Genome-wide Association Study Identifies <i>BICD1</i> as a Susceptibility Gene for Emphysema

Kong, Xiangyang; Cho, Michael H.; Anderson, W. J.; Müller, Néstor L.; Washko, George R.; Hoffman, Eric A.; Bakke, Per; Gulsvik, Amund; Lomas, David A.; Silverman, Edwin K.; Pillai, Sreekumar

doi:10.1164/rccm.201004-0541oc

Cited by 103 publications

(88 citation statements)

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“…However, computed tomographic scans from the National Emphysema Treatment Trial cohort have greater variation in slice thickness than that seen here and have been extensively analyzed for emphysema using quantitative densitometry (18,41). We also adjusted for slice thickness, which did not alter our results.…”

Section: Original Researchmentioning

confidence: 99%

Regional Emphysema of a Non-Small Cell Tumor Is Associated with Larger Tumors and Decreased Survival

Kinsey¹,

Estépar²,

Wei

et al. 2015

Annals ATS

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Rationale: Chronic obstructive pulmonary disease is associated with a worse overall survival in non-small cell lung cancer. Lung emphysema is one component of chronic obstructive pulmonary disease. We hypothesized that emphysema of the tumor region may result in larger tumors and a poorer overall survival. Methods:We evaluated 304 cases of non-small cell lung cancer from a prospectively enrolled cohort. The lung was divided into equal volumetric thirds (upper, middle, or lower region). Emphysema was defined as percentage of low-attenuation areas less than 2950 Hounsfield units (%LAA2950) and measured for each region. Wholelung %LAA2950 was defined as the emphysema score of the entire lung parenchyma, whereas regional %LAA2950 was the score within that particular region (upper, middle, or lower). The emphysema score of the region in which the tumor occurred was defined as the tumor %LAA2950. Tumor diameter was measured while blinded to characteristics of the lung parenchyma. A proportional hazards model was used to control for multiple factors associated with survival.Measurements and Main Results: Increasing tumor %LAA2950 was associated with larger tumors (P = 0.024). Survival, stratified by stage, was significantly worse in those with tumor %LAA2950 greater than or equal to the 50th percentile versus less than the 50th percentile (P = 0.046). Whole-lung %LAA2950 and regional %LAA2950 (e.g., regional emphysema without tumor occurring in the region) were not significantly associated with survival. There were no differences in presenting symptoms or locations of mediastinal or distant metastasis by emphysema score. Increasing tumor %LAA2950 was associated with an increased risk of death (adjusted hazard ratio, 1.36; confidence interval, 1.09-1.68; P = 0.006) after adjustment for age, sex, smoking status, histology, stage, performance status, chemotherapy, radiation, and surgery. Sensitivity analyses revealed no significant difference in the effect size or test of significance for each of the following conditions: (1) exclusion of cases with central tumor location, (2) exclusion of cases where surgery was performed, (3) exclusion of cases where radiation therapy was performed, (4) exclusion of cases where epidermal growth factor receptor tyrosine kinase inhibitors were administered, and (5) inclusion of only stage IV disease.Conclusions: Increasing emphysema of the region in which a nonsmall cell lung cancer tumor occurs is associated with increasing tumor size and worse overall survival.

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Section: Original Researchmentioning

confidence: 99%

Regional Emphysema of a Non-Small Cell Tumor Is Associated with Larger Tumors and Decreased Survival

Kinsey¹,

Estépar²,

Wei

et al. 2015

Annals ATS

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“…Quantitative measures of emphysema can be assessed in vivo with computed tomography (CT), and semiautomated processes for extracting this information have enabled efficient quantitative characterization of emphysema in large-scale studies. Numerous studies have demonstrated association between quantitative measures of emphysema severity and physiologic parameters of lung function (2)(3)(4)(5), functional status and dyspnea (6)(7)(8)(9), genetic polymorphisms (10)(11)(12)(13)(14)(15)(16)(17)(18), and clinical outcomes (19)(20)(21).…”

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confidence: 99%

Distinct Quantitative Computed Tomography Emphysema Patterns Are Associated with Physiology and Function in Smokers

Castaldi

Estépar

Mendoza

et al. 2013

Am J Respir Crit Care Med

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123

125

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Rationale: Emphysema occurs in distinct pathologic patterns, but little is known about the epidemiologic associations of these patterns. Standard quantitative measures of emphysema from computed tomography (CT) do not distinguish between distinct patterns of parenchymal destruction. Objectives: To study the epidemiologic associations of distinct emphysema patterns with measures of lung-related physiology, function, and health care use in smokers. Methods: Using a local histogram-based assessment of lung density, we quantified distinct patterns of low attenuation in 9,313 smokers in the COPDGene Study. To determine if such patterns provide novel insights into chronic obstructive pulmonary disease epidemiology, we tested for their association with measures of physiology, function, and health care use. Measurements and Main Results: Compared with percentage of lowattenuation area less than 2950 Hounsfield units (%LAA-950), local histogram-based measures of distinct CT low-attenuation patterns are more predictive of measures of lung function, dyspnea, quality of life, and health care use. These patterns are strongly associated with a wide array of measures of respiratory physiology and function, and most of these associations remain highly significant (P , 0.005) after adjusting for %LAA-950. In smokers without evidence of chronic obstructive pulmonary disease, the mild centrilobular disease pattern is associated with lower FEV 1 and worse functional status (P , 0.005). Conclusions: Measures of distinct CT emphysema patterns provide novel information about the relationship between emphysema and key measures of physiology, physical function, and health care use. Measures of mild emphysema in smokers with preserved lung function can be extracted from CT scans and are significantly associated with functional measures.Keywords: emphysema; chronic obstructive pulmonary disease; spiral computed tomography; epidemiology Emphysema, defined as alveolar destruction and airspace enlargement distal to the terminal bronchiole, is a characteristic pathologic process of chronic obstructive pulmonary disease (COPD) (1). Quantitative measures of emphysema can be assessed in vivo with computed tomography (CT), and semiautomated processes for extracting this information have enabled efficient quantitative characterization of emphysema in large-scale studies. Numerous studies have demonstrated association between quantitative measures of emphysema severity and physiologic parameters of lung function (2-5), functional status and dyspnea (6-9), genetic polymorphisms (10-18), and clinical outcomes (19-21).The standard approach to CT-based quantification of emphysema is to define a threshold in the lung density histogram that differentiates emphysematous from preserved lung (22). One limitation of this approach is that, by representing the burden of emphysema as a single number, information present in the local patterns of emphysematous involvement is lost. Three distinct patterns of emphysema based on distribution within the secondary lob...

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“…Shorter telomeres have also been observed in peripheral leukocytes from COPD patients [33] and a decreased telomere length was observed in the tissue of emphysematous lungs [34]. Intriguingly, a recent GWA study also identified genetic variants in BICD1, which are known to correlate with short telomeres, as susceptibility factors for emphysema [35]. In addition to genetic predisposition, which we observed in this study, telomere shortening in COPD and emphysema may also result from an increased number of cell divisions due to ongoing inflammation [36].…”

Section: Discussionmentioning

confidence: 94%

TheTERT-CLPTM1Llocus for lung cancer predisposes to bronchial obstruction and emphysema

Wauters¹,

Smeets²,

Coolen³

et al. 2011

Eur Respir J

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Clinical studies suggest that bronchial obstruction and emphysema increase susceptibility to lung cancer. We assessed the possibility of a common genetic origin and investigated whether the lung cancer susceptibility locus on chromosome 5p15.33 increases the risk for bronchial obstruction and emphysema.Three variants in the 5p15.33 locus encompassing the TERT and CLPTM1L genes were genotyped in 777 heavy smokers and 212 lung cancer patients. Participants underwent pulmonary function tests and computed tomography of the chest, and completed questionnaires assessing smoking behaviour.The rs31489 C-allele correlated with reduced forced expiratory volume in 1 s (p50.006). Homozygous carriers of the rs31489 C-allele exhibited increased susceptibility to bronchial obstruction (OR 1.82, 95% CI 1.24-2.69; p50.002). A similar association was observed for diffusing capacity of the lung for carbon monoxide (p50.004). Consistent with this, CC-carriers had an increased risk of emphysema (OR 2.04, 95% CI 1. 41-2.94; p51.73610 -4 ) and displayed greater alveolar destruction. Finally, CC-carriers also had an increased risk for lung cancer (OR 1.90, 95% CI 1.21-2.99; p50.005), and were more susceptible to developing both lung cancer and bronchial obstruction than lung cancer alone (OR 2.11, 95% CI 1.04-4.26; p50.038).The rs31489 variant on 5p15.33 is associated with bronchial obstruction, presence and severity of emphysema, and lung cancer.KEYWORDS: Chronic obstructive pulmonary disease, emphysema, lung cancer, susceptibility, telomerase reverse transcriptase gene A round 50-70% of patients diagnosed with lung cancer exhibit some evidence of chronic obstructive pulmonary disease (COPD). Although cigarette smoking is generally considered to be responsible for this correlation, substantial epidemiological data show that the prevalence of COPD in lung cancer patients is 2-6-fold higher compared with the prevalence of COPD in a cohort of heavy smokers, and this was independent of age or pack-yrs smoked [1]. Moreover, reduced forced expiratory volume in 1 s (FEV1) has been shown to increase the risk for incident lung cancer independently of smoking history [2]. COPD is also associated with lung cancer in never-smokers [3], thereby suggesting that additional risk factors might explain the link between COPD and lung cancer. Emphysema, which is characterised by alveolar destruction, is an important clinical phenotype of COPD. Indeed, COPD patients with emphysema have a poorer health-related quality of life and exhibit an increased risk of non-cancer related respiratory death [4]. Epidemiological data suggest that emphysema and bronchial obstruction independently increase susceptibility to lung cancer. For instance, a large study revealed a .2-fold increase of lung cancer risk in patients with bronchial obstruction, after adjusting for smoking history, and a .3-fold increase in patients with emphysema, after adjusting for both smoking history and COPD severity [2]. Although these data were not confirmed in a second smaller...

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Genome-wide Association Study Identifies BICD1 as a Susceptibility Gene for Emphysema

Cited by 103 publications

References 53 publications

Regional Emphysema of a Non-Small Cell Tumor Is Associated with Larger Tumors and Decreased Survival

Regional Emphysema of a Non-Small Cell Tumor Is Associated with Larger Tumors and Decreased Survival

Distinct Quantitative Computed Tomography Emphysema Patterns Are Associated with Physiology and Function in Smokers

TheTERT-CLPTM1Llocus for lung cancer predisposes to bronchial obstruction and emphysema

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