Genetic susceptibility for chronic bronchitis in chronic obstructive pulmonary disease

Jin Hwa Lee, Michael H Cho, Craig P Hersh, Merry-Lynn N McDonald, James D Crapo, Per S Bakke, Amund Gulsvik, Alejandro P Comellas, Christine H Wendt, David A Lomas, Victor Kim, Edwin K Silverman, COPDGene and ECLIPSE Investigators, Jin Hwa Lee, Michael H Cho, Craig P Hersh, Merry-Lynn N McDonald, James D Crapo, Per S Bakke, Amund Gulsvik, Alejandro P Comellas, Christine H Wendt, David A Lomas, Victor Kim, Edwin K Silverman, COPDGene and ECLIPSE Investigators

Abstract

Background: Chronic bronchitis (CB) is one of the classic phenotypes of COPD. The aims of our study were to investigate genetic variants associated with COPD subjects with CB relative to smokers with normal spirometry, and to assess for genetic differences between subjects with CB and without CB within the COPD population.

Methods: We analyzed data from current and former smokers from three cohorts: the COPDGene Study; GenKOLS (Bergen, Norway); and the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE). CB was defined as having a cough productive of phlegm on most days for at least 3 consecutive months per year for at least 2 consecutive years. CB COPD cases were defined as having both CB and at least moderate COPD based on spirometry. Our primary analysis used smokers with normal spirometry as controls; secondary analysis was performed using COPD subjects without CB as controls. Genotyping was performed on Illumina platforms; results were summarized using fixed-effect meta-analysis.

Results: For CB COPD relative to smoking controls, we identified a new genome-wide significant locus on chromosome 11p15.5 (rs34391416, OR = 1.93, P = 4.99 × 10-8) as well as significant associations of known COPD SNPs within FAM13A. In addition, a GWAS of CB relative to those without CB within COPD subjects showed suggestive evidence for association on 1q23.3 (rs114931935, OR = 1.88, P = 4.99 × 10-7).

Conclusions: We found genome-wide significant associations with CB COPD on 4q22.1 (FAM13A) and 11p15.5 (EFCAB4A, CHID1 and AP2A2), and a locus associated with CB within COPD subjects on 1q23.3 (RPL31P11 and ATF6). This study provides further evidence that genetic variants may contribute to phenotypic heterogeneity of COPD.

Trial registration: ClinicalTrials.gov NCT00608764, NCT00292552.

Figures

Figure 1
Figure 1
Genome-wide association study design for chronic bronchitis. Definition of abbreviations: CB = chronic bronchitis; COPD = chronic obstructive pulmonary disease; GOLD = Global initiative for chronic Obstructive Lung Disease. GOLD 2-4 was defined as having a post-bronchodilator FEV1/FVC < 0.7 and FEV1 < 80% predicted. Normal spirometry was defined as having a post-bronchodilator FEV1/FVC ≥ 0.7 and FEV1 ≥ 80% predicted.
Figure 2
Figure 2
The quantile–quantile plots for the three-cohort meta-analysis including 1000 Genomes project imputed data for (A) COPD subjects with chronic bronchitis (CB)versussmoking controls and (B) CBversusno CB within COPD subjects, after adjustment for age, sex, pack-years of cigarette smoking and genetic ancestry using principal components.
Figure 3
Figure 3
Manhattan plots of –log10Pvalues for meta-analysis of three cohorts for (A) COPD subjects with chronic bronchitis (CB)versussmoking controls and (B) CBversusno CB within COPD subjects, after adjustment for age, sex, pack-years of cigarette smoking and genetic ancestry using principal components.
Figure 4
Figure 4
Local association plots for significant loci in the meta-analysis of cases with chronic bronchitis and COPD versus smoking control subjects in COPDGene non-Hispanic whites, GenKOLS, and ECLIPSE. A. rs2869967 on chromosome 4q22.1. B. rs34391416 on 11p15. The x-axis is chromosomal position, and the y-axis shows the –log10 P value. The most significant SNP at each locus is labeled in purple, with other SNPs colored by degree of linkage disequilibrium (r2). Plots were created using LocusZoom.
Figure 5
Figure 5
Local association plots for the top two loci in the meta-analysis of COPD subjects with chronic bronchitis versus COPD subjects without chronic bronchitis in COPDGene non-Hispanic whites, GenKOLS, and ECLIPSE. A. rs114931935 on 1q23. B. rs924777 on 1q23. The x-axis is chromosomal position, and the y-axis shows the –log10 P value. The most significant SNP at each gene is labeled in purple, with other SNPs colored by degree of linkage disequilibrium (r2). Plots were created using LocusZoom.

References

    1. 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. doi: 10.1164/rccm.200704-565OC.
    1. Burrows B, Fletcher CM, Heard BE, Jones NL, Wootliff JS. The emphysematous and bronchial types of chronic airways obstruction. A clinicopathological study of patients in London and Chicago. Lancet. 1966;1:830–835. doi: 10.1016/S0140-6736(66)90181-4.
    1. Ferre A, Fuhrman C, Zureik M, Chouaid C, Vergnenegre A, Huchon G, Delmas MC, Roche N. Chronic bronchitis in the general population: influence of age, gender and socio-economic conditions. Respir Med. 2012;106:467–471. doi: 10.1016/j.rmed.2011.12.002.
    1. Patel BD, Coxson HO, Pillai SG, Agusti AG, Calverley PM, Donner CF, Make BJ, Muller NL, Rennard SI, Vestbo J, Wouters EF, Hiorns MP, Nakano Y, Camp PG, Nasute Fauerbach PV, Screaton NJ, Campbell EJ, Anderson WH, Paré PD, Levy RD, Lake SL, Silverman EK, Lomas DA, International COPD Genetics Network Airway wall thickening and emphysema show independent familial aggregation in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2008;178:500–505. doi: 10.1164/rccm.200801-059OC.
    1. Kong X, Cho MH, Anderson W, Coxson HO, Muller N, Washko G, Hoffman EA, Bakke P, Gulsvik A, Lomas DA, Silverman EK, Pillai SG, ECLIPSE Study NETT Investigators Genome-wide association study identifies BICD1 as a susceptibility gene for emphysema. Am J Respir Crit Care Med. 2011;183:43–49. doi: 10.1164/rccm.201004-0541OC.
    1. Kim V, Han MK, Vance GB, Make BJ, Newell JD, Hokanson JE, Hersh CP, Stinson D, Silverman EK, Criner GJ. The chronic bronchitic phenotype of COPD: an analysis of the COPDGene Study. Chest. 2011;140:626–633. doi: 10.1378/chest.10-2948.
    1. Kim V, Garfield JL, Grabianowski CL, Krahnke JS, Gaughan JP, Jacobs MR, Criner GJ. The effect of chronic sputum production on respiratory symptoms in severe COPD. COPD. 2011;8:114–120. doi: 10.3109/15412555.2011.558546.
    1. Burgel PR, Nesme-Meyer P, Chanez P, Caillaud D, Carre P, Perez T, Roche N. Cough and sputum production are associated with frequent exacerbations and hospitalizations in COPD subjects. Chest. 2009;135:975–982. doi: 10.1378/chest.08-2062.
    1. Silverman EK, Mosley JD, Palmer LJ, Barth M, Senter JM, Brown A, Drazen JM, Kwiatkowski DJ, Chapman HA, Campbell EJ, Province MA, Rao DC, Reilly JJ, Ginns LC, Speizer FE, Weiss ST. Genome-wide linkage analysis of severe, early-onset chronic obstructive pulmonary disease: airflow obstruction and chronic bronchitis phenotypes. Hum Mol Genet. 2002;11:623–632. doi: 10.1093/hmg/11.6.623.
    1. Zhu G, Agusti A, Gulsvik A, Bakke P, Coxson H, Lomas DA, Silverman EK, Pillai SG. CTLA4 gene polymorphisms are associated with chronic bronchitis. Eur Respir J. 2009;34:598–604. doi: 10.1183/09031936.00141808.
    1. Dijkstra AE, Smolonska J, van den Berge M, Wijmenga C, Zanen P, Luinge MA, Platteel M, Lammers JW, Dahlback M, Tosh K, Hiemstra PS, Sterk PJ, Spira A, Vestbo J, Nordestgaard BG, Benn M, Nielsen SF, Dahl M, Verschuren WM, Picavet HS, Smit HA, Owsijewitsch M, Kauczor HU, de Koning HJ, Nizankowska-Mogilnicka E, Mejza F, Nastalek P, van Diemen CC, Cho MH, Silverman EK, et al. Susceptibility to chronic mucus hypersecretion, a genome wide association study. PLoS One. 2014;9:e91621. doi: 10.1371/journal.pone.0091621.
    1. 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, ECLIPSE investigators Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points (ECLIPSE) Eur Respir J. 2008;31:869–873. doi: 10.1183/09031936.00111707.
    1. 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. doi: 10.3109/15412550903499522.
    1. 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. doi: 10.1164/rccm.200611-1723OC.
    1. Society AT. Chronic bronchitis, asthma and pulmonary emphysema: a statement by the Committee on Diagnostic Standards for Nontuberculous Respiratory Diseases. Am Rev Respir Dis. 1962;85:762–768.
    1. 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. doi: 10.1164/rccm.201204-0596PP.
    1. 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. doi: 10.1002/gepi.20533.
    1. 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. doi: 10.1038/ng.2354.
    1. 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. doi: 10.1038/nature11632.
    1. 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, ICGN Investigators A genome-wide association study in chronic obstructive pulmonary disease (COPD): identification of two major susceptibility loci. PLoS Genet. 2009;5:e1000421. doi: 10.1371/journal.pgen.1000421.
    1. 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. doi: 10.1038/ng.535.
    1. 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. A genome-wide association study of COPD identifies a susceptibility locus on chromosome 19q13. Hum Mol Genet. 2012;21:947–957. doi: 10.1093/hmg/ddr524.
    1. 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, NETT Genetics, ICGN, ECLIPSE and COPDGene Investigators Risk loci for chronic obstructive pulmonary disease: a genome-wide association study and meta-analysis. Lancet Respir Med. 2014;2:214–225. doi: 10.1016/S2213-2600(14)70002-5.
    1. 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. doi: 10.1086/519795.
    1. 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. doi: 10.1093/hmg/ddn288.
    1. Willer CJ, Li Y, Abecasis GR. METAL: fast and efficient meta-analysis of genomewide association scans. Bioinformatics. 2010;26:2190–2191. doi: 10.1093/bioinformatics/btq340.
    1. Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327:557–560. doi: 10.1136/bmj.327.7414.557.
    1. 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. doi: 10.1016/j.ajhg.2011.04.014.
    1. Devlin B, Roeder K. Genomic control for association studies. Biometrics. 1999;55:997–1004. doi: 10.1111/j.0006-341X.1999.00997.x.
    1. Aulchenko YS, Ripke S, Isaacs A, van Duijn CM. GenABEL: an R library for genome-wide association analysis. Bioinformatics. 2007;23:1294–1296. doi: 10.1093/bioinformatics/btm108.
    1. 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. doi: 10.1093/bioinformatics/btq419.
    1. Hancock DB, Artigas MS, Gharib SA, Henry A, Manichaikul A, Ramasamy A, Loth DW, Imboden M, Koch B, McArdle WL, Smith AV, Smolonska J, Sood A, Tang W, Wilk JB, Zhai G, Zhao JH, Aschard H, Burkart KM, Curjuric I, Eijgelsheim M, Elliott P, Gu X, Harris TB, Janson C, Homuth G, Hysi PG, Liu JZ, Loehr LR, Lohman K, et al. Genome-wide joint meta-analysis of SNP and SNP-by-smoking interaction identifies novel loci for pulmonary function. PLoS Genet. 2012;8:e1003098. doi: 10.1371/journal.pgen.1003098.
    1. Hancock DB, Eijgelsheim M, Wilk JB, Gharib SA, Loehr LR, Marciante KD, Franceschini N, van Durme YM, Chen TH, Barr RG, Schabath MB, Couper DJ, Brusselle GG, Psaty BM, van Duijn CM, Rotter JI, Uitterlinden AG, Hofman A, Punjabi NM, Rivadeneira F, Morrison AC, Enright PL, North KE, Heckbert SR, Lumley T, Stricker BH, O'Connor GT, London SJ. Meta-analyses of genome-wide association studies identify multiple loci associated with pulmonary function. Nat Genet. 2010;42:45–52. doi: 10.1038/ng.500.
    1. Rose MC, Voynow JA. Respiratory tract mucin genes and mucin glycoproteins in health and disease. Physiol Rev. 2006;86:245–278. doi: 10.1152/physrev.00010.2005.
    1. Thai P, Loukoianov A, Wachi S, Wu R. Regulation of airway mucin gene expression. Annu Rev Physiol. 2008;70:405–429. doi: 10.1146/annurev.physiol.70.113006.100441.
    1. Rossi AH, Salmon WC, Chua M, Davis CW. Calcium signaling in human airway goblet cells following purinergic activation. Am J Physiol Lung Cell Mol Physiol. 2007;292:L92–L98. doi: 10.1152/ajplung.00081.2006.
    1. Manral S, Bhatia S, Sinha R, Kumar A, Rohil V, Arya A, Dhawan A, Arya P, Joshi R, Sreedhara SC, Gangopadhyay S, Bansal SK, Chatterjee S, Chaudhury NK, Vijayan VK, Saso L, Parmar VS, DePass AL, Prasad AK, Raj HG. Normalization of deranged signal transduction in lymphocytes of COPD patients by the novel calcium channel blocker H-DHPM. Biochimie. 2011;93:1146–1156. doi: 10.1016/j.biochi.2011.04.004.
    1. Ross AJ, Dailey LA, Brighton LE, Devlin RB. Transcriptional profiling of mucociliary differentiation in human airway epithelial cells. Am J Respir Cell Mol Biol. 2007;37:169–185. doi: 10.1165/rcmb.2006-0466OC.
    1. Yanai I, Benjamin H, Shmoish M, Chalifa-Caspi V, Shklar M, Ophir R, Bar-Even A, Horn-Saban S, Safran M, Domany E, Lancet D, Shmueli O. Genome-wide midrange transcription profiles reveal expression level relationships in human tissue specification. Bioinformatics. 2005;21:650–659. doi: 10.1093/bioinformatics/bti042.
    1. Meng G, Zhao Y, Bai X, Liu Y, Green TJ, Luo M, Zheng X. Structure of human stabilin-1 interacting chitinase-like protein (SI-CLP) reveals a saccharide-binding cleft with lower sugar-binding selectivity. J Biol Chem. 2010;285:39898–39904. doi: 10.1074/jbc.M110.130781.
    1. Kzhyshkowska J, Mamidi S, Gratchev A, Kremmer E, Schmuttermaier C, Krusell L, Haus G, Utikal J, Schledzewski K, Scholtze J, Goerdt S. Novel stabilin-1 interacting chitinase-like protein (SI-CLP) is up-regulated in alternatively activated macrophages and secreted via lysosomal pathway. Blood. 2006;107:3221–3228. doi: 10.1182/blood-2005-07-2843.
    1. Lee CG, Da Silva CA, Lee JY, Hartl D, Elias JA. Chitin regulation of immune responses: an old molecule with new roles. Curr Opin Immunol. 2008;20:684–689. doi: 10.1016/j.coi.2008.10.002.
    1. Letuve S, Kozhich A, Humbles A, Brewah Y, Dombret MC, Grandsaigne M, Adle H, Kolbeck R, Aubier M, Coyle AJ, Pretolani M. Lung chitinolytic activity and chitotriosidase are elevated in chronic obstructive pulmonary disease and contribute to lung inflammation. Am J Pathol. 2010;176:638–649. doi: 10.2353/ajpath.2010.090455.
    1. Letuve S, Kozhich A, Arouche N, Grandsaigne M, Reed J, Dombret MC, Kiener PA, Aubier M, Coyle AJ, Pretolani M. YKL-40 is elevated in patients with chronic obstructive pulmonary disease and activates alveolar macrophages. J Immunol. 2008;181:5167–5173. doi: 10.4049/jimmunol.181.7.5167.
    1. Aminuddin F, Akhabir L, Stefanowicz D, Pare PD, Connett JE, Anthonisen NR, Fahy JV, Seibold MA, Burchard EG, Eng C, Gulsvik A, Bakke P, Cho MH, Litonjua A, Lomas DA, Anderson WH, Beaty TH, Crapo JD, Silverman EK, Sandford AJ. Genetic association between human chitinases and lung function in COPD. Hum Genet. 2012;131:1105–1114. doi: 10.1007/s00439-011-1127-1.
    1. Chen H, Fre S, Slepnev VI, Capua MR, Takei K, Butler MH, Di Fiore PP, De CP. Epsin is an EH-domain-binding protein implicated in clathrin-mediated endocytosis. Nature. 1998;394:793–797. doi: 10.1038/28660.
    1. Okabayashi Y, Sugimoto Y, Totty NF, Hsuan J, Kido Y, Sakaguchi K, Gout I, Waterfield MD, Kasuga M. Interaction of Shc with adaptor protein adaptins. J Biol Chem. 1996;271:5265–5269. doi: 10.1074/jbc.271.9.5265.
    1. Gosalia N, Leir SH, Harris A. Coordinate regulation of the gel-forming mucin genes at chromosome 11p15.5. J Biol Chem. 2013;288:6717–6725. doi: 10.1074/jbc.M112.437400.
    1. Vinall LE, Fowler JC, Jones AL, Kirkbride HJ, de BC, Laine A, Porchet N, Gum JR, Kim YS, Moss FM, Mitchell DM, Swallow DM. Polymorphism of human mucin genes in chest disease: possible significance of MUC2. Am J Respir Cell Mol Biol. 2000;23:678–686. doi: 10.1165/ajrcmb.23.5.4176.
    1. Rousseau K, Byrne C, Griesinger G, Leung A, Chung A, Hill AS, Swallow DM. Allelic association and recombination hotspots in the mucin gene (MUC) complex on chromosome 11p15.5. Ann Hum Genet. 2007;71:561–569. doi: 10.1111/j.1469-1809.2007.00374.x.
    1. Hao K, Bosse Y, Nickle DC, Pare PD, Postma DS, Laviolette M, Sandford A, Hackett TL, Daley D, Hogg JC, Elliott WM, Couture C, Lamontagne M, Brandsma CA, van den Berge M, Koppelman G, Reicin AS, Nicholson DW, Malkov V, Derry JM, Suver C, Tsou JA, Kulkarni A, Zhang C, Vessey R, Opiteck GJ, Curtis SP, Timens W, Sin DD. Lung eQTLs to help reveal the molecular underpinnings of asthma. PLoS Genet. 2012;8:e1003029. doi: 10.1371/journal.pgen.1003029.
    1. Bartoszewski R, Rab A, Twitty G, Stevenson L, Fortenberry J, Piotrowski A, Dumanski JP, Bebok Z. The mechanism of cystic fibrosis transmembrane conductance regulator transcriptional repression during the unfolded protein response. J Biol Chem. 2008;283:12154–12165. doi: 10.1074/jbc.M707610200.
    1. Kerbiriou M, Le Drevo MA, Ferec C, Trouve P. Coupling cystic fibrosis to endoplasmic reticulum stress: differential role of Grp78 and ATF6. Biochim Biophys Acta. 2007;1772:1236–1249. doi: 10.1016/j.bbadis.2007.10.004.
    1. Cantin AM, Hanrahan JW, Bilodeau G, Ellis L, Dupuis A, Liao J, Zielenski J, Durie P. Cystic fibrosis transmembrane conductance regulator function is suppressed in cigarette smokers. Am J Respir Crit Care Med. 2006;173:1139–1144. doi: 10.1164/rccm.200508-1330OC.
    1. Dransfield MT, Wilhelm AM, Flanagan B, Courville C, Tidwell SL, Raju SV, Gaggar A, Steele C, Tang LP, Liu B, Rowe SM. Acquired cystic fibrosis transmembrane conductance regulator dysfunction in the lower airways in COPD. Chest. 2013;144:498–506. doi: 10.1378/chest.13-0274.
    1. Lambert JA, Raju SV, Tang LP, McNicholas CM, Li Y, Courville CA, Farris RF, Coricor GE, Smoot LH, Mazur MM, Dransfield MT, Bolger GB, Rowe SM. Cystic fibrosis transmembrane conductance regulator activation by roflumilast contributes to therapeutic benefit in chronic bronchitis. Am J Respir Cell Mol Biol. 2014;50:549–558. doi: 10.1165/rcmb.2013-0228OC.
    1. Fliegauf M, Frohlich C, Horvath J, Olbrich H, Hildebrandt F, Omran H. Identification of the human CYS1 gene and candidate gene analysis in Boichis disease. Pediatr Nephrol. 2003;18:498–505.
    1. Orlandi I, Moroni C, Camiciottoli G, Bartolucci M, Pistolesi M, Villari N, Mascalchi M. Chronic obstructive pulmonary disease: thin-section CT measurement of airway wall thickness and lung attenuation. Radiology. 2005;234:604–610. doi: 10.1148/radiol.2342040013.

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