|
|
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 |
|
|
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
|
|
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
|
|
Viewed |
|
|
|
Full text
|
|
|
|
|
Abstract
|
|
|
|
|
Cited |
|
|
|
|
|
Shared |
|
|
|
|
|
Discussed |
|
|
|
|