Respiratory System Commons^™

Polygenic And Transcriptional Risk Scores Identify Chronic Obstructive Pulmonary Disease Subtypes In The Copdgene And Eclipse Cohort Studies, Matthew Moll, Julian Hecker, John Platig, Jingzhou Zhang, Auyon J. Ghosh, Katherine A. Pratte, Rui-Sheng Wang, Davin Hill, Iain R. Konigsberg, Joe W. Chiles, Craig P. Hersh, Peter J. Castaldi, Kimberly Glass, Jennifer G. Dy, Don D. Sin, Ruth Tal-Singer, Majd Mouded, Stephen I. Rennard, Gary P. Anderson, Gregory L. Kinney, Russell P. Bowler, Jeffrey L. Curtis, Merry-Lynn Mcdonald, Edwin K. Silverman, Brian D. Hobbs, Michael H. Cho

Journal Articles: Pulmonary & Critical Care Med

BACKGROUND: Genetic variants and gene expression predict risk of chronic obstructive pulmonary disease (COPD), but their effect on COPD heterogeneity is unclear. We aimed to define high-risk COPD subtypes using genetics (polygenic risk score, PRS) and blood gene expression (transcriptional risk score, TRS) and assess differences in clinical and molecular characteristics.

METHODS: We defined high-risk groups based on PRS and TRS quantiles by maximising differences in protein biomarkers in a COPDGene training set and identified these groups in COPDGene and ECLIPSE test sets. We tested multivariable associations of subgroups with clinical outcomes and compared protein-protein interaction networks and drug repurposing …

Body Mass Index Change In Gastrointestinal Cancer And Chronic Obstructive Pulmonary Disease Is Associated With Dedicator Of Cytokinesis 1, Merry-Lynn Noelle Mcdonald, Sungho Won, Manuel Mattheisen, Peter J. Castaldi, Michael H. Cho, Erica Rutten, Megan Hardin, Wai-Ki Yip, Stephen I. Rennard, David A. Lomas, Emiel F.M. Wouters, Alvar Agusti, Richard Casaburi, Christoph P. Lange, George O'Connor, Craig P. Hersh, Edwin K. Silverman

Journal Articles: Pulmonary & Critical Care Med

BACKGROUND: There have been a number of candidate gene association studies of cancer cachexia-related traits, but no genome-wide association study (GWAS) has been published to date. Cachexia presents in patients with a number of complex traits, including both cancer and COPD. The objective of the current investigation was to search for a shared genetic aetiology for change in body mass index (ΔBMI) among cancer and COPD by using GWAS data in the Framingham Heart Study.

METHODS: A linear mixed effects model accounting for age, sex, and change in smoking status was used to calculate ΔBMI in participants over 40 years …

Role Of A Genetic Variant On The 15q25.1 Lung Cancer Susceptibility Locus In Smoking-Associated Nasopharyngeal Carcinoma, Xuemei Ji, Weidong Zhang, Jiang Gui, Xia Fan, Weiwei Zhang, Yafang Li, Guangyu An, Dakai Zhu, Qiang Hu

Dartmouth Scholarship

Background: The 15q25.1 lung cancer susceptibility locus, containing CHRNA5, could modify lung cancer susceptibility and multiple smoking related phenotypes. However, no studies have investigated the association between CHRNA5 rs3841324, which has been proven to have the highest association with CHRNA5 mRNA expression, and the risk of other smoking-associated cancers, except lung cancer. In the current study we examined the association between rs3841324 and susceptibility to smoking-associated nasopharyngeal carcinoma (NPC).

Methods: In this case-control study we genotyped the CHRNA5 rs3841324 polymorphism with 400 NPC cases and 491 healthy controls who were Han Chinese and frequency-matched by age (±5 years), gender, and …

Analyzing Networks Of Phenotypes In Complex Diseases: Methodology And Applications In Copd, Jen-Hwa Chu, Craig P. Hersh, Peter J. Castaldi, Michael H. Cho, Benjamin A. Raby, Nan Laird, Russell Bowler, Stephen I. Rennard, Joseph Loscalzo, John Quackenbush, Edwin K. Silverman

Journal Articles: Pulmonary & Critical Care Med

BACKGROUND: The investigation of complex disease heterogeneity has been challenging. Here, we introduce a network-based approach, using partial correlations, that analyzes the relationships among multiple disease-related phenotypes.

RESULTS: We applied this method to two large, well-characterized studies of chronic obstructive pulmonary disease (COPD). We also examined the associations between these COPD phenotypic networks and other factors, including case-control status, disease severity, and genetic variants. Using these phenotypic networks, we have detected novel relationships between phenotypes that would not have been observed using traditional epidemiological approaches.

CONCLUSION: Phenotypic network analysis of complex diseases could provide novel insights into disease susceptibility, disease …

Dnah5 Is Associated With Total Lung Capacity In Chronic Obstructive Pulmonary Disease, Jin Hwa Lee, Merry-Lynn N Mcdonald, Michael H. Cho, Emily S. Wan, Peter J. Castaldi, Gary M. Hunninghake, Nathaniel Marchetti, David A. Lynch, James D. Crapo, David A. Lomas, Harvey O. Coxson, Per S. Bakke, Edwin K. Silverman, Craig P. Hersh, The Copdgene And Eclipse Investigators

Journal Articles: Pulmonary & Critical Care Med

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is characterized by expiratory flow limitation, causing air trapping and lung hyperinflation. Hyperinflation leads to reduced exercise tolerance and poor quality of life in COPD patients. Total lung capacity (TLC) is an indicator of hyperinflation particularly in subjects with moderate-to-severe airflow obstruction. The aim of our study was to identify genetic variants associated with TLC in COPD.

METHODS: We performed genome-wide association studies (GWASs) in white subjects from three cohorts: the COPDGene Study; the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE); and GenKOLS (Bergen, Norway). All subjects were current or ex-smokers …

Association Of Ireb2 And Chrna3 Polymorphisms With Airflow Obstruction In Severe Alpha-1 Antitrypsin Deficiency., Woo Jin Kim, Alice M. Wood, Alan F. Barker, Mark L. Brantly, Edward J. Campbell, Edward Eden, Gerard Mcelvaney, Stephen I. Rennard, Robert A. Sandhaus, James M. Stocks, James K. Stoller, Charlie Strange, Gerard Turino, Edwin K. Silverman, Robert A. Stockley, Dawn L. Demeo

Journal Articles: Pulmonary & Critical Care Med

BACKGROUND: The development of COPD in subjects with alpha-1 antitrypsin (AAT) deficiency is likely to be influenced by modifier genes. Genome-wide association studies and integrative genomics approaches in COPD have demonstrated significant associations with SNPs in the chromosome 15q region that includes CHRNA3 (cholinergic nicotine receptor alpha3) and IREB2 (iron regulatory binding protein 2).We investigated whether SNPs in the chromosome 15q region would be modifiers for lung function and COPD in AAT deficiency.

METHODS: The current analysis included 378 PIZZ subjects in the AAT Genetic Modifiers Study and a replication cohort of 458 subjects from the UK AAT Deficiency National …

Genetics Of Sputum Gene Expression In Chronic Obstructive Pulmonary Disease, Weiliang Qiu, Michael H. Cho, John H. Riley, Wayne H. Anderson, Dave Singh, Per Bakke, Amund Gulsvik, Augusto A. Litonjua, David A. Lomas, James D. Crapo, Terri H. Beaty, Bartolome R. Celli, Stephen I. Rennard, Ruth Tal-Singer, Steven M. Fox, Edwin K. Silverman, Craig P. Hersh, Eclipse Investigators

Journal Articles: Pulmonary & Critical Care Med

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 …

A Genome-Wide Association Study In Chronic Obstructive Pulmonary Disease (Copd): Identification Of Two Major Susceptibility Loci, Sreekumar G. Pillai, Dongliang Ge, Guohua Zhu, Xiangyang Kong, Kevin V. Shianna, Anna C. Need, Sheng Feng, Craig P. Hersh, Per Bakke, Amund Gulsvik, Andreas Ruppert, Karin C. Lødrup Carlsen, Allen Roses, Wayne Anderson, Stephen I. Rennard, David A. Lomas, Edwin K. Silverman, David B. Goldstein, Icgn Investigators

Journal Articles: Pulmonary & Critical Care Med

There is considerable variability in the susceptibility of smokers to develop chronic obstructive pulmonary disease (COPD). The only known genetic risk factor is severe deficiency of alpha(1)-antitrypsin, which is present in 1-2% of individuals with COPD. We conducted a genome-wide association study (GWAS) in a homogenous case-control cohort from Bergen, Norway (823 COPD cases and 810 smoking controls) and evaluated the top 100 single nucleotide polymorphisms (SNPs) in the family-based International COPD Genetics Network (ICGN; 1891 Caucasian individuals from 606 pedigrees) study. The polymorphisms that showed replication were further evaluated in 389 subjects from the US National Emphysema Treatment Trial …