Genome‐Wide Association Study of the Genetic Determinants of Emphysema Distribution

Rationale: Emphysema has considerable variability in the severity and distribution of parenchymal destruction throughout the lungs. Upper lobe‐predominant emphysema has emerged as an important predictor of response to lung volume reduction surgery. Yet, aside from alpha‐1 antitrypsin deficiency, the genetic determinants of emphysema distribution remain largely unknown. Objectives: To identify the genetic influences of emphysema distribution in non‐alpha‐1 antitrypsin‐deficient smokers. Methods: A total of 11,532 subjects with complete genotype and computed tomography densitometry data in the COPDGene (Genetic Epidemiology of Chronic Obstructive Pulmonary Disease [COPD]; non‐Hispanic white and African American), ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints), and GenKOLS (Genetics of Chronic Obstructive Lung Disease) studies were analyzed. Two computed tomography scan emphysema distribution measures (difference between upper‐third and lower‐third emphysema; ratio of upper‐third to lower‐third emphysema) were tested for genetic associations in all study subjects. Separate analyses in each study population were followed by a fixed effect metaanalysis. Single‐nucleotide polymorphism‐, gene‐, and pathway‐based approaches were used. In silico functional evaluation was also performed. Measurements and Main Results: We identified five loci associated with emphysema distribution at genome‐wide significance. These loci included two previously reported associations with COPD susceptibility (4q31 near HHIP and 15q25 near CHRNA5) and three new associations near SOWAHB, TRAPPC9, and KIAA1462. Gene set analysis and in silico functional evaluation revealed pathways and cell types that may potentially contribute to the pathogenesis of emphysema distribution. Conclusions: This multicohort genome‐wide association study identified new genomic loci associated with differential emphysematous destruction throughout the lungs. These findings may point to new biologic pathways on which to expand diagnostic and therapeutic approaches in chronic obstructive pulmonary disease. Clinical trial registered with www.clinicaltrials.gov (NCT 00608764).

[1]  E. Silverman.  Genetics of COPD. , 2019, Annual review of physiology.

[2]  C. Marquette,et al.  Lung Volume Reduction Coil Treatment vs Usual Care in Patients With Severe Emphysema: The REVOLENS Randomized Clinical Trial. , 2016, JAMA.

[3]  F. Sciurba,et al.  Bronchoscopic Lung Volume Reduction in COPD: Lessons in Implementing Clinically Based Precision Medicine. , 2016, JAMA.

[4]  John Quackenbush,et al.  Mitochondrial iron chelation ameliorates cigarette-smoke induced bronchitis and emphysema in mice , 2015, Nature Medicine.

[5]  L. Wain,et al.  Molecular mechanisms underlying variations in lung function: a systems genetics analysis. , 2015, The Lancet. Respiratory medicine.

[6]  Raúl San José Estépar,et al.  A Genome-Wide Association Study of Emphysema and Airway Quantitative Imaging Phenotypes. , 2015, American journal of respiratory and critical care medicine.

[7]  H. Kauczor,et al.  Quantitative Emphysema Distribution in Anatomic and Non-anatomic Lung Regions , 2015, COPD.

[8]  John Quackenbush,et al.  Genetic control of gene expression at novel and established chronic obstructive pulmonary disease loci. , 2015, Human molecular genetics.

[9]  R. Colvin,et al.  Intronic locus determines SHROOM3 expression and potentiates renal allograft fibrosis. , 2015, The Journal of clinical investigation.

[10]  S. MacGregor,et al.  VEGAS2: Software for More Flexible Gene-Based Testing , 2014, Twin Research and Human Genetics.

[11]  Raúl San José Estépar,et al.  Genome-wide association identifies regulatory Loci associated with distinct local histogram emphysema patterns. , 2014, American journal of respiratory and critical care medicine.

[12]  Christoph Lange,et al.  Risk loci for chronic obstructive pulmonary disease: a genome-wide association study and meta-analysis. , 2014, The Lancet. Respiratory medicine.

[13]  Stephanie A. Santorico,et al.  Cluster analysis in the COPDGene study identifies subtypes of smokers with distinct patterns of airway disease and emphysema , 2014, Thorax.

[14]  Benjamin M. Smith,et al.  Genome-wide study of percent emphysema on computed tomography in the general population. The Multi-Ethnic Study of Atherosclerosis Lung/SNP Health Association Resource Study. , 2014, American journal of respiratory and critical care medicine.

[15]  B. Suki,et al.  Emphysema and mechanical stress-induced lung remodeling. , 2013, Physiology.

[16]  N. Laird,et al.  Heritability of chronic obstructive pulmonary disease and related phenotypes in smokers. , 2013, American journal of respiratory and critical care medicine.

[17]  T. Senga,et al.  The role of PLK1-phosphorylated SVIL in myosin II activation and cytokinetic furrowing , 2013, Journal of Cell Science.

[18]  R. Bowler,et al.  Endothelial cell adhesion molecule CD146: implications for its role in the pathogenesis of COPD , 2013, The Journal of pathology.

[19]  Ellen T. Gelfand,et al.  The Genotype-Tissue Expression (GTEx) project , 2013, Nature Genetics.

[20]  D. Warburton,et al.  TGF-β-Smad3 signaling in emphysema and pulmonary fibrosis: an epigenetic aberration of normal development? , 2013, American journal of physiology. Lung cellular and molecular physiology.

[21]  Edwin K Silverman,et al.  Genome-wide association studies identify CHRNA5/3 and HTR4 in the development of airflow obstruction. , 2012, American journal of respiratory and critical care medicine.

[22]  Shane J. Neph,et al.  Systematic Localization of Common Disease-Associated Variation in Regulatory DNA , 2012, Science.

[23]  Avrum Spira,et al.  A gene expression signature of emphysema-related lung destruction and its reversal by the tripeptide GHK , 2012, Genome Medicine.

[24]  J. Marchini,et al.  Fast and accurate genotype imputation in genome-wide association studies through pre-phasing , 2012, Nature Genetics.

[25]  T. V. Kolesnikova,et al.  EWI-2 Association with α-Actinin Regulates T Cell Immune Synapses and HIV Viral Infection , 2012, The Journal of Immunology.

[26]  F. Kronenberg,et al.  Genome-wide association study of lung function decline in adults with and without asthma. , 2012, The Journal of allergy and clinical immunology.

[27]  Manolis Kellis,et al.  HaploReg: a resource for exploring chromatin states, conservation, and regulatory motif alterations within sets of genetically linked variants , 2011, Nucleic Acids Res..

[28]  F. Venuta,et al.  Long-term follow-up after bronchoscopic lung volume reduction in patients with emphysema , 2011, European Respiratory Journal.

[29]  T. Beaty,et al.  Genetics of Sputum Gene Expression in Chronic Obstructive Pulmonary Disease , 2011, PloS one.

[30]  P. Jones,et al.  TESRA (Treatment Of Emphysema With A Selective Retinoid Agonist) Study Results , 2011, ATS 2011.

[31]  P. Visscher,et al.  GCTA: a tool for genome-wide complex trait analysis. , 2011, American journal of human genetics.

[32]  明石 昌也.  A coronary artery disease-associated gene product, JCAD/KIAA1462, is a novel component of endothelial cell-cell junctions , 2011 .

[33]  C. Gieger,et al.  Genome-wide association study identifies a new locus for coronary artery disease on chromosome 10p11.23. , 2011, European heart journal.

[34]  Edwin K Silverman,et al.  Genome-wide association study identifies BICD1 as a susceptibility gene for emphysema. , 2011, American journal of respiratory and critical care medicine.

[35]  Inês Barroso,et al.  Genome-wide association study identifies five loci associated with lung function , 2010, Nature Genetics.

[36]  E. Regan,et al.  Genetic Epidemiology of COPD (COPDGene) Study Design , 2011, COPD.

[37]  L. Edwards,et al.  Loci identified by genome-wide association studies influence different disease-related phenotypes in chronic obstructive pulmonary disease. , 2010, American journal of respiratory and critical care medicine.

[38]  Edwin K Silverman,et al.  Characterisation of COPD heterogeneity in the ECLIPSE cohort , 2010, Respiratory research.

[39]  P. Visscher,et al.  A versatile gene-based test for genome-wide association studies. , 2010, American journal of human genetics.

[40]  Yun Li,et al.  METAL: fast and efficient meta-analysis of genomewide association scans , 2010, Bioinform..

[41]  P. Korošec,et al.  Complement Factor C5a in Acute Exacerbation of Chronic Obstructive Pulmonary Disease , 2010, Scandinavian journal of immunology.

[42]  J. Seo,et al.  Slope of emphysema index: an objective descriptor of regional heterogeneity of emphysema and an independent determinant of pulmonary function. , 2010, AJR. American journal of roentgenology.

[43]  B. van Ginneken,et al.  Distribution of emphysema in heavy smokers: impact on pulmonary function. , 2010, Respiratory medicine.

[44]  O. Eickelberg,et al.  TGF-beta signaling in COPD: deciphering genetic and cellular susceptibilities for future therapeutic regimen. , 2009, Swiss medical weekly.

[45]  T Mark Beasley,et al.  Rank-Based Inverse Normal Transformations are Increasingly Used, But are They Merited? , 2009, Behavior genetics.

[46]  A. Gulsvik,et al.  Quantitative computed tomography: emphysema and airway wall thickness by sex, age and smoking , 2009, European Respiratory Journal.

[47]  E. Bleecker,et al.  Adam33 polymorphisms are associated with COPD and lung function in long-term tobacco smokers , 2009, Respiratory research.

[48]  W. MacNee,et al.  Computed tomographic emphysema distribution: relationship to clinical features in a cohort of smokers , 2009, European Respiratory Journal.

[49]  K. Shianna,et al.  A Genome-Wide Association Study in Chronic Obstructive Pulmonary Disease (COPD): Identification of Two Major Susceptibility Loci , 2009, PLoS genetics.

[50]  W. MacNee,et al.  Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points (ECLIPSE) , 2008, European Respiratory Journal.

[51]  Manuel A. R. Ferreira,et al.  PLINK: a tool set for whole-genome association and population-based linkage analyses. , 2007, American journal of human genetics.

[52]  B. Make,et al.  Genetic determinants of emphysema distribution in the national emphysema treatment trial. , 2007, American journal of respiratory and critical care medicine.

[53]  D. Postma,et al.  A disintegrin and metalloprotease 33 and chronic obstructive pulmonary disease pathophysiology , 2006, Thorax.

[54]  S. Ryter,et al.  Functional Significance of Apoptosis in Chronic Obstructive Pulmonary Disease , 2007, COPD.

[55]  D. Reich,et al.  Principal components analysis corrects for stratification in genome-wide association studies , 2006, Nature Genetics.

[56]  D. Postma,et al.  Remodeling in asthma and chronic obstructive pulmonary disease. , 2006, Proceedings of the American Thoracic Society.

[57]  Robert Wise,et al.  Predictors of mortality in patients with emphysema and severe airflow obstruction. , 2006, American journal of respiratory and critical care medicine.

[58]  D. Postma,et al.  Cigarette smoke-induced emphysema: A role for the B cell? , 2006, American journal of respiratory and critical care medicine.

[59]  S. Muro,et al.  Matrix metalloproteinase-9 promoter polymorphism associated with upper lung dominant emphysema. , 2005, American journal of respiratory and critical care medicine.

[60]  Sharyn MacDonald,et al.  Functional impairment in emphysema: contribution of airway abnormalities and distribution of parenchymal disease. , 2005, AJR. American journal of roentgenology.

[61]  Jan Stolk,et al.  Pattern of emphysema distribution in alpha1-antitrypsin deficiency influences lung function impairment. , 2004, American journal of respiratory and critical care medicine.

[62]  Irfan Rahman,et al.  Cigarette smoke alters chromatin remodeling and induces proinflammatory genes in rat lungs. , 2004, American journal of respiratory cell and molecular biology.

[63]  John D. Storey,et al.  Statistical significance for genomewide studies , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[64]  Steven Piantadosi,et al.  A randomized trial comparing lung-volume-reduction surgery with medical therapy for severe emphysema. , 2003, The New England journal of medicine.

[65]  L. Fabbri,et al.  Nuclear localisation of p65 in sputum macrophages but not in sputum neutrophils during COPD exacerbations. , 2003, Thorax.

[66]  I. Adcock,et al.  Increased expression of nuclear factor-κB in bronchial biopsies from smokers and patients with COPD , 2002, European Respiratory Journal.

[67]  D. Postma,et al.  Chronic obstructive pulmonary disease. , 2002, Clinical evidence.

[68]  F. Speizer,et al.  Expiratory and inspiratory forced vital capacity and one-second forced volume in asymptomatic never-smokers in Norway. , 2001, Clinical physiology.

[69]  H. Tanaka,et al.  Lobar distribution of emphysema in computed tomographic densitometric analysis. , 2000, Investigative radiology.

[70]  S Muro,et al.  Comparison of low attenuation areas on computed tomographic scans between inner and outer segments of the lung in patients with chronic obstructive pulmonary disease: incidence and contribution to lung function , 1999, Thorax.

[71]  P. Paré,et al.  A quantification of the lung surface area in emphysema using computed tomography. , 1999, American journal of respiratory and critical care medicine.

[72]  A. Conde.  Staphylococcus aureus infections. , 1998, The New England journal of medicine.

[73]  J E Cotes,et al.  Lung volumes and forced ventilatory flows. Report Working Party Standardization of Lung Function Tests, European Community for Steel and Coal. Official Statement of the European Respiratory Society. , 1993, The European respiratory journal. Supplement.

[74]  J. Gurney.  Cross-sectional physiology of the lung. , 1991, Radiology.

[75]  J B West,et al.  Distribution of mechanical stress in the lung, a possible factor in localisation of pulmonary disease. , 1971, Lancet.