Please wait a minute...
Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

Postal Subscription Code 80-967

2018 Impact Factor: 1.847

Front Med    2013, Vol. 7 Issue (4) : 425-432    https://doi.org/10.1007/s11684-013-0295-x
REVIEW
Heterogeneity of chronic obstructive pulmonary disease: from phenotype to genotype
Xu Chen1, Xiaomao Xu2, Fei Xiao1()
1. Key Laboratory of Geriatrics, Beijing Institute of Geriatrics; 2. Department of Respiratory Medicine, Beijing Hospital, Ministry of Health, Beijing 100730, China
 Download: PDF(186 KB)   HTML
 Export: BibTeX | EndNote | Reference Manager | ProCite | RefWorks
Abstract

Chronic obstructive pulmonary disease (COPD) is one of the leading causes of morbidity and mortality throughout the world and is mainly characterized by persistent airflow limitation. Given that multiple systems other than the lung can be impaired in COPD patients, the traditional FEV1/FVC ratio shows many limitations in COPD diagnosis and assessment. Certain heterogeneities are found in terms of clinical manifestations, physiology, imaging findings, and inflammatory reactions in COPD patients; thus, phenotyping can provide effective information for the prognosis and treatment. However, phenotypes are often based on symptoms or pathophysiological impairments in late-stage COPD, and the role of phenotypes in COPD prevention and early diagnosis remains unclear. This shortcoming may be overcome by the potential genotypes defined by the heterogeneities in certain genes. This review briefly describes the heterogeneity of COPD, with focus on recent advances in the correlations between genotypes and phenotypes. The potential roles of these genotypes and phenotypes in the molecular mechanisms and management of COPD are also elucidated.

Keywords chronic obstructive pulmonary disease      heterogeneity      phenotype      genotype      prediction     
Corresponding Author(s): Xiao Fei,Email:xiaofei@bjhmoh.cn   
Issue Date: 05 December 2013
 Cite this article:   
Xu Chen,Xiaomao Xu,Fei Xiao. Heterogeneity of chronic obstructive pulmonary disease: from phenotype to genotype[J]. Front Med, 2013, 7(4): 425-432.
 URL:  
https://academic.hep.com.cn/fmd/EN/10.1007/s11684-013-0295-x
https://academic.hep.com.cn/fmd/EN/Y2013/V7/I4/425
PhenotypesDescriptions
Clinical phenotypeIncluding age, gender, smoking history, ethnicity, etc.
Rapid decline in FEV1A distinct phenotype; the rate may decrease after smoking cessation
Imaging phenotypeLung structural abnormalities measured by CT or quantitative CT
AECOPDMore severe impairments and higher risks of hospitalization and death
Systemic inflammationCOPD is also an inflammatory response to noxious stimuli
Lymphatic vessels phenotypeReflects the stages by the changes of distal lung immune cell traffic
ComorbiditiesChronic bronchitis, cardiovascular diseases, asthma, diabetes, etc.
Tab.1  Phenotypes of COPD
PhenotypeGeneGenotypeFunction
Clinical
SmokingET-1[44]198G/GHigher incidence of COPD in smokers (-)
CHRNA3/5[45-50]rs6495309 C/T& T/Trs8034191 C/CSignificantly decreased risk of COPD (+)Population attributable risk of 12.2% (-)
EPHX1[61]H139RWeakly protective, significant in Asian(+)
Physiological
FEV1MMP12[53]rs2276109 G/GReduced risk of the onset of COPD (+)
SOD3[54]rs8192287 G/Trs8192288 G/THigher risk, reduced FEV1% predicted and FVC%predicted (-)
HHIP[55]rs11938704rs10013495Significantly associated with FEV1 in subjects with COPD
Imaging
EmphysemaSERPINA1[43]PI Z/ZIncidence:1% to 2%; Highest risk of COPD(-)
MMP-9[54]-1562C/TAlter promoter activity, increased risk (-)
Inflammation
IL6/IL6R[56]rs4129267 C/TSmoking induced inflammation (-)
IL1RN[58]*2 AllelesStrong risk of COPD in Asian females (-)
TNFA[56,57]-308A alleleRisk for the development of COPD (-)
TNFB1[57]rs2241712 A/GProtective (+)
rs1982073 T/C
rs1800469 C/T
rs6957 A/GIncreased risk of COPD (-)
Tab.2  Correlations between the phenotypes and genotypes of COPD
Fig.1  Interactions among different COPD factors
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(4): 347–365
doi: 10.1164/rccm.201204-0596PP pmid:22878278
2 Salvi SS, Barnes PJ. Chronic obstructive pulmonary disease in non-smokers. Lancet 2009; 374(9691): 733–743
doi: 10.1016/S0140-6736(09)61303-9 pmid:19716966
3 Halbert RJ, Natoli JL, Gano A, Badamgarav E, Buist AS, Mannino DM. Global burden of COPD: systematic review and meta-analysis. Eur Respir J 2006; 28(3): 523–532
doi: 10.1183/09031936.06.00124605 pmid:16611654
4 Mathers CD, Loncar D. Projections of global mortality and burden of disease from 2002 to 2030. PLoS Med 2006; 3(11): e442
doi: 10.1371/journal.pmed.0030442 pmid:17132052
5 Corhay JL, Frusch N, Louis R. COPD: genetics and environmental interactions. Rev Med Liege 2012; 67(5–6): 292–297 (in French)
pmid:22891481
6 Force USPST. Screening for chronic obstructive pulmonary disease using spirometry: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 2008; 148(7): 529–534
doi: 10.7326/0003-4819-148-7-200804010-00212 pmid:18316747
7 van Dijk WD. Does spirometry still measure up in the diagnosis of COPD? Chest 2013; 143(1): 276–277
doi: 10.1378/chest.12-2083 pmid:23276864
8 Mohamed Hoesein FA, Zanen P, Lammers JW. Lower limit of normal or FEV1/FVC<0.70 in diagnosing COPD: an evidence-based review. Respir Med 2011; 105(6): 907–915
doi: 10.1016/j.rmed.2011.01.008 pmid:21295958
9 Han MK, Kim MG, Mardon R, Renner P, Sullivan S, Diette GB, Martinez FJ. Spirometry utilization for COPD: how do we measure up? Chest 2007; 132(2): 403–409
doi: 10.1378/chest.06-2846 pmid:17550936
10 Cerveri I, Corsico AG, Accordini S, Niniano R, Ansaldo E, Antó JM, Künzli N, Janson C, Sunyer J, Jarvis D, Svanes C, Gislason T, Heinrich J, Schouten JP, Wjst M, Burney P, de Marco R. Underestimation of airflow obstruction among young adults using FEV1/FVC<70% as a fixed cut-off: a longitudinal evaluation of clinical and functional outcomes. Thorax 2008; 63(12): 1040–1045
doi: 10.1136/thx.2008.095554 pmid:18492741
11 Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease, updated 2013. Global initiative for Chronic Obstructive Lung Disease, Inc .
12 Carolan BJ, Sutherland ER. Clinical phenotypes of chronic obstructive pulmonary disease and asthma: recent advances. J Allergy Clin Immunol 2013; 131(3): 627–634, quiz 635
doi: 10.1016/j.jaci.2013.01.010 pmid:23360757
13 Han MK, Agusti A, Calverley PM, Celli BR, Criner G, Curtis JL, Fabbri LM, Goldin JG, Jones PW, Macnee W, Make BJ, Rabe KF, Rennard SI, Sciurba FC, Silverman EK, Vestbo J, Washko GR, Wouters EF, Martinez FJ. Chronic obstructive pulmonary disease phenotypes: the future of COPD. Am J Respir Crit Care Med 2010; 182(5): 598–604
doi: 10.1164/rccm.200912-1843CC pmid:20522794
14 Han MK, Postma D, Mannino DM, Giardino ND, Buist S, Curtis JL, Martinez FJ. Gender and chronic obstructive pulmonary disease: why it matters. Am J Respir Crit Care Med 2007; 176(12): 1179–1184
doi: 10.1164/rccm.200704-553CC pmid:17673696
15 Blanchette CM, Berry SR, Lane SJ. Advances in chronic obstructive pulmonary disease among older adults. Curr Opin Pulm Med 2011; 17(2): 84–89
doi: 10.1097/MCP.0b013e32834316ff pmid:21178625
16 Kamil F, Pinzon I, Foreman MG. Sex and race factors in early-onset COPD. Curr Opin Pulm Med 2013; 19(2): 140–144
doi: 10.1097/MCP.0b013e32835d903b pmid:23361195
17 Li Y, Yamagishi K, Yatsuya H, Tamakoshi A, Iso H. Smoking cessation and COPD mortality among Japanese men and women: the JACC study. Prev Med 2012; 55(6): 639–643
doi: 10.1016/j.ypmed.2012.09.006 pmid:22982769
18 Silva RO. Clinical phenotypes in chronic obstructive pulmonary disease. Rev Med Chil 2012; 140(7): 926–933 (in Spanish)
pmid:23282708
19 Celli B, Vestbo J, Jenkins CR, Jones PW, Ferguson GT, Calverley PM, Yates JC, Anderson JA, Willits LR, Wise RA; Investigators of the TS. Sex differences in mortality and clinical expressions of patients with chronic obstructive pulmonary disease. The TORCH experience. Am J Respir Crit Care Med 2011; 183(3): 317–322
doi: 10.1164/rccm.201004-0665OC pmid:20813884
20 Devanarayan V, Scholand MB, Hoidal J, Leppert MF, Crackower MA, O’Neill GP, Gervais FG. Identification of distinct plasma biomarker signatures in patients with rapid and slow declining forms of COPD. COPD 2010; 7(1): 51–58
doi: 10.3109/15412550903499530 pmid:20214463
21 Lee PN, Fry JS. Systematic review of the evidence relating FEV1 decline to giving up smoking. BMC Med 2010; 8(1): 84
doi: 10.1186/1741-7015-8-84 pmid:21156048
22 Wise RA. The value of forced expiratory volume in 1 second decline in the assessment of chronic obstructive pulmonary disease progression. Am J Med 2006; 119(10 Suppl 1): 4–11
doi: 10.1016/j.amjmed.2006.08.002 pmid:16996894
23 Lindberg A, Larsson LG, R?nmark E, Jonsson AC, Larsson K, Lundb?ck B. Decline in FEV1 in relation to incident chronic obstructive pulmonary disease in a cohort with respiratory symptoms. COPD 2007; 4(1): 5–13
doi: 10.1080/15412550601168358 pmid:17364672
24 Ley-Zaporozhan J, van Beek EJ. Imaging phenotypes of chronic obstructive pulmonary disease. J Magn Reson Imaging 2010; 32(6): 1340–1352
doi: 10.1002/jmri.22376 pmid:21105139
25 Galbán CJ, Han MK, Boes JL, Chughtai KA, Meyer CR, Johnson TD, Galbán S, Rehemtulla A, Kazerooni EA, Martinez FJ, Ross BD. Computed tomography-based biomarker provides unique signature for diagnosis of COPD phenotypes and disease progression. Nat Med 2012; 18(11): 1711–1715
doi: 10.1038/nm.2971 pmid:23042237
26 Han MK, Kazerooni EA, Lynch DA, Liu LX, Murray S, Curtis JL, Criner GJ, Kim V, Bowler RP, Hanania NA, Anzueto AR, Make BJ, Hokanson JE, Crapo JD, Silverman EK, Martinez FJ, Washko GR; the COPDGene Investigators.Chronic obstructive pulmonary disease exacerbations in the COPDGene study: associated radiologic phenotypes. Radiology 2011; 261(1): 274–282
doi: 10.1148/radiol.11110173 pmid:21788524
27 Hansel NN, Washko GR, Foreman MG, Han MK, Hoffman EA, DeMeo DL, Barr RG, Van Beek EJ, Kazerooni EA, Wise RA, Brown RH, Black-Shinn J, Hokanson JE, Hanania NA, Make B, Silverman EK, Crapo JD, Dransfield MT; COPDGene Investigators. Racial differences in CT phenotypes in COPD. COPD 2013; 10(1): 20–27
doi: 10.3109/15412555.2012.727921 pmid:23413893
28 Burge S, Wedzicha JA. COPD exacerbations: definitions and classifications. Eur Respir J Suppl 2003; 21(41 Supplement): 46s–53s
doi: 10.1183/09031936.03.00078002 pmid:12795331
29 Holloway RA, Donnelly LE. Immunopathogenesis of chronic obstructive pulmonary disease. Curr Opin Pulm Med 2013; 19(2): 95–102
doi: 10.1097/MCP.0b013e32835cfff5 pmid:23325031
30 Agustí A, Edwards LD, Rennard SI, MacNee W, Tal-Singer R, Miller BE, Vestbo J, Lomas DA, Calverley PM, Wouters E, Crim C, Yates JC, Silverman EK, Coxson HO, Bakke P, Mayer RJ, Celli B;Evaluation of CLtIPSEI. Persistent systemic inflammation is associated with poor clinical outcomes in COPD: a novel phenotype. PLoS ONE 2012; 7(5): e37483
doi: 10.1371/journal.pone.0037483 pmid:22624038
31 Mori M, Andersson CK, Graham GJ, L?fdahl CG, Erjef?lt JS. Increased number and altered phenotype of lymphatic vessels in peripheral lung compartments of patients with COPD. Respir Res 2013; 14(1): 65
doi: 10.1186/1465-9921-14-65 pmid:23758732
32 Carlin BW. COPD and associated comorbidities: a review of current diagnosis and treatment. Postgrad Med 2012; 124(4): 225–240
doi: 10.3810/pgm.2012.07.2582 pmid:22913911
33 Sin DD, Anthonisen NR, Soriano JB, Agusti AG. Mortality in COPD: role of comorbidities. Eur Respir J 2006; 28(6): 1245–1257
doi: 10.1183/09031936.00133805 pmid:17138679
34 Tsiligianni IG, Kosmas E, Van der Molen T, Tzanakis N. Managing comorbidity in COPD: a difficult task. Curr Drug Targets 2013; 14(2): 158–176
doi: 10.2174/1389450111314020004 pmid:23256716
35 Kim V, Han M, Vance G, Make B, Newell J, Hokanson J, Hersh C, Stinson D, Silverman E, Criner G. The chronic bronchitic phenotype of chronic obstructive pulmonary disease: an analysis of the COPDGene study. Chest 2011; 140: 626–633
doi: 10.1378/chest.10-2948 pmid:21474571
36 Celli BR, Cote CG, Marin JM, Casanova C, Montes de Oca M, Mendez RA, Pinto Plata V, Cabral HJ. The body-mass index, airflow obstruction, dyspnea, and exercise capacity index in chronic obstructive pulmonary disease. N Engl J Med 2004; 350(10): 1005–1012
doi: 10.1056/NEJMoa021322 pmid:14999112
37 Schünemann H. From BODE to ADO to outcomes in multimorbid COPD patients. Lancet 2009; 374(9691): 667–668
doi: 10.1016/S0140-6736(09)61539-7 pmid:19716945
38 Azarisman MS, Fauzi MA, Faizal MP, Azami Z, Roslina AM, Roslan H. The SAFE (SGRQ score, air-flow limitation and exercise tolerance) Index: a new composite score for the stratification of severity in chronic obstructive pulmonary disease. Postgrad Med J 2007; 83(981): 492–497
doi: 10.1136/pgmj.2006.052399 pmid:17621621
39 Soler-Catalu?a JJ, Martínez-García MA, Sánchez LS, Tordera MP, Sánchez PR. Severe exacerbations and BODE index: two independent risk factors for death in male COPD patients. Respir Med 2009; 103(5): 692–699
doi: 10.1016/j.rmed.2008.12.005 pmid:19131231
40 Miravitlles M, Jose Soler-Cataluna J, Calle M, Soriano JB. Treatment of COPD by clinical phenotypes: putting old evidence into clinical practice. Eur Respir J 2013; 41(6): 1252–1256
doi: 10.1183/09031936.00118912 pmid:23060631
41 F?hndrich S, Guttmann C, Bals R. Chronic obstructive pulmonary disease: pathophysiology, diagnosis, and therapy. Dtsch Med Wochenschr 2011; 136(37): 1847–1860, quiz 1861–1862 (in German)
doi: 10.1055/s-0031-1286356 pmid:21898277
42 Burgel PR, Paillasseur JL, Peene B, Dusser D, Roche N, Coolen J, Troosters T, Decramer M, Janssens W. Two distinct chronic obstructive pulmonary disease (COPD) phenotypes are associated with high risk of mortality. PLoS ONE 2012; 7(12): e51048
doi: 10.1371/journal.pone.0051048 pmid:23236428
43 Burgel PR, Paillasseur JL, Caillaud D, Tillie-Leblond I, Chanez P, Escamilla R, Court-Fortune I, Perez T, Carré P, Roche N, Initiatives BSC. Clinical COPD phenotypes: a novel approach using principal component and cluster analyses. Eur Respir J 2010; 36(3): 531–539
doi: 10.1183/09031936.00175109 pmid:20075045
44 Wood AM, Stockley RA. The genetics of chronic obstructive pulmonary disease. Respir Res 2006; 7(1): 130
doi: 10.1186/1465-9921-7-130 pmid:17054776
45 Hersh CP, Dahl M, Ly NP, Berkey CS, Nordestgaard BG, Silverman EK. Chronic obstructive pulmonary disease in alpha1-antitrypsin PI MZ heterozygotes: a meta-analysis. Thorax 2004; 59(10): 843–849
doi: 10.1136/thx.2004.022541 pmid:15454649
46 Sampsonas F, Antonacopoulou A, Spathas D, Lykouras D, Kalofonos H, Flordellis C, Spiropoulos K, Siafakas N. Positive association between two polymorphic sites (+134 insA/delA and G198T) of the endothelin-1 gene and chronic obstructive pulmonary disease. A case-control study. Respir Med 2010; 104(1): 114–120
doi: 10.1016/j.rmed.2009.06.012 pmid:19640695
47 Lee JY, Yoo SS, Kang HG, Jin G, Bae EY, Choi YY, Choi JE, Jeon HS, Lee J, Lee SY, Cha SI, Kim CH, Park JY. A functional polymorphism in the CHRNA3 gene and risk of chronic obstructive pulmonary disease in a Korean population. J Korean Med Sci 2012; 27(12): 1536–1540
doi: 10.3346/jkms.2012.27.12.1536 pmid:23255854
48 Li Y, Huang J, Amos CI. Genetic association analysis of complex diseases incorporating intermediate phenotype information. PLoS ONE 2012; 7(10): e46612
doi: 10.1371/journal.pone.0046612 pmid:23094028
49 Yang L, Qiu F, Lu X, Huang D, Ma G, Guo Y, Hu M, Zhou Y, Pan M, Tan Y, Zhong H, Ji W, Wei Q, Ran P, Zhong N, Zhou Y, Lu J. Functional polymorphisms of CHRNA3 predict risks of chronic obstructive pulmonary disease and lung cancer in Chinese. PLoS ONE 2012; 7(10): e46071
doi: 10.1371/journal.pone.0046071 pmid:23056235
50 Zhou H, Yang J, Li D, Xiao J, Wang B, Wang L, Ma C, Xu S, Ou X, Feng Y. Association of IREB2 and CHRNA3/5 polymorphisms with COPD and COPD-related phenotypes in a Chinese Han population. J Hum Genet 2012; 57(11): 738–746
doi: 10.1038/jhg.2012.104 pmid:22914670
51 Wilk JB, Shrine NR, Loehr LR, Zhao JH, Manichaikul A, Lopez LM, Smith AV, Heckbert SR, Smolonska J, Tang W, Loth DW, Curjuric I, Hui J, Cho MH, Latourelle JC, Henry AP, Aldrich M, Bakke P, Beaty TH, Bentley AR, Borecki IB, Brusselle GG, Burkart KM, Chen TH, Couper D, Crapo JD, Davies G, Dupuis J, Franceschini N, Gulsvik A, Hancock DB, Harris TB, Hofman A, Imboden M, James AL, Khaw KT, Lahousse L, Launer LJ, Litonjua A, Liu Y, Lohman KK, Lomas DA, Lumley T, Marciante KD, McArdle WL, Meibohm B, Morrison AC, Musk AW, Myers RH, North KE, Postma DS, Psaty BM, Rich SS, Rivadeneira F, Rochat T, Rotter JI, Artigas MS, Starr JM, Uitterlinden AG, Wareham NJ, Wijmenga C, Zanen P, Province MA, Silverman EK, Deary IJ, Palmer LJ, Cassano PA, Gudnason V, Barr RG, Loos RJ, Strachan DP, London SJ, Boezen HM, Probst-Hensch N, Gharib SA, Hall IP, O’Connor GT, Tobin MD, Stricker BH. Genome-wide association studies identify CHRNA5/3 and HTR4 in the development of airflow obstruction. Am J Respir Crit Care Med 2012; 186(7): 622–632
doi: 10.1164/rccm.201202-0366OC pmid:22837378
52 Hardin M, Zielinski J, Wan ES, Hersh CP, Castaldi PJ, Schwinder E, Hawrylkiewicz I, Sliwinski P, Cho MH, Silverman EK. CHRNA3/5, IREB2, and ADCY2 are associated with severe chronic obstructive pulmonary disease in Poland. Am J Respir Cell Mol Biol 2012; 47(2): 203–208
doi: 10.1165/rcmb.2012-0011OC pmid:22461431
53 Pillai SG, Ge D, Zhu G, Kong X, Shianna KV, Need AC, Feng S, Hersh CP, Bakke P, Gulsvik A, Ruppert A, L?drup 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(3): e1000421
doi: 10.1371/journal.pgen.1000421 pmid:19300482
54 Mocchegiani E, Giacconi R, Costarelli L. Metalloproteases/anti-metalloproteases imbalance in chronic obstructive pulmonary disease: genetic factors and treatment implications. Curr Opin Pulm Med 2011; 17(Suppl 1): S11–S19
doi: 10.1097/01.mcp.0000410743.98087.12 pmid:22209925
55 Hunninghake GM, Cho MH, Tesfaigzi Y, Soto-Quiros ME, Avila L, Lasky-Su J, Stidley C, Melén E, S?derh?ll C, Hallberg J, Kull I, Kere J, Svartengren M, Pershagen G, Wickman M, Lange C, Demeo DL, Hersh CP, Klanderman BJ, Raby BA, Sparrow D, Shapiro SD, Silverman EK, Litonjua AA, Weiss ST, Celedón JC. MMP12, lung function, and COPD in high-risk populations. N Engl J Med 2009; 361(27): 2599–2608
doi: 10.1056/NEJMoa0904006 pmid:20018959
56 Dahl M, Bowler RP, Juul K, Crapo JD, Levy S, Nordestgaard BG. Superoxide dismutase 3 polymorphism associated with reduced lung function in two large populations. Am J Respir Crit Care Med 2008; 178(9): 906–912
doi: 10.1164/rccm.200804-549OC pmid:18703790
57 Berndt A, Leme AS, Shapiro SD. Emerging genetics of COPD. EMBO Mol Med 2012; 4(11): 1144–1155
doi: 10.1002/emmm.201100627 pmid:23090857
58 Wu L, Chau J, Young RP, Pokorny V, Mills GD, Hopkins R, McLean L, Black PN. Transforming growth factor-beta1 genotype and susceptibility to chronic obstructive pulmonary disease. Thorax 2004; 59(2): 126–129
doi: 10.1136/thorax.2003.005769 pmid:14760152
59 Zhang L, Chang WW, Ding H, Su H, Wang HY. Transforming growth factor-β1 polymorphisms and chronic obstructive pulmonary disease: a meta-analysis. Int J Tuberc Lung Dis 2011; 15(10): 1301–1307
doi: 10.5588/ijtld.10.0295 pmid:21740629
60 Shukla RK, Kant S, Bhattacharya S, Mittal B. Association of cytokine gene polymorphisms in patients with chronic obstructive pulmonary disease. Oman Med J 2012; 27(4): 285–290
doi: 10.5001/omj.2012.71 pmid:23071879
61 Hurst JR, Wedzicha JA. The biology of a chronic obstructive pulmonary disease exacerbation. Clin Chest Med 2007; 28(3): 525–536, v
doi: 10.1016/j.ccm.2007.05.003 pmid:17720041
62 Murphy TF. The role of bacteria in airway inflammation in exacerbations of chronic obstructive pulmonary disease. Curr Opin Infect Dis 2006; 19(3): 225–230
doi: 10.1097/01.qco.0000224815.89363.15 pmid:16645482
63 Hu G, Shi Z, Hu J, Zou G, Peng G, Ran P. Association between polymorphisms of microsomal epoxide hydrolase and COPD: results from meta-analyses. Respirology 2008; 13(6): 837–850
doi: 10.1111/j.1440-1843.2008.01356.x pmid:18811882
64 Smolonska J, Wijmenga C, Postma DS, Boezen HM. Meta-analyses on suspected chronic obstructive pulmonary disease genes: a summary of 20 years’ research. Am J Respir Crit Care Med 2009; 180(7): 618–631
doi: 10.1164/rccm.200905-0722OC pmid:19608716
65 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(1): 32–43
doi: 10.3109/15412550903499522 pmid:20214461
66 Fang X, Wang X, Bai C. COPD in China: the burden and importance of proper management. Chest 2011; 139(4): 920–929
doi: 10.1378/chest.10-1393 pmid:21467059
67 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, Loos RJ, Manning AK, Marciante KD, Obeidat M, Postma DS, Aldrich MC, Brusselle GG, Chen TH, Eiriksdottir G, Franceschini N, Heinrich J, Rotter JI, Wijmenga C, Williams OD, Bentley AR, Hofman A, Laurie CC, Lumley T, Morrison AC, Joubert BR, Rivadeneira F, Couper DJ, Kritchevsky SB, Liu Y, Wjst M, Wain LV, Vonk JM, Uitterlinden AG, Rochat T, Rich SS, Psaty BM, O’Connor GT, North KE, Mirel DB, Meibohm B, Launer LJ, Khaw KT, Hartikainen AL, Hammond CJ, Gl?ser S, Marchini J, Kraft P, Wareham NJ, V?lzke H, Stricker BH, Spector TD, Probst-Hensch NM, Jarvis D, Jarvelin MR, Heckbert SR, Gudnason V, Boezen HM, Barr RG, Cassano PA, Strachan DP, Fornage M, Hall IP, Dupuis J, Tobin MD, London SJ. Genome-wide joint meta-analysis of SNP and SNP-by-smoking interaction identifies novel loci for pulmonary function. PLoS Genet 2012; 8(12): e1003098
doi: 10.1371/journal.pgen.1003098 pmid:23284291
[1] Ke Sheng. Artificial intelligence in radiotherapy: a technological review[J]. Front. Med., 2020, 14(4): 431-449.
[2] Honglu Zhou, Songmei Wang, Lorenz von Seidlein, Xuanyi Wang. The epidemiology of norovirus gastroenteritis in China: disease burden and distribution of genotypes[J]. Front. Med., 2020, 14(1): 1-7.
[3] Won-Mo Jung, In-Soo Park, Ye-Seul Lee, Chang-Eop Kim, Hyangsook Lee, Dae-Hyun Hahm, Hi-Joon Park, Bo-Hyoung Jang, Younbyoung Chae. Characterization of hidden rules linking symptoms and selection of acupoint using an artificial neural network model[J]. Front. Med., 2019, 13(1): 112-120.
[4] Meijuan Zheng, Haoyu Sun, Zhigang Tian. Natural killer cells in liver diseases[J]. Front. Med., 2018, 12(3): 269-279.
[5] Haican Liu, Yuanyuan Zhang, Zhiguang Liu, Jinghua Liu, Yolande Hauck, Jiao Liu, Haiyan Dong, Jie Liu, Xiuqin Zhao, Bing Lu, Yi Jiang, Gilles Vergnaud, Christine Pourcel, Kanglin Wan. Associations between Mycobacterium tuberculosis Beijing genotype and drug resistance to four first-line drugs: a survey in China[J]. Front. Med., 2018, 12(1): 92-97.
[6] Jingjing Yan, Shuye Zhang, Jun Sun, Jianqing Xu, Xiaoyang Zhang. Irreversible phenotypic perturbation and functional impairment of B cells during HIV-1 infection[J]. Front. Med., 2017, 11(4): 536-547.
[7] Jing Ma,Fei Liu,Xin Du,Duan Ma,Likuan Xiong. Changes in lncRNAs and related genes in β-thalassemia minor and β-thalassemia major[J]. Front. Med., 2017, 11(1): 74-86.
[8] Minghang Wang,Jiansheng Li,Suyun Li,Yang Xie. Effects of comprehensive therapy based on traditional Chinese medicine patterns on older patients with chronic obstructive pulmonary disease: a subgroup analysis from a four-center, randomized, controlled study[J]. Front. Med., 2014, 8(3): 368-375.
[9] Xuezhong Zhou,Yubing Li,Yonghong Peng,Jingqing Hu,Runshun Zhang,Liyun He,Yinghui Wang,Lijie Jiang,Shiyan Yan,Peng Li,Qi Xie,Baoyan Liu. Clinical phenotype network: the underlying mechanism for personalized diagnosis and treatment of traditional Chinese medicine[J]. Front. Med., 2014, 8(3): 337-346.
[10] Jia-Xin XIE, Jian-Hua YIN, Qi ZHANG, Rui PU, Wen-Ying LU, Hong-Wei ZHANG, Guang-Wen CAO, Jun ZHAO, Hong-Yang WANG, . Association of novel mutations and heplotypes in the preS region of hepatitis B virus with hepatocellular carcinoma[J]. Front. Med., 2010, 4(4): 419-429.
[11] ZHANG Tiejun, ZHOU Xiaoming, ZHANG Tao, YU Shunzhang, JIANG Qingwu, CHEN Yue. Using RAPD in genotyping and transmission detection[J]. Front. Med., 2008, 2(3): 269-275.
[12] QIN Lunxiu, TANG Zhaoyou, GUAN Xinyuan, YE Qinghai, JIA Huliang, REN Ning. The predictive value of chromosome 8p deletion for metastasis of hepatocellular carcinoma: a summary of works in 10 years[J]. Front. Med., 2008, 2(3): 211-215.
Viewed
Full text


Abstract

Cited

  Shared   
  Discussed