Stratification of asthma phenotypes by airway proteomic signatures

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:144

Article

Strazzeri, Fabio^1,3  Folisi, Caterina¹  Bansal, Aruna T.⁴  Rowe, Anthony⁶  Corfield, Julie⁷  Wilson, Susan²  Lutter, Rene^8,9  Shaw, Dominick E.¹⁰  Bakke, Per S.¹¹  Caruso, Massimo¹²  Dahlen, Sven-Erik¹³  Fowler, Stephen J.¹⁴  Horvath, Ildiko¹⁵  Howarth, Peter²  Krug, Norbert¹⁶  Montuschi, Paolo¹⁷  Sanak, Marek¹⁸  Sandstrom, Thomas^19,20,21  Auffray, Charles²²  De Meulder, Bertrand²²  Lefaudeux, Diane²²  Sousa, Ana R.²³  Adcock, Ian M.²⁴  Chung, Kian Fan²⁴  Sterk, Peter J.⁹  Djukanovic, Ratko²  Behndig, A. F.³²  Bush, A.^40,42  Campagna, D.⁴³  Delin, I.⁴⁵  Gahlemann, M.⁵⁰  Garissi, D.⁵²  Hohlfeld, J. M.²⁸  Knowles, R.⁵⁶  Lantz, A. -S.³⁴  Larminie, C.⁵⁸  Latzin, P.⁴⁴  Lowe, L. A.⁵⁵  Manta, A.³¹  Murray, C. S.⁶²  Nihlen, U.^63,64  Niven, R.⁶⁵  Nordlund, B.⁶⁷  Nsubuga, S.⁵⁴  Pratico, G.⁶⁸  Puig Valls, M.⁶⁹  Rossios, C.³⁰  Saqi, M.²⁵  Scott, S.⁷⁰  Sehgal, N.²⁷  Selby, A.⁷¹  Soderman, P.^66,72  Sogbesan, A.⁶⁰  Spycher, F.⁵⁹  Stephan, S.⁷³  Stokholm, J.^37,38  Sunther, M.⁷⁴  Valente, S.⁶¹  Vyas, A.^26,75  Zetterquist, W.⁷⁶  Zolkipli, Z.^77,78,79  Aliprantis, Antonios⁸⁰  Alving, Kjell⁸¹  Bakke, Per⁸²  Bochenek, Grazyna⁸⁷  Brandsma, Joost²  Burg, Dominic^1,2,89  Rocha, Joao Pedro Carvalho da Purificacao⁵³  De Alba, Jorge⁸⁶  Draper, Aleksandra⁴⁹  Emma, Rosalia⁹²  Gozzard, Neil⁵⁷  Hohlfeld, Jens⁸⁸  Holweg, Cecile⁹⁵  Hu, Richard³⁶  Kerry, Dyson⁹⁷  Kots, Maxim⁹⁹  Lambrecht, Bart¹⁰⁰  Miralpeix, Montse¹⁰⁴  Monk, Philip¹⁰⁵  Nicholas, Ben²  Nilsson, Peter^102,103  Pacino, Antonio¹⁰⁶  Palkonen, Susanna⁹³  Powell, Pippa¹⁰¹  Rao, Navin²⁹  Riley, John^23,84  Rutgers, Michael⁹⁶  Santoninco, Marco⁹⁰  Schofield, James P. R.^1,2  Skipp, Paul J.^1,107  Smith, Caroline⁴⁶  Smith, Katherine M.¹⁰⁸  Staykova, Doroteya^1,47  Thorngren, John-Olof³³  Thornton, Bob⁸⁵  Thorsen, Jonathan¹⁰⁹  van de Pol, Marianne³⁹  van Geest, Marleen⁴⁸  Vink, Anton⁹⁸  Walker, Samantha⁹¹  Ward, Jonathan²  Weiszhart, Zsoka⁵¹  Wetzel, Kristiane³⁵  Wheelock, Craig E.⁸³  Wiegman, Coen⁴¹  Williams, Sian⁹⁴  Wilson, Susan J.¹¹⁰  Woodcock, Ashley^111,112  Yang, Xian⁵  Yeyasingham, Elizabeth¹¹³  Prins, Jan-Bas¹¹⁴  Puhl, Martine¹¹⁷  Buzermaniene, Lina¹¹⁸  Hudson, Val¹¹⁹  Bond, Laura¹¹⁹  Widdershoven, Guy¹²⁰  Visintin, Luigi¹¹⁶  Gahlemann, Martina¹¹⁵  Sigmund, Ralf¹²¹ 

[1] Ctr Prote Res, Biol Sci, Southampton, Hants, England

[2] NIHR Southampton Biomed Res Ctr, Clin & Expt Sci, Fac Med, Southampton, Hants, England

[3] Univ Southampton, Math Sci, Southampton, Hants, England

[4] Acclarogen, Cambridge, England

[5] Imperial Coll, Data Sci Inst, London, England

[6] Janssen Res & Dev, High Wycombe, Bucks, England

[7] Areteva, Nottingham, England

[8] AMC, Dept Expt Immunol, Amsterdam, Netherlands

[9] Univ Amsterdam, Amsterdam UMC, Amsterdam, Netherlands

[10] Univ Nottingham, Resp Res Unit, Nottingham, England

[11] Univ Bergen, Inst Med, Bergen, Norway

[12] Univ Catania, Univ Hosp, Dept Clin & Expt Med, Catania, Italy

[13] Karolinska Inst, Inst Environm Med, Ctr Allergy Res, Stockholm, Sweden

[14] Univ Manchester, Resp & Allergy Res Grp, Manchester, Lancs, England

[15] Semmelweis Univ, Dept Pulmonol, Budapest, Hungary

[16] Fraunhofer Inst Toxicol & Expt Med Hannover, Hannover, Germany

[17] Univ Cattolica Sacro Cuore, Fac Med, Rome, Italy

[18] Jagiellonian Univ, Coll Med, Lab Mol Biol & Clin Genet, Krakow, Poland

[19] Umea Univ, Dept Med, Umea, Sweden

[20] Umea Univ, Dept Publ Hlth, Umea, Sweden

[21] Umea Univ, Clin Med Resp Med Unit, Umea, Sweden

[22] Univ Lyon, European Inst Syst Biol & Med, CNRS, ENS,UCBL,INSERM, Lyon, France

[23] GlaxoSmithKline, Resp Therapeut Unit, Stockley Pk, England

[24] Imperial Coll London, Natl Heart & Lung Inst, Cell & Mol Biol Grp, Airways Dis Sect, London, England

[25] Univ Lyon, European Inst Syst Biol & Med, Lyon, France

[26] North West Severe Asthma Network, Manchester, Lancs, England

[27] Pennine Acute Hosp NHS Trust, Manchester, Lancs, England

[28] Fraunhofer ITEM, Hannover, Germany

[29] Janssen R&D, Beerse, Belgium

[30] Imperial Coll, London, England

[31] Roche Diagnost GmbH, Mannheim, Germany

[32] Umea Univ, Umea, Sweden

[33] Karolinska Univ Hosp, Stockholm, Sweden

[34] Karolinska Inst, Stockholm, Sweden

[35] Boehringer Ingelheim Pharma GmbH & Co KG, Biberach, Germany

[36] Amgen Inc, Thousand Oaks, CA USA

[37] Univ Copenhagen, Copenhagen, Denmark

[38] Univ Copenhagen, Gentofte Hosp, Danish Pediat Asthma Ctr, Copenhagen, Denmark

[39] Univ Amsterdam, Acad Med Ctr, Amsterdam, Netherlands

[40] Imperial Coll, Dept Paediat, London, England

[41] Imperial Coll, Natl Heart & Lung Inst, London, England

[42] Royal Brompton Hosp, Dept Resp Paediat, London, England

[43] Univ Catania, Catania, Italy

[44] Univ Childrens Hosp Bern, Bern, Switzerland

[45] Karolinska Inst, Inst Environm Med, Stockholm, Sweden

[46] NIHR Southampton Resp Biomed Res Unit, Southampton, Hants, England

[47] Univ Southampton, Southampton, Hants, England

[48] AstraZeneca, Molndal, Sweden

[49] BioSci Consulting, Maasmechelen, Belgium

[50] Boehringer Ingelheim Schweiz GmbH, Basel, Switzerland

[51] Semmelweis Univ, Budapest, Hungary

[52] CROMSOURCE, Global Head Clin Res Div, Verona, Italy

[53] Royal Brompton & Harefield NHS Fdn Trust, London, England

[54] Royal Brompton Hosp, London, England

[55] Univ Hosp South Manchester NHS Fdn Trust, Ctr Resp Med & Allergy, Inst Inflammat & Repair, Manchester, Lancs, England

[56] Arachos Pharma, Stevenage, Herts, England

[57] UCB, Slough, Berks, England

[58] GSK, London, England

[59] Univ Hosp, Dept Pulm Med, Bern, Switzerland

[60] Royal Brompton & Harefield NHS Fdn Trust, Harefield, Middx, England

[61] Univ Cattolica Sacro Cuore, Rome, Italy

[62] Univ Manchester, Univ Hosp South Manchester NHS Fdn Trust, Manchester Acad Hlth Sci Ctr, Ctr Resp Med & Allergy, Manchester, Lancs, England

[63] Skane Univ Hosp, Dept Resp Med & Allergol, Lund, Sweden

[64] AstraZeneca R&D, Molndal, Sweden

[65] Univ Hosp South Manchester NHS Trust, North West Severe Asthma Network, Manchester, Lancs, England

[66] Karolinska Univ Hosp, Astrid Lindgren Childrens Hosp, Stockholm, Sweden

[67] Karolinska Inst, Dept Womens & Childrens Hlth, Stockholm, Sweden

[68] CROMSOURCE, Verona, Italy

[69] CROMSOURCE, Barcelona, Spain

[70] Countess Chester NHS Trust, Chester, Cheshire, England

[71] NIHR Southampton Resp Biomed Res Unit, Clin & Expt Sci & Human Dev & Hlth, Southampton, Hants, England

[72] Dept Womens & Childrens Hlth, Stockholm, Sweden

[73] Univ Hosp South Manchester NHS Fdn Trust, Inst Inflammat & repair, Ctr Resp Med & Allergy, Manchester, Lancs, England

[74] Univ Hosp South Manchester NHS Fdn Trust, Inst Inflammat & Repair, Ctr Resp Med & Allergy, Manchester, Lancs, England

[75] Lancashire Teaching Hosp NHS Trust, Manchester, Lancs, England

[76] Karolinska Inst, Dept Woman & Child Hlth, Stockholm, Sweden

[77] Univ Hosp Southampton NHS Fdn Trust, NIHR Southampton Resp Biomed Res Unit, Southampton, Hants, England

[78] Univ Southampton, Fac Med, Clin & Expt Sci & Human Dev Hlth Acad Unit, Southampton, Hants, England

[79] St Marys Hosp, David Hide Asthma & Allergy Res Ctr, Newport, Wight, England

[80] Merck Res Labs, Boston, MA USA

[81] Uppsala Univ, Dept Womens & Childrens Hlth, Uppsala, Sweden

[82] Univ Bergen, Dept Clin Sci, Bergen, Norway

[83] Karolinska Inst, Ctr Allergy Res, Stockholm, Sweden

[84] GSK, Resp Therapeut Unit, London, England

[85] MSD, Brussels, Belgium

[86] Almirall SA, Barcelona, Spain

[87] Jagiellonian Univ, Coll Med, Dept Internal Med 2, Krakow, Poland

[88] Fraunhofer Inst Toxicol & Expt Med, Hannover, Germany

[89] Univ Southampton, Ctr Prote Res, Inst Life Sci, Southampton, Hants, England

[90] Univ Roma Tor Vergata, Rome, Italy

[91] Asthma UK, London, England

[92] Univ Catania, Dept Clin & Expt Med, Catania, Italy

[93] European Federat Allergy & Airways Dis Patients A, Brussels, Belgium

[94] Int Primary Care Resp Grp, Aberdeen, Scotland

[95] Genentech Inc, Resp & Allergy Dis, San Francisco, CA USA

[96] Longfonds, Amersfoort, Netherlands

[97] CromSource, Stirling, Scotland

[98] Philips Res Labs, Eindhoven, Netherlands

[99] Chiesi Pharmaceut SPA, Parma, Italy

[100] Univ Ghent, Ghent, Belgium

[101] European Lung Fdn, Sheffield, S Yorkshire, England

[102] Sci Life Lab, Stockholm, Sweden

[103] Royal Inst Technol, Stockholm, Sweden

[104] Almirall, Barcelona, Spain

[105] Synairgen Res, Southampton, Hants, England

[106] Lega Italiano Anti Fumo, Catania, Italy

[107] Univ Southampton, Inst Life Sci, Ctr Prote Res, Southampton, Hants, England

[108] Univ Nottingham, Nottingham, England

[109] Univ Copenhagen, Copenhagen Prospect Studies Asthma Childhood, Herlev & Gentofte Hosp, COPSAC, Copenhagen, Denmark

[110] Univ Southampton, Fac Med, Histochem Res Unit, Southampton, Hants, England

[111] Univ Manchester, Inst Inflammat & Repair, Ctr Resp Med & Allergy, Manchester, Lancs, England

[112] Univ Hosp South Manchester, Manchester Acad Hlth Sci Ctr, Manchester, Lancs, England

[113] GSK, UK Clin Operat, Stockley Pk, England

[114] LUMC, Biomed Res, Leiden, Netherlands

[115] BI, Clin Care, Ingelheim, Germany

[116] LIAF, Legal Affairs, Catania, Italy

[117] NAF, Nijmegen, Netherlands

[118] EFA, Patient Representat, Vilnius, Lithuania

[119] Asthma UK, Patient Representat, London, England

[120] Vrije Univ Amsterdam Med Ctr, Res Eth, Amsterdam, Netherlands

[121] BI, Res Methodol & Biostat, Ingelheim, Germany

关键词: Asthma;    proteomics;    biomarkers;    eosinophils;    neutrophils;   

DOI  :  10.1016/j.jaci.2019.03.013

来源: Elsevier

【 摘 要 】

Background: Stratification by eosinophil and neutrophil counts increases our understanding of asthma and helps target therapy, but there is room for improvement in our accuracy in prediction of treatment responses and a need for better understanding of the underlying mechanisms. Objective: We sought to identify molecular subphenotypes of asthma defined by proteomic signatures for improved stratification. Methods: Unbiased label-free quantitative mass spectrometry and topological data analysis were used to analyze the proteomes of sputum supernatants from 246 participants (206 asthmatic patients) as a novel means of asthma stratification. Microarray analysis of sputum cells provided transcriptomics data additionally to inform on underlying mechanisms. Results: Analysis of the sputum proteome resulted in 10 clusters (ie, proteotypes) based on similarity in proteomic features, representing discrete molecular subphenotypes of asthma. Overlaying granulocyte counts onto the 10 clusters as metadata further defined 3 of these as highly eosinophilic, 3 as highly neutrophilic, and 2 as highly atopic with relatively low granulocytic inflammation. For each of these 3 phenotypes, logistic regression analysis identified candidate protein biomarkers, and matched transcriptomic data pointed to differentially activated underlying mechanisms. Conclusion: This study provides further stratification of asthma currently classified based on quantification of granulocytic inflammation and provided additional insight into their underlying mechanisms, which could become targets for novel therapies.

【 授权许可】

Free