Genetics, Chronic Obstructive Pulmonary Disease, and the Arrow of Time.
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ABSTRACT:
SUBMITTER: Calverley PMA
PROVIDER: S-EPMC6775883 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease caused by the interaction of genetic susceptibility and environmental influences. There is increasing evidence that genes link to disease pathogenesis and heterogeneity by causing variation in protease anti-protease systems, defence against oxidative stress and inflammation. The main methods of genomic research for complex disease traits are described, together with the genes implicated in COPD thus far, their roles in disease causation and the future for this area of investigation.
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Project description:Familial aggregation of chronic obstructive pulmonary disease (COPD) has been demonstrated, suggesting that genetic factors likely influence the variable development of chronic airflow obstruction in response to smoking. A variety of approaches have been used to identify novel COPD susceptibility genes, including association studies, linkage analysis, and rare variant analysis. Future directions for COPD research include genomewide association studies and animal model genetic studies.
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Project description:Chronic obstructive pulmonary disease (COPD) fulfills criteria for a complex genetic disease in which environmental factors interact with multiple polymorphic genes to influence susceptibility. Finding the genes that influence susceptibility can be approached in hypothesis testing or unbiased study designs. In candidate gene association studies, genetic variation in, and/or levels of, expression of genes known or suspected to be involved in the pathogenesis of COPD are compared in affected and unaffected individuals. Although this approach is useful it is limited by our present knowledge of disease pathophysiology. Genomewide studies of gene expression and of genetic variation are now possible and are not constrained by our limited knowledge. Although both of these unbiased approaches are in their infancy, they have already provided exciting new avenues for future investigation and potentially now approaches to risk prediction and therapy.
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Project description:Diaphragm muscles in Chronic Obstructive Pulmonary Disease (COPD) patients undergo an adaptive fast to slow transformation that includes cellular adaptations. This project studies the signaling mechanisms responsible for this transformation. Keywords: other
2003-07-16 | GSE475 | GEO
Project description:Investigation of whole genome gene expression level changes of the dynamic gene profiling of peripheral blood mononuclear cells (PBMCs) from patients with AECOPD) on day1, 3 and 10, compared to the normal people and stable COPD patients. A five chip study using total RNA recovered from Peripheral Blood Mononuclear Cell of Peripheral Blood.Evaluating the dynamic gene profiling of peripheral blood mononuclear cells (PBMCs) from patients with AECOPD) on day1, 3 and 10 after the hospital admission, to compared with healthy controls or patients with stable COPD. Slides were scanned at 5 μm/pixel resolution using an Axon GenePix 4000B scanner (Molecular Devices Corporation) piloted by GenePix Pro 6.0 software (Axon). Scanned images (TIFF format) were then imported into NimbleScan software (version 2.5) for grid alignment and expression data analysis. Expression data were normalized through quantile normalization and the Robust Multichip Average (RMA) algorithm included in the NimbleScan software. The Probe level (*_norm_RMA.pair) files and Gene level (*_RMA.calls) files were generated after normalization.
2014-08-14 | E-GEOD-60399 | biostudies-arrayexpress
Project description:Previous expression quantitative trait loci (eQTL) studies have performed genetic association studies for gene expression, but most of these studies examined lymphoblastoid cell lines from non-diseased individuals. We examined the genetics of gene expression in a relevant disease tissue from chronic obstructive pulmonary disease (COPD) patients to identify functional effects of known susceptibility genes and to find novel disease genes. By combining gene expression profiling on induced sputum samples from 131 COPD cases from the ECLIPSE Study with genomewide single nucleotide polymorphism (SNP) data, we found 4315 significant cis-eQTL SNP-probe set associations (3309 unique SNPs). The 3309 SNPs were tested for association with COPD in a genomewide association study (GWAS) dataset, which included 2940 COPD cases and 1380 controls. Adjusting for 3309 tests (p<1.5e-5), the two SNPs which were significantly associated with COPD were located in two separate genes in a known COPD locus on chromosome 15: CHRNA5 and IREB2. Detailed analysis of chromosome 15 demonstrated additional eQTLs for IREB2 mapping to that gene. eQTL SNPs for CHRNA5 mapped to multiple linkage disequilibrium (LD) bins. The eQTLs for IREB2 and CHRNA5 were not in LD. Seventy-four additional eQTL SNPs were associated with COPD at p<0.01. These were genotyped in two COPD populations, finding replicated associations with a SNP in PSORS1C1, in the HLA-C region on chromosome 6. Integrative analysis of GWAS and gene expression data from relevant tissue from diseased subjects has located potential functional variants in two known COPD genes and has identified a novel COPD susceptibility locus.
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Project description:BackgroundAlthough subtypes of chronic obstructive pulmonary disease are recognized, it is unknown what happens to these subtypes over time. Our objectives were to assess the stability of cluster-based subtypes in patients with stable disease and explore changes in clusters over 1 year.MethodsMultiple correspondence and cluster analysis were used to evaluate data collected from 543 stable patients included consecutively from 5 respiratory outpatient clinics.ResultsFour subtypes were identified. Three of them, A, B, and C, had marked respiratory profiles with a continuum in severity of several variables, while the fourth, subtype D, had a more systemic profile with intermediate respiratory disease severity. Subtype A was associated with less dyspnea, better health-related quality of life and lower Charlson comorbidity scores, and subtype C with the most severe dyspnea, and poorer pulmonary function and quality of life, while subtype B was between subtypes A and C. Subtype D had higher rates of hospitalization the previous year, and comorbidities. After 1 year, all clusters remained stable. Generally, patients continued in the same subtype but 28% migrated to another cluster. Together with movement across clusters, patients showed changes in certain characteristics (especially exercise capacity, some variables of pulmonary function and physical activity) and changes in outcomes (quality of life, hospitalization and mortality) depending on the new cluster they belonged to.ConclusionsChronic obstructive pulmonary disease clusters remained stable over 1 year. Most patients stayed in their initial subtype cluster, but some moved to another subtype and accordingly had different outcomes.
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Project description:Chronic obstructive pulmonary disease (COPD) Metagenome
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Project description:Investigation of whole genome gene expression level changes of the dynamic gene profiling of peripheral blood mononuclear cells (PBMCs) from patients with AECOPD) on day1, 3 and 10, compared to the normal people and stable COPD patients.
2014-08-14 | GSE60399 | GEO
Project description:BACKGROUND:Smoking is the principal modifiable environmental risk factor for chronic obstructive pulmonary disease (COPD) which affects 300 million people and is the 3rd leading cause of death worldwide. Most of the genetic studies of smoking have relied on self-reported smoking status which is vulnerable to reporting and recall bias. Using data from the Lung Health Study (LHS), we sought to identify genetic variants associated with quantitative smoking and cessation in individuals with mild to moderate COPD. METHODS:The LHS is a longitudinal multicenter study of mild-to-moderate COPD subjects who were all smokers at recruitment. We performed genome-wide association studies (GWASs) for salivary cotinine (n?=?4024), exhaled carbon monoxide (eCO) (n?=?2854), cigarettes per day (CPD) (n?=?2706) and smoking cessation at year 5 follow-up (n?=?717 quitters and 2175 smokers). The GWAS analyses were adjusted for age, gender, and genetic principal components. RESULTS:For cotinine levels, SNPs near UGT2B10 gene achieved genome-wide significance (i.e. P?<?5?×?10-?8) with top SNP rs10023464, P?=?1.27?×?10-?11. For eCO levels, one significant SNP was identified which mapped to the CHRNA3 gene (rs12914385, P?=?2.38?×?10-?8). A borderline region mapping to KCNMA1 gene was associated with smoking cessation (rs207675, P?=?5.95?×?10-?8). Of the identified loci, only the CHRNA3/5 locus showed significant associations with lung function but only in heavy smokers. No regions met genome-wide significance for CPD. CONCLUSION:The study demonstrates that using objective measures of smoking such as eCO and/or salivary cotinine can more precisely capture the genetic contribution to multiple aspects of smoking behaviour. The KCNMA1 gene association with smoking cessation may represent a potential therapeutic target and warrants further studies. TRIAL REGISTRATION:The Lung Health Study ClinicalTrials.gov Identifier: NCT00000568 . Date of registration: October 28, 1999.
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