Lung cancer gene associated with COPD: triple whammy or possible confounding effect?

Young, Robert P.; Hopkins, Robert E.; Hay, Bryan A.; Epton, Michael; Black, Peter; Gamble, Gregory D.

doi:10.1183/09031936.00093908

Cited by 91 publications

(134 citation statements)

References 35 publications

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“…However, the results of many small candidate gene studies have been inconsistent (9,10). Genomewide association studies (GWASs) of COPD (11)(12)(13) have, to date, identified three susceptibility loci that have been well replicated (14)(15)(16)(17)(18)(19)(20)(21). We report the results of a follow-up GWAS in four cohorts that identifiy a new COPD susceptibility locus.…”

Section: Introductionmentioning

confidence: 98%

A Genome-Wide Association Study In COPD Identifies A Susceptibility Locus On Chromosome 19q13

Cho

Castaldi

Hersh

et al. 2011

A95. Cutting Edge Insights to the Pathobiology of Copd and Interstitial Lung Disease

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The genetic risk factors for chronic obstructive pulmonary disease (COPD) are still largely unknown. To date, genome-wide association studies (GWASs) of limited size have identified several novel risk loci for COPD at CHRNA3/CHRNA5/IREB2, HHIP and FAM13A; additional loci may be identified through larger studies. We performed a GWAS using a total of 3499 cases and 1922 control subjects from four cohorts: the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE); the Normative Aging Study (NAS) and National Emphysema Treatment Trial (NETT); Bergen, Norway (GenKOLS); and the COPDGene study. Genotyping was performed on Illumina platforms with additional markers imputed using 1000 Genomes data; results were summarized using fixed-effect meta-analysis. We identified a new genomewide significant locus on chromosome 19q13 (rs7937, OR 5 0.74, P 5 2.9 3 10 29 ). Genotyping this single * Molecular Genetics, 2012, Vol. 21, No. 4 947-957 doi:10.1093/hmg/ddr524 Advance Access published on November 11, 2011nucleotide polymorphism (SNP) and another nearby SNP in linkage disequilibrium (rs2604894) in 2859 subjects from the family-based International COPD Genetics Network study (ICGN) demonstrated supportive evidence for association for COPD (P 5 0.28 and 0.11 for rs7937 and rs2604894), pre-bronchodilator FEV 1 (P 5 0.08 and 0.04) and severe (GOLD 3&4) COPD (P 5 0.09 and 0.017). This region includes RAB4B, EGLN2, MIA and CYP2A6, and has previously been identified in association with cigarette smoking behavior.

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Section: Introductionmentioning

confidence: 98%

A Genome-Wide Association Study In COPD Identifies A Susceptibility Locus On Chromosome 19q13

Cho

Castaldi

Hersh

et al. 2011

A95. Cutting Edge Insights to the Pathobiology of Copd and Interstitial Lung Disease

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“…The observation could be explained by possible pathologic relations between COPD and lung cancer (24,25). Recent genetic linkage studies have identified common, biologically potential genetic markers in families who have susceptibility for both COPD and lung cancer (25). Therefore, discrimination of NSCLC from the benign disease has presented a difficult problem in past studies, in which a relatively high percentage of false-positive classification of NSCLC was observed.…”

Section: Discussionmentioning

confidence: 98%

“…Furthermore, we found that these lung cancer-associated genetic changes were also related to COPD. The observation could be explained by possible pathologic relations between COPD and lung cancer (24,25). Recent genetic linkage studies have identified common, biologically potential genetic markers in families who have susceptibility for both COPD and lung cancer (25).…”

Section: Discussionmentioning

confidence: 99%

A Panel of Sputum-Based Genomic Marker for Early Detection of Lung Cancer

Jiang

Todd

et al. 2010

Cancer Prevention Research

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Non-small cell lung cancer (NSCLC) is the leading cause of cancer death. Early detection of NSCLC will improve its outcome. We previously identified genetic signatures whose genomic copy number aberrations were associated with early stage NSCLC. Here, we aimed to develop a panel of genes that could be detected in sputum for NSCLC early detection. We first optimized a panel of genes by using an in situ minichip for measuring changes of the signatures in sputum of a case-control cohort of 49 NSCLC patients, 49 patients with chronic obstructive pulmonary disease (COPD), and 49 healthy smokers. We then validated the genes in an independent cohort of 69 NSCLC patients and 65 noncancer subjects. The results were compared with those of sputum cytology. Fifteen genes showed significant differences of their copy number changes in sputum between NSCLC and both COPD and healthy subjects. A logistic regression model with the best prediction was built on the basis of 6 genes, ENO1, FHIT, HYAL2, SKP2, p16, and 14-3-3zeta. The composite of the 6 genes produced 86.7% sensitivity and 93.9% specificity in distinguishing stage I NSCLC patients from the noncancer individuals. Furthermore, the genes had higher sensitivity (86.9%) in identification of squamous cell carcinoma (SCC) than in adenocarcinoma of the lungs (80.8%; P < 0.05). Validation of the genes in the independent cohort confirmed their diagnostic power that also showed higher accuracy for lung SCCs than for sputum cytology. The gene panel could provide sputumbased markers that have the potential to improve early detection of lung SCCs.

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“…There is currently much interest in genetic markers in the 15q25 locus, encompassing the cluster of nicotinic cholinergic receptor genes CHRNA3/CHRNA5/CHRNB4, which have been associated with chronic obstructive pulmonary disease (COPD) and smoking behavior. 3,8 It has been speculated that functional variants in this region may actually be primarily influencing nicotine addiction, as observed in recent GWASs on smoking intensity, and are thus only associated with COPD due to the well-known links between smoking and COPD. [9][10][11] To determine if the genetic marker influences COPD through pathways other than smoking, the COPD case-control binary variable has the role of target phenotype 'T' , smoking, represented as cumulative exposure to tobacco smoke (ie pack-years smoked) or number of cigarettes smoked per day, has the role of secondary phenotype 'K' , the well-known diagnostic criteria for smoking, such as gender, has the role of variable 'L' .…”

Section: Methodsmentioning

confidence: 99%

CGene: an R package for implementation of causal genetic analyses

Lipman

Lange

2011

Eur J Hum Genet

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The excitement over findings from Genome-Wide Association Studies (GWASs) has been tempered by the difficulty in finding the location of the true causal disease susceptibility loci (DSLs), rather than markers that are correlated with the causal variants. In addition, many recent GWASs have studied multiple phenotypes -often highly correlated -making it difficult to understand which associations are causal and which are seemingly causal, induced by phenotypic correlations. In order to identify DSLs, which are required to understand the genetic etiology of the observed associations, statistical methodology has been proposed that distinguishes between a direct effect of a genetic locus on the primary phenotype and an indirect effect induced by the association with the intermediate phenotype that is also correlated with the primary phenotype. However, so far, the application of this important methodology has been challenging, as no user-friendly software implementation exists. The lack of software implementation of this sophisticated methodology has prevented its large-scale use in the genetic community. We have now implemented this statistical approach in a user-friendly and robust R package that has been thoroughly tested. The R package 'CGene' is available for download at http://cran.r-project.org/. The R code is also available at http://people.hsph.harvard.edu/ plipman. European Journal of Human Genetics (2011Genetics ( ) 19, 1292Genetics ( -1294 doi:10.1038/ejhg.2011; published online 6 July 2011Keywords: causal modeling; statistical genetics; software INTRODUCTIONThe excitement over positive findings from recently published Genome-Wide Association Studies (GWASs) has been tempered by the difficulty in finding the location of the true causal disease susceptibility loci (DSLs), rather than markers that are correlated with the DSL. 1 Complicating the picture is that many recent GWASs have studied multiple phenotypes, which are often highly correlated. [2][3][4] This has made it very difficult to understand which associations that were discovered by GWASs are causal and which are seemingly causal, induced by phenotypic correlations. The ability to distinguish between causal genetic associations and seemingly causal associations induced by the intermediate phenotypes can provide important clues into the underlying genetic architecture of the disease. In addition, there is much interest in identifying endo-phenotypes or expression profiles that may lie in the 'genetic path' between the marker locus and the phenotype of interest to better understand how the genetic mechanisms influence the complex trait. The recent interest in understanding causal genetic pathways has led to the development of new statistical techniques that look to distinguish between direct and indirect causal genetic mechanisms. For quantitative and binary traits, VanSteenlandt et al 5 proposed a regression adjustment procedure that is applied to the quantitative phenotype of interest, adjusting for the potential presence of an association between...

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Lung cancer gene associated with COPD: triple whammy or possible confounding effect?

Cited by 91 publications

References 35 publications

A Genome-Wide Association Study In COPD Identifies A Susceptibility Locus On Chromosome 19q13

A Genome-Wide Association Study In COPD Identifies A Susceptibility Locus On Chromosome 19q13

A Panel of Sputum-Based Genomic Marker for Early Detection of Lung Cancer

CGene: an R package for implementation of causal genetic analyses

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