DNAH5 is associated with total lung capacity in chronic obstructive pulmonary disease

Respiratory Research

Craig P Hersh⁴  Edwin K Silverman⁴  Per S Bakke²  Harvey O Coxson¹  David A Lomas⁵  James D Crapo³  David A Lynch³  Nathaniel Marchetti⁸  Gary M Hunninghake⁴  Peter J Castaldi⁷  Emily S Wan⁴  Michael H Cho⁴  Merry-Lynn N McDonald⁷  Jin Hwa Lee⁶ 

[1] Department of Radiology, University of British Columbia, Vancouver, Canada;Department of Thoracic Medicine, Haukeland University Hospital, Bergen, Norway;National Jewish Health, Denver, CO, USA;Division of Pulmonary and Critical Care, Brigham and Women¿s Hospital, Boston, MA, USA;Wolfson Institute for Biomedical Research, University College London, London, UK;Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, School of Medicine, Ewha Womans University, Seoul, South Korea;Channing Division of Network Medicine, Brigham and Women¿s Hospital, 181 Longwood Avenue, Boston 02115, MA, USA;Division of Pulmonary and Critical Care Medicine, Department of Medicine, Temple University School of Medicine, Philadelphia, PA, USA

关键词: DNAH5;    Total lung capacity;    Genome-wide association analysis;    Hyperinflation;    Chronic obstructive;    Pulmonary disease;   

Others  :  1146267
DOI  :  10.1186/s12931-014-0097-y

 received in 2014-04-04, accepted in 2014-08-07,  发布年份 2014

【 摘 要 】

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 with at least moderate airflow obstruction, defined by a ratio of forced expiratory volume in 1 second to forced vital capacity (FEV₁/FVC) <0.7 and FEV₁?CT). Genotyping in each cohort was completed, with statistical imputation of additional markers. To find genetic variants associated with TLC_CT, linear regression models were used, with adjustment for age, sex, pack-years of smoking, height, and principal components for genetic ancestry. Results were summarized using fixed-effect meta-analysis.

Results

Analysis of a total of 4,543 COPD subjects identified one genome-wide significant locus on chromosome 5p15.2 (rs114929486, ??=?0.42L, P?=?4.66?×?10^?8).

Conclusions

In COPD, TLC_CT was associated with a SNP in dynein, axonemal, heavy chain 5 (DNAH5), a gene in which genetic variants can cause primary ciliary dyskinesia. DNAH5 could have an effect on hyperinflation in COPD.

【 授权许可】

   
2014 Lee et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

【 参考文献 】

• [1]The state of US health, 1990-2010: burden of diseases, injuries, and risk factors.JAMA 2013, 310:591¿608.
• [2]Hallberg J, Dominicus A, Eriksson UK, Gerhardsson de Verdier M, Pedersen NL, Dahlback M, Nihlen U, Higenbottam T, Svartengren M: Interaction between smoking and genetic factors in the development of chronic bronchitis. Am J Respir Crit Care Med 2008, 177:486-490.
• [3]Vestbo J, Hurd SS, Agusti AG, Jones PW, Vogelmeier C, Anzueto A, Barnes PJ, Fabbri LM, Martinez FJ, Nishimura M, Stockley RA, Sin DD, Rodriguez-Roisin R: Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med 2013, 187:347-365.
• [4]Agusti A, Calverley PM, Celli B, Coxson HO, Edwards LD, Lomas DA, MacNee W, Miller BE, Rennard S, Silverman EK, Tal-Singer R, Wouters E, Yates JC, Vestbo J: Characterisation of COPD heterogeneity in the ECLIPSE cohort. Respir Res 2010, 11:122.
• [5]O'Donnell DE: Hyperinflation, dyspnea, and exercise intolerance in chronic obstructive pulmonary disease. Proc Am Thorac Soc 2006, 3:180-184.
• [6]Casaburi R, Porszasz J: Reduction of hyperinflation by pharmacologic and other interventions. Proc Am Thorac Soc 2006, 3:185-189.
• [7]Casanova C, Cote C, de Torres JP, Aguirre-Jaime A, Marin JM, Pinto-Plata V, Celli BR: Inspiratory-to-total lung capacity ratio predicts mortality in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2005, 171:591-597.
• [8]Bancalari E, Clausen J: Pathophysiology of changes in absolute lung volumes. Eur Respir J 1998, 12:248-258.
• [9]Cho MH, Castaldi PJ, Wan ES, Siedlinski M, Hersh CP, DeMeo DL, Himes BE, Sylvia JS, Klanderman BJ, Ziniti JP, Lange C, Litonjua AA, Sparrow D, Regan EA, Make BJ, Hokanson JE, Murray T, Hetmanski JB, Pillai SG, Kong X, Anderson WH, Tal-Singer R, Lomas DA, Coxson HO, Edwards LD, MacNee W, Vestbo J, Yates JC, Agusti A, Calverley PM, et al.: A genome-wide association study of COPD identifies a susceptibility locus on chromosome 19q13. Hum Mol Genet 2012, 21:947-957.
• [10]Regan EA, Hokanson JE, Murphy JR, Make B, Lynch DA, Beaty TH, Curran-Everett D, Silverman EK, Crapo JD: Genetic epidemiology of COPD (COPDGene) study design. COPD 2010, 7:32-43.
• [11]Vestbo J, Anderson W, Coxson HO, Crim C, Dawber F, Edwards L, Hagan G, Knobil K, Lomas DA, MacNee W, Silverman EK, Tal-Singer R: Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points (ECLIPSE). Eur Respir J 2008, 31:869-873.
• [12]Zhu G, Warren L, Aponte J, Gulsvik A, Bakke P, Anderson WH, Lomas DA, Silverman EK, Pillai SG: The SERPINE2 gene is associated with chronic obstructive pulmonary disease in two large populations. Am J Respir Crit Care Med 2007, 176:167-173.
• [13]Grydeland TB, Dirksen A, Coxson HO, Pillai SG, Sharma S, Eide GE, Gulsvik A, Bakke PS: Quantitative computed tomography: emphysema and airway wall thickness by sex, age and smoking. Eur Respir J 2009, 34:858-865.
• [14]Cho MH, Boutaoui N, Klanderman BJ, Sylvia JS, Ziniti JP, Hersh CP, DeMeo DL, Hunninghake GM, Litonjua AA, Sparrow D, Lange C, Won S, Murphy JR, Beaty TH, Regan EA, Make BJ, Hokanson JE, Crapo JD, Kong X, Anderson WH, Tal-Singer R, Lomas DA, Bakke P, Gulsvik A, Pillai SG, Silverman EK: Variants in FAM13A are associated with chronic obstructive pulmonary disease. Nat Genet 2010, 42:200-202.
• [15]Cho MH, McDonald ML, Zhou X, Mattheisen M, Castaldi PJ, Hersh CP, Demeo DL, Sylvia JS, Ziniti J, Laird NM, Lange C, Litonjua AA, Sparrow D, Casaburi R, Barr RG, Regan EA, Make BJ, Hokanson JE, Lutz S, Dudenkov TM, Farzadegan H, Hetmanski JB, Tal-Singer R, Lomas DA, Bakke P, Gulsvik A, Crapo JD, Silverman EK, Beaty TH: Risk loci for chronic obstructive pulmonary disease: a genome-wide association study and meta-analysis. Lancet Respir Med 2014, 2:214-225.
• [16]Gietema HA, Edwards LD, Coxson HO, Bakke PS: Impact of emphysema and airway wall thickness on quality of life in smoking-related COPD. Respir Med 2013, 107:1201-1209.
• [17]Li Y, Willer CJ, Ding J, Scheet P, Abecasis GR: MaCH: using sequence and genotype data to estimate haplotypes and unobserved genotypes. Genet Epidemiol 2010, 34:816-834.
• [18]Howie B, Fuchsberger C, Stephens M, Marchini J, Abecasis GR: Fast and accurate genotype imputation in genome-wide association studies through pre-phasing. Nat Genet 2012, 44:955-959.
• [19]Abecasis GR, Auton A, Brooks LD, DePristo MA, Durbin RM, Handsaker RE, Kang HM, Marth GT, McVean GA: An integrated map of genetic variation from 1,092 human genomes. Nature 2012, 491:56-65.
• [20]Kong X, Cho MH, Anderson W, Coxson HO, Muller N, Washko G, Hoffman EA, Bakke P, Gulsvik A, Lomas DA, Silverman EK, Pillai SG: Genome-wide association study identifies BICD1 as a susceptibility gene for emphysema. Am J Respir Crit Care Med 2011, 183:43-49.
• [21]Pillai SG, Ge D, Zhu G, Kong X, Shianna KV, Need AC, Feng S, Hersh CP, Bakke P, Gulsvik A, Ruppert A, Lødrup Carlsen KC, Roses A, Anderson W, Rennard SI, Lomas DA, Silverman EK, Goldstein DB: A genome-wide association study in chronic obstructive pulmonary disease (COPD): identification of two major susceptibility loci. PLoS Genet 2009, 5:e1000421.
• [22]Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, Maller J, Sklar P, de Bakker PI, Daly MJ, Sham PC: PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet 2007, 81:559-575.
• [23]de Bakker PI, Ferreira MA, Jia X, Neale BM, Raychaudhuri S, Voight BF: Practical aspects of imputation-driven meta-analysis of genome-wide association studies. Hum Mol Genet 2008, 17:R122-R128.
• [24]Willer CJ, Li Y, Abecasis GR: METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics 2010, 26:2190-2191.
• [25]Higgins JP, Thompson SG, Deeks JJ, Altman DG: Measuring inconsistency in meta-analyses. BMJ 2003, 327:557-560.
• [26]Han B, Eskin E: Random-effects model aimed at discovering associations in meta-analysis of genome-wide association studies. Am J Hum Genet 2011, 88:586-598.
• [27]Devlin B, Roeder K: Genomic control for association studies. Biometrics 1999, 55:997-1004.
• [28]Aulchenko YS, Ripke S, Isaacs A, van Duijn CM: GenABEL: an R library for genome-wide association analysis. Bioinformatics 2007, 23:1294-1296.
• [29]Pruim RJ, Welch RP, Sanna S, Teslovich TM, Chines PS, Gliedt TP, Boehnke M, Abecasis GR, Willer CJ: LocusZoom: regional visualization of genome-wide association scan results. Bioinformatics 2010, 26:2336-2337.
• [30]Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls Nature 2007, 447:661-678.
• [31]Failly M, Bartoloni L, Letourneau A, Munoz A, Falconnet E, Rossier C, de Santi MM, Santamaria F, Sacco O, DeLozier-Blanchet CD, Lazor R, Blouin JL: Mutations in DNAH5 account for only 15% of a non-preselected cohort of patients with primary ciliary dyskinesia. J Med Genet 2009, 46:281-286.
• [32]Hornef N, Olbrich H, Horvath J, Zariwala MA, Fliegauf M, Loges NT, Wildhaber J, Noone PG, Kennedy M, Antonarakis SE, Blouin JL, Bartoloni L, Nüsslein T, Ahrens P, Griese M, Kuhl H, Sudbrak R, Knowles MR, Reinhardt R, Omran H: DNAH5 mutations are a common cause of primary ciliary dyskinesia with outer dynein arm defects. Am J Respir Crit Care Med 2006, 174:120-126.
• [33]Leigh MW, Pittman JE, Carson JL, Ferkol TW, Dell SD, Davis SD, Knowles MR, Zariwala MA: Clinical and genetic aspects of primary ciliary dyskinesia/Kartagener syndrome. Genet Med 2009, 11:473-487.
• [34]Green K, Buchvald FF, Marthin JK, Hanel B, Gustafsson PM, Nielsen KG: Ventilation inhomogeneity in children with primary ciliary dyskinesia. Thorax 2012, 67:49-53.
• [35]Stanescu D: Small airways obstruction syndrome. Chest 1999, 116:231-233.
• [36]Pifferi M, Bush A, Pioggia G, Caramella D, Tartarisco G, Di CM, Zangani M, Chinellato I, Maggi F, Tezza G, Macchia P, Boner A: Evaluation of pulmonary disease using static lung volumes in primary ciliary dyskinesia. Thorax 2012, 67:993-999.
• [37]Hogg JC, Macklem PT, Thurlbeck WM: Site and nature of airway obstruction in chronic obstructive lung disease. N Engl J Med 1968, 278:1355-1360.
• [38]McDonough JE, Yuan R, Suzuki M, Seyednejad N, Elliott WM, Sanchez PG, Wright AC, Gefter WB, Litzky L, Coxson HO, Paré PD, Sin DD, Pierce RA, Woods JC, McWilliams AM, Mayo JR, Lam SC, Cooper JD, Hogg JC: Small-airway obstruction and emphysema in chronic obstructive pulmonary disease. N Engl J Med 2011, 365:1567-1575.
• [39]Yanai M, Sekizawa K, Ohrui T, Sasaki H, Takishima T: Site of airway obstruction in pulmonary disease: direct measurement of intrabronchial pressure. J Appl Physiol (1985) 1992, 72:1016-1023.
• [40]Buro-Auriemma LJ, Salit J, Hackett NR, Walters MS, Strulovici-Barel Y, Staudt MR, Fuller J, Mahmoud M, Stevenson CS, Hilton H, Ho MW, Crystal RG: Cigarette smoking induces small airway epithelial epigenetic changes with corresponding modulation of gene expression. Hum Mol Genet 2013, 22:4726-4738.
• [41]Blair DR, Lyttle CS, Mortensen JM, Bearden CF, Jensen AB, Khiabanian H, Melamed R, Rabadan R, Bernstam EV, Brunak S, Jensen LJ, Nicolae D, Shah NH, Grossman RL, Cox NJ, White KP, Rzhetsky A: A nondegenerate code of deleterious variants in Mendelian loci contributes to complex disease risk. Cell 2013, 155:70-80.
• [42]Flintoft L: Disease genetics: A Mendelian code for complex disease. Nat Rev Genet 2013, 14:746.
• [43]Knowlden S, Georas SN: The Autotaxin-LPA Axis Emerges as a Novel Regulator of Lymphocyte Homing and Inflammation. J Immunol 2014, 192:851-857.
• [44]Oikonomou N, Mouratis MA, Tzouvelekis A, Kaffe E, Valavanis C, Vilaras G, Karameris A, Prestwich GD, Bouros D, Aidinis V: Pulmonary autotaxin expression contributes to the pathogenesis of pulmonary fibrosis. Am J Respir Cell Mol Biol 2012, 47:566-574.
• [45]Tager AM: Autotaxin emerges as a therapeutic target for idiopathic pulmonary fibrosis: limiting fibrosis by limiting lysophosphatidic acid synthesis. Am J Respir Cell Mol Biol 2012, 47:563-565.
• [46]Park GY, Lee YG, Berdyshev E, Nyenhuis S, Du J, Fu P, Gorshkova IA, Li Y, Chung S, Karpurapu M, Deng J, Ranjan R, Xiao L, Jaffe HA, Corbridge SJ, Kelly EA, Jarjour NN, Chun J, Prestwich GD, Kaffe E, Ninou I, Aidinis V, Morris AJ, Smyth SS, Ackerman SJ, Natarajan V, Christman JW: Autotaxin production of lysophosphatidic acid mediates allergic asthmatic inflammation. Am J Respir Crit Care Med 2013, 188:928-940.
• [47]Cheng HY, Dong A, Panchatcharam M, Mueller P, Yang F, Li Z, Mills G, Chun J, Morris AJ, Smyth SS: Lysophosphatidic acid signaling protects pulmonary vasculature from hypoxia-induced remodeling. Arterioscler Thromb Vasc Biol 2012, 32:24-32.
• [48]Zaporozhan J, Ley S, Eberhardt R, Weinheimer O, Iliyushenko S, Herth F, Kauczor HU: Paired inspiratory/expiratory volumetric thin-slice CT scan for emphysema analysis: comparison of different quantitative evaluations and pulmonary function test. Chest 2005, 128:3212-3220.
• [49]Coxson HO, Nasute Fauerbach PV, Storness-Bliss C, Muller NL, Cogswell S, Dillard DH, Finger CL, Springmeyer SC: Computed tomography assessment of lung volume changes after bronchial valve treatment. Eur Respir J 2008, 32:1443-1450.
• [50]Gierada DS, Hakimian S, Slone RM, Yusen RD: MR analysis of lung volume and thoracic dimensions in patients with emphysema before and after lung volume reduction surgery. Am J Roentgenol 1998, 170:707-714.
• [51]Kauczor HU, Heussel CP, Fischer B, Klamm R, Mildenberger P, Thelen M: Assessment of lung volumes using helical CT at inspiration and expiration: comparison with pulmonary function tests. Am J Roentgenol 1998, 171:1091-1095.
• [52]O'Donnell CR, Bankier AA, Stiebellehner L, Reilly JJ, Brown R, Loring SH: Comparison of plethysmographic and helium dilution lung volumes: which is best for COPD? Chest 2010, 137:1108-1115.