T‐T/T” genotype, p = 0.026) and in the Log‐additive model (p = 0.022). Conclusion Our data shed new light on the association between TERT SNPs and COPD susceptibility in the Chinese Li population.

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Recent advances in chronic obstructive pulmonary disease pathogenesis: from disease mechanisms to precision medicine

Brandsma

Berge

Hackett

et al. 2019

The Journal of Pathology

129

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Chronic obstructive pulmonary disease (COPD) is a devastating lung disease with a high personal and societal burden. Exposure to toxic particles and gases, including cigarette smoke, is the main risk factor for COPD. Together with smoking cessation, current treatment strategies of COPD aim to improve symptoms and prevent exacerbations, but there is no disease-modifying treatment. The biggest drawback of today's COPD treatment regimen is the 'one size fits all' pharmacological intervention, mainly based on disease severity and symptoms and not the individual's disease pathology. To halt the worrying increase in the burden of COPD, disease management needs to be advanced with a focus on personalized treatment. The main pathological feature of COPD includes a chronic and abnormal inflammatory response within the lungs, which results in airway and alveolar changes in the lung as reflected by (small) airways disease and emphysema. Here we discuss recent developments related to the abnormal inflammatory response, ECM and age-related changes, structural changes in the small airways and the role of sex-related differences, which are all relevant to explain the individual differences in the disease pathology of COPD and improve disease endotyping. Furthermore, we will discuss the most recent developments of new treatment strategies using biologicals to target specific pathological features or disease endotypes of COPD.

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Telomerase mutations in smokers with severe emphysema

Cited by 158 publications

References 38 publications

Telomerase and the Genetics of Emphysema Susceptibility. Implications for Pathogenesis Paradigms and Patient Care

Telomerase and the Genetics of Emphysema Susceptibility. Implications for Pathogenesis Paradigms and Patient Care

TERT gene polymorphisms are associated with chronic obstructive pulmonary disease risk in the Chinese Li population

Recent advances in chronic obstructive pulmonary disease pathogenesis: from disease mechanisms to precision medicine

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