Telomerase mutations in smokers with severe emphysema.
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ABSTRACT:
SUBMITTER: Stanley SE
PROVIDER: S-EPMC4319417 | biostudies-literature | 2015 Feb
REPOSITORIES: biostudies-literature
Publications
Telomerase mutations in smokers with severe emphysema.
Stanley Susan E SE Chen Julian J L JJ Podlevsky Joshua D JD Alder Jonathan K JK Hansel Nadia N NN Mathias Rasika A RA Qi Xiaodong X Rafaels Nicholas M NM Wise Robert A RA Silverman Edwin K EK Barnes Kathleen C KC Armanios Mary M
The Journal of clinical investigation 20141222 2
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 prev ...[more]
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Project description:BackgroundTelomerase is an enzyme specialized in maintaining telomere lengths in highly proliferative cells. Loss-of-function mutations cause critical telomere shortening and are associated with the bone marrow failure syndromes dyskeratosis congenita and aplastic anemia and with idiopathic pulmonary fibrosis. Here, we sought to determine the spectrum of clinical manifestations associated with telomerase loss-of-function mutations.Methodology/principal findingsSixty-nine individuals from five unrelated families with a variety of hematologic, hepatic, and autoimmune disorders were screened for telomerase complex gene mutations; leukocyte telomere length was measured by flow fluorescence in situ hybridization in mutation carriers and some non-carriers; the effects of the identified mutations on telomerase activity were determined; and genetic and clinical data were correlated. In six generations of a large family, a loss-of-function mutation in the telomerase enzyme gene TERT associated with severe telomere shortening and a range of hematologic manifestations, from macrocytosis to acute myeloid leukemia, with severe liver diseases marked by fibrosis and inflammation, and one case of idiopathic pulmonary fibrosis but not with autoimmune disorders. Additionally, we identified four unrelated families in which loss-of-function TERC or TERT gene mutations tracked with marrow failure, pulmonary fibrosis, and a spectrum of liver disorders.Conclusions/significanceThese results indicate that heterozygous telomerase loss-of-function mutations associate with but are not determinant of a large spectrum of hematologic and liver abnormalities, with the latter sometimes occurring in the absence of marrow failure. Our findings, along with the link between pulmonary fibrosis and telomerase mutations, also suggest a common pathogenic mechanism for fibrotic diseases in which defective telomere repair plays important role.
| S-EPMC2775683 | biostudies-literature
Project description:Background: Emphysema is an important component of COPD; however, in previous studies of the correlation between airflow limitation (AFL) and computed tomography (CT) lung density as a surrogate for emphysema has varied. We hypothesised a good correlation between lung function (forced expiratory volume in first second [FEV1]) and emphysema (15th percentile density [PD15]) and that this correlation also exists between loss of lung tissue and decline in lung function even within the time frame of longitudinal studies of relatively short duration. Methods: We combined 2 large longitudinal studies (the Danish Lung Cancer Screening Trial [DLCST] and the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints [ECLIPSE]) of smokers or former smokers, with a wide range of AFL and CT lung density, and analysed data from 2148 participants who did not change smoking habits and who had at least 2 CT scans and 2 FEV1 measurements at least 3 years apart. Results: Baseline correlation between FEV1 and PD15 was high (r=0.716, 95% confidence interval [CI]: 0.694-0.736, p<0.001) indicating that at least half of the variation in FEV1 can be explained by variation in CT lung density. Correlation between the decline in FEV1 and progression of PD15 was considerably weaker (r= 0.081, 95% CI: 0.038-0.122, p<0.001). Conclusions: Correlation is very high between lung density and lung function in a broad spectrum of smokers and ex-smokers. In contrast, the temporal associations (slopes) are weakly correlated, probably due to uncertainty in the estimation of slopes within a time frame of 3-4 years.
| S-EPMC5556883 | biostudies-other
Project description:Cigarette smoking is associated with emphysema and radiographic interstitial lung abnormalities. The degree to which interstitial lung abnormalities are associated with reduced total lung capacity and the extent of emphysema is not known.We looked for interstitial lung abnormalities in 2416 (96%) of 2508 high-resolution computed tomographic (HRCT) scans of the lung obtained from a cohort of smokers. We used linear and logistic regression to evaluate the associations between interstitial lung abnormalities and HRCT measurements of total lung capacity and emphysema.Interstitial lung abnormalities were present in 194 (8%) of the 2416 HRCT scans evaluated. In statistical models adjusting for relevant covariates, interstitial lung abnormalities were associated with reduced total lung capacity (-0.444 liters; 95% confidence interval [CI], -0.596 to -0.292; P<0.001) and a lower percentage of emphysema defined by lung-attenuation thresholds of -950 Hounsfield units (-3%; 95% CI, -4 to -2; P<0.001) and -910 Hounsfield units (-10%; 95% CI, -12 to -8; P<0.001). As compared with participants without interstitial lung abnormalities, those with abnormalities were more likely to have a restrictive lung deficit (total lung capacity <80% of the predicted value; odds ratio, 2.3; 95% CI, 1.4 to 3.7; P<0.001) and were less likely to meet the diagnostic criteria for chronic obstructive pulmonary disease (COPD) (odds ratio, 0.53; 95% CI, 0.37 to 0.76; P<0.001). The effect of interstitial lung abnormalities on total lung capacity and emphysema was dependent on COPD status (P<0.02 for the interactions). Interstitial lung abnormalities were positively associated with both greater exposure to tobacco smoke and current smoking.In smokers, interstitial lung abnormalities--which were present on about 1 of every 12 HRCT scans--were associated with reduced total lung capacity and a lesser amount of emphysema. (Funded by the National Institutes of Health and the Parker B. Francis Foundation; ClinicalTrials.gov number, NCT00608764.).
| S-EPMC3074462 | biostudies-literature
Project description:RATIONALE:Expiratory central airway collapse is associated with respiratory morbidity independent of underlying lung disease. However, not all smokers develop expiratory central airway collapse, and the etiology of expiratory central airway collapse in adult smokers is unclear. Paraseptal emphysema in the paratracheal location, by untethering airway walls, may predispose smokers to developing expiratory central airway collapse. OBJECTIVES:To evaluate whether paratracheal paraseptal emphysema is associated with expiratory central airway collapse. METHODS:We analyzed paired inspiratory and expiratory computed tomography scans from participants enrolled in a multicenter study (Genetic Epidemiology of Chronic Obstructive Pulmonary Disease) of smokers aged 45 to 80 years. Expiratory central airway collapse was defined as greater than or equal to 50% reduction in cross-sectional area of the trachea during expiration. In a nested case-control design, participants with and without expiratory central airway collapse were included in a 1:2 fashion, and inspiratory scans were further analyzed using the Fleischner Society criteria for presence of centrilobular emphysema, paraseptal emphysema, airway wall thickening, and paratracheal paraseptal emphysema (maximal diameter???0.5 cm). RESULTS:A total of 1,320 patients were included, 440 with and 880 without expiratory central airway collapse. Those with expiratory central airway collapse were older, had higher body mass index, and were less likely to be men or current smokers. Paratracheal paraseptal emphysema was more frequent in those with expiratory central airway collapse than control subjects (16.6 vs. 11.8%; P?=?0.016), and after adjustment for age, race, sex, body mass index, smoking pack-years, and forced expiratory volume in 1 second, paratracheal paraseptal emphysema was independently associated with expiratory central airway collapse (adjusted odds ratio, 1.53; 95% confidence interval, 1.18-1.98; P?=?0.001). Furthermore, increasing size of paratracheal paraseptal emphysema (maximal diameter of at least 1 cm and 1.5 cm) was associated with greater odds of expiratory central airway collapse (adjusted odds ratio, 1.63; 95% confidence interval, 1.18-2.25; P?=?0.003 and 1.77; 95% confidence interval, 1.19-2.64; P?=?0.005, respectively). CONCLUSIONS:Paraseptal emphysema adjacent to the trachea is associated with expiratory central airway collapse. The identification of this risk factor on inspiratory scans should prompt further evaluation for expiratory central airway collapse. Clinical trial registered with ClinicalTrials.gov (NCT 00608764).
| S-EPMC5879141 | biostudies-literature
Project description:Recent studies have emphasized the difficulty of early detection of chronic obstructive pulmonary disease (COPD) in symptomatic smokers with normal routine spirometry. This includes post-bronchodilator normal forced expiratory volume in 1 second (FEV1)(L)≥80% predicted, forced vital capacity (FVC)(L)≥80% predicted, and FEV1/FVC ≥70% or greater than age corrected lower limit of normal (LLN). However, in COPD the pathologic site of small airway obstruction and emphysema begins in the small peripheral airways ≤2 mm id which normally contribute <20% of total airway resistance. Expiratory airflow at high and low lung volumes post-bronchodilator were measured and correlated with lung computed tomography (CT) and lung pathology (6 patients) in 16 symptomatic, treated smokers, and all with normal routine spirometry. Despite normal routine spirometry, all16 patients had isolated, abnormal forced expiratory flow at 75% of FVC (FEF75) using data from Knudson et al, Hankinson et al NHAMES III, and Quanjer et al and the Global Lung Function Initiative. This reflects isolated detection of small airways obstruction and/or emphysema. Measuring airflow at FEF50 detected only 8 of 16 patients, maximal expiratory flow at 25%-75% of FVC (MEF25-75) only 4 of 16, residual volume (RV) 4 of 16, and RV to total lung capacity ratio only 2 of 16. There was excellent correlation between limited lung pathology and lung CT for absence of emphysema. This study confirms our earlier observations that detection of small airways obstruction and/or emphysema, in symptomatic smokers with normal routine spirometry, requires analysis of expiratory airflow at low lung volumes, including FEF75. Dependence upon normal routine spirometry may result in clinical and physiologic delay in the diagnosis and treatment in symptomatic smokers with emphysema and small airways obstruction.
| S-EPMC8047618 | biostudies-literature
Project description:BackgroundLittle is known about factors associated with emphysema progression in cigarette smokers. We evaluated factors associated with change in emphysema and forced expiratory volume in 1 second (FEV1) in participants with and without chronic obstructive pulmonary disease (COPD).MethodsThis retrospective study included individuals participating in the COPD Genetic Epidemiology study who completed the 5-year follow-up, including inspiratory and expiratory computed tomography (CT) and spirometry. All paired CT scans were analyzed using micro-mapping, which classifies individual voxels as emphysema or functional small airway disease (fSAD). Presence and progression of emphysema and FEV1 were determined based on comparison to nonsmoker values. Logistic regression analyses were used to identify clinical parameters associated with disease progression.ResultsA total of 3088 participants were included with a mean ± SD age of 60.7±8.9 years, including 72 nonsmokers. In all Global initiative for chronic Obstructive Lung Disease (GOLD) stages, the presence of emphysema at baseline was associated with emphysema progression (odds ratio [OR]: GOLD 0: 4.32; preserved ratio-impaired spirometry [PRISm]; 5.73; GOLD 1: 5.16; GOLD 2: 5.69; GOLD 3/4: 5.55; all p ≤0.01). If there was no emphysema at baseline, the amount of fSAD at baseline was associated with emphysema progression (OR for 1% increase: GOLD 0: 1.06; PRISm: 1.20; GOLD 1: 1.7; GOLD 3/4: 1.08; all p ≤ 0.03).In 1735 participants without spirometric COPD, progression in emphysema occurred in 105 (6.1%) participants and only 21 (1.2%) had progression in both emphysema and FEV1.ConclusionsThe presence of emphysema is an important predictor of emphysema progression. In patients without emphysema, fSAD is associated with the development of emphysema. In participants without spirometric COPD, emphysema progression occurred independently of FEV1 decline.
| S-EPMC8237975 | biostudies-literature
Project description:It has been reported that the prevalence of kidney dysfunction may be increased in patients exposed to tobacco with airflow obstruction. We hypothesized that kidney dysfunction would associate with emphysema rather than with airflow obstruction measured by the FEV₁.Five hundred eight current and former smokers completed a chest CT scan, pulmonary function tests, medical questionnaires, and measurement of serum creatinine. Glomerular filtration rates (eGFRs) were estimated using the method of the Chronic Kidney Disease Epidemiology Collaboration. Quantitative determinants of emphysema and airway dimension were measured from multidetector chest CT scans.The mean age was 66 ± 7 years, and mean eGFR was 101 ± 22 mL/min/1.73 m². Univariate and multivariate analysis showed a significant association between radiographically measured emphysema and eGFR: Participants with 10% more emphysema had an eGFR that was lower by 4.4 mL/min/1.73 m² (P = .01), independent of airflow obstruction (FEV₁), age, sex, race, height, BMI, diabetes mellitus, hypertension, coronary artery disease, patient-reported dyspnea, pack-years of smoking, and current smoking. There was no association between eGFR and either FEV₁ or quantitative CT scan measures of airway dimension.More severe emphysema, rather than airflow obstruction, is associated with kidney dysfunction in tobacco smokers, independent of common risk factors for kidney disease. This finding adds to recent observations of associations between emphysema and comorbidities of COPD, including osteoporosis and lung cancer, which are independent of the traditional measure of reduced FEV₁. The mechanisms and clinical implications of kidney dysfunction in patients with emphysema need further investigation.
| S-EPMC3435137 | biostudies-other
Project description:RationaleLimited data on sex differences in advanced COPD are available.ObjectivesTo compare male and female emphysema patients with severe disease.MethodsOne thousand fifty-three patients (38.8% female) evaluated for lung volume reduction surgery as part of the National Emphysema Treatment Trial were analyzed.Measurements and main resultsDetailed clinical, physiological, and radiological assessment, including quantitation of emphysema severity and distribution from helical chest computed tomography, was completed. In a subgroup (n = 101), airway size and thickness was determined by histological analyses of resected tissue. Women were younger and exhibited a lower body mass index (BMI), shorter smoking history, less severe airflow obstruction, lower Dl(co) and arterial Po(2), higher arterial Pco(2), shorter six-minute walk distance, and lower maximal wattage during oxygen-supplemented cycle ergometry. For a given FEV(1)% predicted, age, number of pack-years, and proportion of emphysema, women experienced greater dyspnea, higher modified BODE, more depression, lower SF-36 mental component score, and lower quality of well-being. Overall emphysema was less severe in women, with the difference from men most evident in the outer peel of the lung. Females had thicker small airway walls relative to luminal perimeters.ConclusionsIn patients with severe COPD, women, relative to men, exhibit anatomically smaller airway lumens with disproportionately thicker airway walls, and emphysema that is less extensive and characterized by smaller hole size and less peripheral involvement.
| S-EPMC1994221 | biostudies-literature
Project description:Recent studies suggest that males with chronic obstructive pulmonary disease (COPD) have more emphysema than females. It is not known if these differences persist across degrees of COPD severity. Our aim was to identify sex-specific differences in quantitative emphysema within COPD subgroups based on COPD severity.We included non-Hispanic white and African-American subjects from the COPDGene study with at least 10 pack-years of smoking and COPD Global Initiative for Chronic Obstructive Lung Disease (GOLD) spirometry grade II or greater. We examined sex-specific differences in log-transformed emphysema (log per cent low-attenuation area (%LAA)) by GOLD spirometry grade among subjects with early-onset COPD (<55 years old) and advanced emphysema (>25% emphysema).Compared with females, males had higher log %LAA: overall (1.97±1.4 versus 1.69±1.6, ?=0.32 (0.04), p=1.34×10(-14)), and among non-Hispanic white (p=8.37×10(-14)) and African-American subjects (p=0.002). Females with early-onset COPD, severe emphysema and GOLD grade IV COPD had similar emphysema as males, but markedly fewer pack-years smoking (early-onset, p=0.01; severe emphysema and GOLD grade IV, p<0.001).This study identifies subsets of female smokers with COPD who are particularly susceptible to parenchymal destruction.
| S-EPMC5374719 | biostudies-literature
Project description:RationaleEmphysema and osteoporosis are epidemiologically associated diseases of cigarette smokers. The causal mechanism(s) linking these illnesses is unknown. We hypothesized autoimmune responses may be involved in both disorders.ObjectivesTo discover an antigen-specific autoimmune response associated with both emphysema and osteoporosis among smokers.MethodsReplicate nonbiased discovery assays indicated that autoimmunity to glucose regulated protein 78 (GRP78), an endoplasmic reticulum chaperone and cell surface signaling receptor, is present in many smokers. Subject assessments included spirometry, chest CT scans, dual x-ray absorptiometry, and immunoblots for anti-GRP78 IgG. Anti-GRP78 autoantibodies were isolated from patient plasma by affinity chromatography, leukocyte functions assessed by flow cytometry, and soluble metabolites and mediators measured by immunoassays.Measurements and main resultsCirculating anti-GRP78 IgG autoantibodies were detected in plasma specimens from 86 (32%) of the 265 smoking subjects. Anti-GRP78 autoantibodies were singularly prevalent among subjects with radiographic emphysema (OR 3.1, 95%CI 1.7-5.7, p?=?0.003). Anti-GRP78 autoantibodies were also associated with osteoporosis (OR 4.7, 95%CI 1.7-13.3, p?=?0.002), and increased circulating bone metabolites (p?=?0.006). Among emphysematous subjects, GRP78 protein was an autoantigen of CD4 T-cells, stimulating lymphocyte proliferation (p?=?0.0002) and IFN-gamma production (p?=?0.03). Patient-derived anti-GRP78 autoantibodies had avidities for osteoclasts and macrophages, and increased macrophage NFkB phosphorylation (p?=?0.005) and productions of IL-8, CCL-2, and MMP9 (p?=?0.005, 0.007, 0.03, respectively).ConclusionsHumoral and cellular GRP78 autoimmune responses in smokers have numerous biologically-relevant pro-inflammatory and other deleterious actions, and are associated with emphysema and osteoporosis. These findings may have relevance for the pathogenesis of smoking-associated diseases, and development of biomarker immunoassays and/or novel treatments for these disorders.
| S-EPMC4162538 | biostudies-literature