A Large-Scale, Consortium-Based Genomewide Association Study of Asthma

被引：1527

作者：

Moffatt, Miriam F. ^{[1
]}

Gut, Ivo G. ^{[7
]}

Demenais, Florence ^{[4
,5
,6
]}

Strachan, David P. ^{[9
]}

Bouzigon, Emmanuelle ^{[4
,5
,6
]}

Heath, Simon ^{[7
]}

von Mutius, Erika ^{[3
]}

Farrall, Martin ^{[2
]}

Lathrop, Mark ^{[5
,7
]}

Cookson, William O. C. M. ^{[1
,8
]}

Kumar, Ashish

Burney, Peter ^{[1
,10
]}

Jarvis, Debbie ^{[1
,10
]}

Wjst, Matthias ^{[11
,12
]}

Kogevinas, Manolis ^{[13
,14
,15
,16
]}

Jogi, Rain ^{[17
]}

Janson, Christer ^{[18
]}

Franklin, Karl A. ^{[19
]}

Omenaas, Ernst ^{[20
,21
]}

Leynaert, Benedicte ^{[22
,23
]}

Pin, Isabelle ^{[24
,25
,26
]}

Heinrich, Joachim ^{[27
]}

Probst-Hensch, Nicole M. ^{[28
,29
,30
]}

Anto, Josep M. ^{[13
,14
,15
]}

Sunyer, Jordi ^{[13
,14
,15
]}

Maldonado, Jose-Antonio ^{[31
,32
]}

Martinez-Moratalla, Jesus ^{[32
]}

Urrutia, Isabel ^{[33
]}

Payo, Felix ^{[34
]}

Kauffmann, Francine ^{[35
,36
]}

Dizier, Marie-Helene ^{[4
,5
,6
]}

Siroux, Valerie ^{[25
,26
]}

Boznanski, Andrzej ^{[37
]}

Braun-Fahrlaender, Charlotte ^{[28
,29
]}

Genuneit, Jon ^{[38
]}

Glas, Juergen ^{[39
,40
]}

Horak, Elisabeth ^{[41
]}

Kabesch, Michael ^{[42
]}

Pillai, Sreekumar G. ^{[43
]}

Helms, Peter J. ^{[44
]}

Carlsen, Karin ^{[45
,46
]}

Carlsen, Kai-Hakon ^{[45
,46
]}

Gerritsen, Jorrit ^{[47
]}

Silverman, Michael ^{[48
]}

Sly, Peter ^{[49
]}

Tsanakas, John ^{[50
]}

Von Berg, Andrea

Whyte, Moira ^{[51
]}

Blumenthal, Malcolm ^{[52
]}

Imboden, Medea ^{[28
,29
,30
]}

机构：

[1] Univ London Imperial Coll Sci Technol & Med, Natl Heart & Lung Inst, London SW3 6LY, England

[2] Univ Oxford, Wellcome Trust Ctr Human Genet, Oxford, England

[3] Univ Munich, Asthma & Allergy Dept, Univ Childrens Hosp, Munich, Germany

[4] Univ Paris 07, Inst Univ Hematol, Paris, France

[5] Fdn Jean Dausset CEPH, Paris, France

[6] Fdn Jean Dausset, CEPH, INSERM, U946, Paris, France

[7] Commissariat Energie Atom, Inst Genom, Ctr Natl Genotypage, Evry, France

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

[9] Univ London, Div Community Hlth Sci, London, England

[10] Imperial Coll, NHLI, Respiratory Epidemiol & Publ Hlth, London, England

[11] Helmholtz Zentrum, Inst Lung Biol & Dis, Munich, Germany

[12] German Res Ctr Environm Hlth GmbH, Neuherberg, Germany

[13] Ctr Res Environm Epidemiol CREAL, Barcelona, Spain

[14] Municipal Inst Med Res IMIM Hosp Mar, Barcelona, Spain

[15] CIBER Epidemiol & Salud Publ CIBERESP, Madrid, Spain

[16] Natl Sch Publ Hlth, Athens, Greece

[17] Tartu Univ Hosp, Lung Clin, Tartu, Estonia

[18] Uppsala Univ, Resp Med & Allergol, Uppsala, Sweden

[19] Umea Univ, Dept Surg, S-90187 Umea, Sweden

[20] Univ Bergen, Inst Med, N-5020 Bergen, Norway

[21] Haukeland Hosp, Ctr Clin Res, Bergen, Norway

[22] Inserm, Unite 700, Paris, France

[23] Univ Paris Diderot, Paris, France

[24] Ctr Hosp Univ, Grenoble, France

[25] Inserm, Unite 823, Grenoble, France

[26] Univ Joseph Fourier, F-38041 Grenoble, France

[27] Helmholtz Zentrum Munich, Inst Epidemiol, Munich, Germany

[28] Swiss Trop & Publ Hlth Inst, Basel, Switzerland

[29] Univ Basel, CH-4003 Basel, Switzerland

[30] Univ Zurich, UPF, Dept Ciencies Expt Salut, CH-8006 Zurich, Switzerland

[31] Hosp Juan Ramon Jimenez, Serv Neumol, Huelva, Spain

[32] Hosp Gen Univ Albacete, Serv Neumol, Albacete, Spain

[33] Galdakao Hosp, Pneumol Serv, Galdakao, Bizkaia, Spain

[34] Hosp Gen Asturias, Serv Neumol, Oviedo, Asturias, Spain

[35] Inserm, Unite 780, Villejuif, France

[36] Univ Paris Sud, IFR69, Villejuif, France

[37] Wroclaw Med Univ, Dep Paediat Allergol & Cardiol 1, Wroclaw, Poland

[38] Ulm Univ, Inst Epidemiol, Ulm, Germany

[39] Univ Munich, Dept Prevent Dentistry & Periodontol, Munich, Germany

[40] Rhein Westfal TH Aachen, Dept Human Genet, Aachen, Germany

[41] Innsbruck Med Univ, Dept Pediat Pediat Pulmonol, Innsbruck, Austria

[42] Hannover Med Sch, Clin Paediat Pneumol & Neonatol, Ctr Paediat Adolescent Med, Hannover, Germany

[43] GlaxoSmithKline R&D, Genet, Res Triangle Pk, NC USA

[44] Univ Aberdeen, Royal Aberdeen Childrens Hosp, Aberdeen, Scotland

[45] Oslo Univ Hosp, Dept Paediat, N-0316 Oslo, Norway

[46] Univ Oslo, Fac Med, Oslo, Norway

[47] Univ Groningen, Univ Med Ctr Groningen, Beatrix Childrens Hosp, Groningen, Netherlands

[48] Univ Leicester, Div Child Hlth, Leicester, Leics, England

[49] Univ Western Australia, Ctr Child Hlth Res, Perth, WA, Australia

[50] Aristotle Univ Thessaloniki, Pediat Pulmonol, Thessaloniki, Greece

来源：

NEW ENGLAND JOURNAL OF MEDICINE | 2010年 / 363卷 / 13期

基金：

英国惠康基金;

关键词：

SUSCEPTIBILITY GENE; POSITIONAL CLONING; IN-VIVO; VARIANTS; DISEASE; EXPRESSION; CYTOKINE; RECEPTOR; ALLERGY; TRAITS;

D O I：

10.1056/NEJMoa0906312

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

BACKGROUND Susceptibility to asthma is influenced by genes and environment; implicated genes may indicate pathways for therapeutic intervention. Genetic risk factors may be useful in identifying subtypes of asthma and determining whether intermediate phenotypes, such as elevation of the total serum IgE level, are causally linked to disease. METHODS We carried out a genomewide association study by genotyping 10,365 persons with physician-diagnosed asthma and 16,110 unaffected persons, all of whom were matched for ancestry. We used random-effects pooled analysis to test for association in the overall study population and in subgroups of subjects with childhood-onset asthma (defined as asthma developing before 16 years of age), later-onset asthma, severe asthma, and occupational asthma. RESULTS We observed associations of genomewide significance between asthma and the following single-nucleotide polymorphisms: rs3771166 on chromosome 2, implicating IL1RL1/IL18R1 (P = 3x10(-9)); rs9273349 on chromosome 6, implicating HLA-DQ (P = 7x10(-14)); rs1342326 on chromosome 9, flanking IL33 (P = 9x10(-10)); rs744910 on chromosome 15 in SMAD3 (P = 4x10(-9)); and rs2284033 on chromosome 22 in IL2RB (P = 1.1x10(-8)). Association with the ORMDL3/GSDMB locus on chromosome 17q21 was specific to childhood-onset disease (rs2305480, P = 6x10(-23)). Only HLA-DR showed a significant genomewide association with the total serum IgE concentration, and loci strongly associated with IgE levels were not associated with asthma. CONCLUSIONS Asthma is genetically heterogeneous. A few common alleles are associated with disease risk at all ages. Implicated genes suggest a role for communication of epithelial damage to the adaptive immune system and activation of airway inflammation. Variants at the ORMDL3/GSDMB locus are associated only with childhood-onset disease. Elevation of total serum IgE levels has a minor role in the development of asthma.

引用

页码：1211 / 1221

页数：11

共 47 条

[1] Positional cloning of a novel gene influencing asthma from Chromosome 2q14 [J].

Allen, M ;

Heinzmann, A ;

Noguchi, E ;

Abecasis, G ;

Broxholme, J ;

Ponting, CP ;

Bhattacharyya, S ;

Tinsley, J ;

Zhang, YM ;

Holt, R ;

Jones, EY ;

Lench, N ;

Carey, A ;

Jones, H ;

Dickens, NJ ;

Dimon, C ;

Nicholls, R ;

Baker, C ;

Xue, LZ ;

Townsend, E ;

Kabesch, M ;

Weiland, SK ;

Carr, D ;

von Mutius, E ;

Adcock, IM ;

Barnes, PJ ;

Lathrop, GM ;

Edwards, M ;

Moffatt, MF ;

Cookson, WOCM .

NATURE GENETICS, 2003, 35 (03) :258-263

[2]

Anthoni M, 2007, INT J BIOL SCI, V3, P477

[3] IRAK-M is involved in the pathogenesis of early-onset persistent asthma [J].

Balaci, Lenuta ;

Spada, Maria Cristina ;

Olla, Nazario ;

Sole, Gabriella ;

Loddo, Laura ;

Anedda, Francesca ;

Naitza, Silvia ;

Zuncheddu, Maria Antonietta ;

Maschio, Andrea ;

Altea, Daniele ;

Uda, Manuela ;

Pilia, Sabrina ;

Sanna, Serena ;

Masala, Marco ;

Crisponi, Laura ;

Fattori, Matilde ;

Devoto, Marcella ;

Doratiotto, Silvia ;

Rassu, Stefania ;

Mereu, Simonetta ;

Giua, Enrico ;

Cadeddu, Natalina Graziella ;

Atzeni, Roberto ;

Pelosi, Umberto ;

Corrias, Adriano ;

Perra, Roberto ;

Torrazza, Pier Luigi ;

Pirina, Pietro ;

Ginesu, Francesco ;

Marcias, Silvano ;

Schintu, Maria Grazia ;

Del Giacco, Gennaro Sergio ;

Manconi, Paolo Emilio ;

Malerba, Giovanni ;

Bisognin, Andrea ;

Trabetti, Elisabetta ;

Boner, Attilio ;

Pescollderungg, Lydia ;

Pignatti, Pier Franco ;

Schlessinger, David ;

Cao, Antonio ;

Pilia, Giuseppe .

AMERICAN JOURNAL OF HUMAN GENETICS, 2007, 80 (06) :1103-1114

[4] Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease [J].

Barrett, Jeffrey C. ;

Hansoul, Sarah ;

Nicolae, Dan L. ;

Cho, Judy H. ;

Duerr, Richard H. ;

Rioux, John D. ;

Brant, Steven R. ;

Silverberg, Mark S. ;

Taylor, Kent D. ;

Barmada, M. Michael ;

Bitton, Alain ;

Dassopoulos, Themistocles ;

Datta, Lisa Wu ;

Green, Todd ;

Griffiths, Anne M. ;

Kistner, Emily O. ;

Murtha, Michael T. ;

Regueiro, Miguel D. ;

Rotter, Jerome I. ;

Schumm, L. Philip ;

Steinhart, A. Hillary ;

Targan, Stephan R. ;

Xavier, Ramnik J. ;

Libioulle, Cecile ;

Sandor, Cynthia ;

Lathrop, Mark ;

Belaiche, Jacques ;

Dewit, Olivier ;

Gut, Ivo ;

Heath, Simon ;

Laukens, Debby ;

Mni, Myriam ;

Rutgeerts, Paul ;

Van Gossum, Andre ;

Zelenika, Diana ;

Franchimont, Denis ;

Hugot, Jean-Pierre ;

de Vos, Martine ;

Vermeire, Severine ;

Louis, Edouard ;

Cardon, Lon R. ;

Anderson, Carl A. ;

Drummond, Hazel ;

Nimmo, Elaine ;

Ahmad, Tariq ;

Prescott, Natalie J. ;

Onnie, Clive M. ;

Fisher, Sheila A. ;

Marchini, Jonathan ;

Ghori, Jilur .

NATURE GENETICS, 2008, 40 (08) :955-962

[5] Effect of 17q21 Variants and Smoking Exposure in Early-Onset Asthma [J].

Bouzigon, Emmanuelle ;

Corda, Eve ;

Aschard, Hugues ;

Dizier, Marie-Helene ;

Boland, Anne ;

Bousquet, Jean ;

Chateigner, Nicolas ;

Gormand, Frederic ;

Just, Jocelyne ;

Le Moual, Nicole ;

Scheinmann, Pierre ;

Siroux, Valerie ;

Vervloet, Daniel ;

Zelenika, Diana ;

Pin, Isabelle ;

Kauffmann, Francine ;

Lathrop, Mark ;

Demenais, Florence .

NEW ENGLAND JOURNAL OF MEDICINE, 2008, 359 (19) :1985-1994

[6] Orm family proteins mediate sphingolipid homeostasis [J].

Breslow, David K. ;

Collins, Sean R. ;

Bodenmiller, Bernd ;

Aebersold, Ruedi ;

Simons, Kai ;

Shevchenko, Andrej ;

Ejsing, Christer S. ;

Weissman, Jonathan S. .

NATURE, 2010, 463 (7284) :1048-U65

[7] Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls [J].

Burton, Paul R. ;

Clayton, David G. ;

Cardon, Lon R. ;

Craddock, Nick ;

Deloukas, Panos ;

Duncanson, Audrey ;

Kwiatkowski, Dominic P. ;

McCarthy, Mark I. ;

Ouwehand, Willem H. ;

Samani, Nilesh J. ;

Todd, John A. ;

Donnelly, Peter ;

Barrett, Jeffrey C. ;

Davison, Dan ;

Easton, Doug ;

Evans, David ;

Leung, Hin-Tak ;

Marchini, Jonathan L. ;

Morris, Andrew P. ;

Spencer, Chris C. A. ;

Tobin, Martin D. ;

Attwood, Antony P. ;

Boorman, James P. ;

Cant, Barbara ;

Everson, Ursula ;

Hussey, Judith M. ;

Jolley, Jennifer D. ;

Knight, Alexandra S. ;

Koch, Kerstin ;

Meech, Elizabeth ;

Nutland, Sarah ;

Prowse, Christopher V. ;

Stevens, Helen E. ;

Taylor, Niall C. ;

Walters, Graham R. ;

Walker, Neil M. ;

Watkins, Nicholas A. ;

Winzer, Thilo ;

Jones, Richard W. ;

McArdle, Wendy L. ;

Ring, Susan M. ;

Strachan, David P. ;

Pembrey, Marcus ;

Breen, Gerome ;

St Clair, David ;

Caesar, Sian ;

Gordon-Smith, Katherine ;

Jones, Lisa ;

Fraser, Christine ;

Green, Elain K. .

NATURE, 2007, 447 (7145) :661-678

[8] IL-33, the IL-1-like cytokine ligand for ST2 receptor, is a chromatin-associated nuclear factor in vivo [J].

Carriere, Virginie ;

Roussel, Lucie ;

Ortega, Nathalie ;

Lacorre, Delphine-Armelle ;

Americh, Laure ;

Aguilar, Luc ;

Bouche, Gerard ;

Girard, Jean-Philippe .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2007, 104 (01) :282-287

[9] Mapping complex disease traits with global gene expression [J].

Cookson, William ;

Liang, Liming ;

Abecasis, Goncalo ;

Moffatt, Miriam ;

Lathrop, Mark .

NATURE REVIEWS GENETICS, 2009, 10 (03) :184-194

[10] Estimation of significance thresholds for genomewide association scans [J].

Dudbridge, Frank ;

Gusnanto, Arief .

GENETIC EPIDEMIOLOGY, 2008, 32 (03) :227-234

← 1 2 3 4 5 →