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PMID: 20860503 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

A large-scale, consortium-based genomewide association study of asthma.

The New England journal of medicine ·Vol. 363 ·No. 13 ·2010-09-23 ·Pages 1211-1221

Moffatt MF, Gut IG, Demenais F, Strachan DP, Bouzigon E, Heath S, von Mutius E, Farrall M, Lathrop M, Cookson WOCM, GABRIEL Consortium

Abstract

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. 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. We observed associations of genomewide significance between asthma and the following single-nucleotide polymorphisms: rs3771166 on chromosome 2, implicating IL1RL1/IL18R1 (P=3×10(−9)); rs9273349 on chromosome 6, implicating HLA-DQ (P=7×10(−14)); rs1342326 on chromosome 9, flanking IL33 (P=9×10(−10)); rs744910 on chromosome 15 in SMAD3 (P=4×10(−9)); and rs2284033 on chromosome 22 in IL2RB (P=1.1×10(−8)). Association with the ORMDL3/GSDMB locus on chromosome 17q21 was specific to childhood-onset disease (rs2305480, P=6×10(−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. 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. (Funded by the European Commission and others.)

MeSH Terms
Adolescent Age of Onset Asthma/genetics,immunology Case-Control Studies Child Chromosomes, Human Female Genetic Loci Genetic Predisposition to Disease Genome-Wide Association Study HLA-DR Antigens/genetics Humans Hypersensitivity/complications Immunoglobulin E/blood Logistic Models Male Occupational Diseases/genetics Odds Ratio Polymorphism, Single Nucleotide Th2 Cells/immunology
Chemicals
HLA-DR Antigens Immunoglobulin E
Authors & Affiliations
11 authors, click to expand affiliations / ORCID
Moffatt Miriam F
National Heart and Lung Institute, Imperial College (M.F.M., W.O.C.M.C.), the Division of Community Health Sciences, St. George's, University of London (D.P.S.), and Royal Brompton and Harefield NHS Foundation Trust (W.O.C.M.C.) - all in London; Commissariat à l'Energie Atomique, Institut de Génomique, Centre National de Génotypage, Evry, France (I.G.G., S.H., M.L.); INSERM, Unité 946, Fondation Jean-Dausset-Centre d'Etude du Polymorphisme Humain (CEPH) (F.D., E.B.), Fondation Jean Dausset-CEPH (F.D., E.B., M.L.), and Université Paris Diderot Paris 7, Institut Universitaire d'Hématologie (F.D., E.B.) - all in Paris; University Children's Hospital, Asthma and Allergy Department, Ludwig Maximilians University, Munich, Germany (E.M.); and Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom (M.F.).
Gut Ivo G
National Heart and Lung Institute, Imperial College (M.F.M., W.O.C.M.C.), the Division of Community Health Sciences, St. George's, University of London (D.P.S.), and Royal Brompton and Harefield NHS Foundation Trust (W.O.C.M.C.) - all in London; Commissariat à l'Energie Atomique, Institut de Génomique, Centre National de Génotypage, Evry, France (I.G.G., S.H., M.L.); INSERM, Unité 946, Fondation Jean-Dausset-Centre d'Etude du Polymorphisme Humain (CEPH) (F.D., E.B.), Fondation Jean Dausset-CEPH (F.D., E.B., M.L.), and Université Paris Diderot Paris 7, Institut Universitaire d'Hématologie (F.D., E.B.) - all in Paris; University Children's Hospital, Asthma and Allergy Department, Ludwig Maximilians University, Munich, Germany (E.M.); and Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom (M.F.).
Demenais Florence
National Heart and Lung Institute, Imperial College (M.F.M., W.O.C.M.C.), the Division of Community Health Sciences, St. George's, University of London (D.P.S.), and Royal Brompton and Harefield NHS Foundation Trust (W.O.C.M.C.) - all in London; Commissariat à l'Energie Atomique, Institut de Génomique, Centre National de Génotypage, Evry, France (I.G.G., S.H., M.L.); INSERM, Unité 946, Fondation Jean-Dausset-Centre d'Etude du Polymorphisme Humain (CEPH) (F.D., E.B.), Fondation Jean Dausset-CEPH (F.D., E.B., M.L.), and Université Paris Diderot Paris 7, Institut Universitaire d'Hématologie (F.D., E.B.) - all in Paris; University Children's Hospital, Asthma and Allergy Department, Ludwig Maximilians University, Munich, Germany (E.M.); and Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom (M.F.).
Strachan David P
National Heart and Lung Institute, Imperial College (M.F.M., W.O.C.M.C.), the Division of Community Health Sciences, St. George's, University of London (D.P.S.), and Royal Brompton and Harefield NHS Foundation Trust (W.O.C.M.C.) - all in London; Commissariat à l'Energie Atomique, Institut de Génomique, Centre National de Génotypage, Evry, France (I.G.G., S.H., M.L.); INSERM, Unité 946, Fondation Jean-Dausset-Centre d'Etude du Polymorphisme Humain (CEPH) (F.D., E.B.), Fondation Jean Dausset-CEPH (F.D., E.B., M.L.), and Université Paris Diderot Paris 7, Institut Universitaire d'Hématologie (F.D., E.B.) - all in Paris; University Children's Hospital, Asthma and Allergy Department, Ludwig Maximilians University, Munich, Germany (E.M.); and Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom (M.F.).
Bouzigon Emmanuelle
National Heart and Lung Institute, Imperial College (M.F.M., W.O.C.M.C.), the Division of Community Health Sciences, St. George's, University of London (D.P.S.), and Royal Brompton and Harefield NHS Foundation Trust (W.O.C.M.C.) - all in London; Commissariat à l'Energie Atomique, Institut de Génomique, Centre National de Génotypage, Evry, France (I.G.G., S.H., M.L.); INSERM, Unité 946, Fondation Jean-Dausset-Centre d'Etude du Polymorphisme Humain (CEPH) (F.D., E.B.), Fondation Jean Dausset-CEPH (F.D., E.B., M.L.), and Université Paris Diderot Paris 7, Institut Universitaire d'Hématologie (F.D., E.B.) - all in Paris; University Children's Hospital, Asthma and Allergy Department, Ludwig Maximilians University, Munich, Germany (E.M.); and Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom (M.F.).
Heath Simon
National Heart and Lung Institute, Imperial College (M.F.M., W.O.C.M.C.), the Division of Community Health Sciences, St. George's, University of London (D.P.S.), and Royal Brompton and Harefield NHS Foundation Trust (W.O.C.M.C.) - all in London; Commissariat à l'Energie Atomique, Institut de Génomique, Centre National de Génotypage, Evry, France (I.G.G., S.H., M.L.); INSERM, Unité 946, Fondation Jean-Dausset-Centre d'Etude du Polymorphisme Humain (CEPH) (F.D., E.B.), Fondation Jean Dausset-CEPH (F.D., E.B., M.L.), and Université Paris Diderot Paris 7, Institut Universitaire d'Hématologie (F.D., E.B.) - all in Paris; University Children's Hospital, Asthma and Allergy Department, Ludwig Maximilians University, Munich, Germany (E.M.); and Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom (M.F.).
von Mutius Erika
National Heart and Lung Institute, Imperial College (M.F.M., W.O.C.M.C.), the Division of Community Health Sciences, St. George's, University of London (D.P.S.), and Royal Brompton and Harefield NHS Foundation Trust (W.O.C.M.C.) - all in London; Commissariat à l'Energie Atomique, Institut de Génomique, Centre National de Génotypage, Evry, France (I.G.G., S.H., M.L.); INSERM, Unité 946, Fondation Jean-Dausset-Centre d'Etude du Polymorphisme Humain (CEPH) (F.D., E.B.), Fondation Jean Dausset-CEPH (F.D., E.B., M.L.), and Université Paris Diderot Paris 7, Institut Universitaire d'Hématologie (F.D., E.B.) - all in Paris; University Children's Hospital, Asthma and Allergy Department, Ludwig Maximilians University, Munich, Germany (E.M.); and Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom (M.F.).
Farrall Martin
National Heart and Lung Institute, Imperial College (M.F.M., W.O.C.M.C.), the Division of Community Health Sciences, St. George's, University of London (D.P.S.), and Royal Brompton and Harefield NHS Foundation Trust (W.O.C.M.C.) - all in London; Commissariat à l'Energie Atomique, Institut de Génomique, Centre National de Génotypage, Evry, France (I.G.G., S.H., M.L.); INSERM, Unité 946, Fondation Jean-Dausset-Centre d'Etude du Polymorphisme Humain (CEPH) (F.D., E.B.), Fondation Jean Dausset-CEPH (F.D., E.B., M.L.), and Université Paris Diderot Paris 7, Institut Universitaire d'Hématologie (F.D., E.B.) - all in Paris; University Children's Hospital, Asthma and Allergy Department, Ludwig Maximilians University, Munich, Germany (E.M.); and Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom (M.F.).
Lathrop Mark
National Heart and Lung Institute, Imperial College (M.F.M., W.O.C.M.C.), the Division of Community Health Sciences, St. George's, University of London (D.P.S.), and Royal Brompton and Harefield NHS Foundation Trust (W.O.C.M.C.) - all in London; Commissariat à l'Energie Atomique, Institut de Génomique, Centre National de Génotypage, Evry, France (I.G.G., S.H., M.L.); INSERM, Unité 946, Fondation Jean-Dausset-Centre d'Etude du Polymorphisme Humain (CEPH) (F.D., E.B.), Fondation Jean Dausset-CEPH (F.D., E.B., M.L.), and Université Paris Diderot Paris 7, Institut Universitaire d'Hématologie (F.D., E.B.) - all in Paris; University Children's Hospital, Asthma and Allergy Department, Ludwig Maximilians University, Munich, Germany (E.M.); and Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom (M.F.).
Cookson William O C M
National Heart and Lung Institute, Imperial College (M.F.M., W.O.C.M.C.), the Division of Community Health Sciences, St. George's, University of London (D.P.S.), and Royal Brompton and Harefield NHS Foundation Trust (W.O.C.M.C.) - all in London; Commissariat à l'Energie Atomique, Institut de Génomique, Centre National de Génotypage, Evry, France (I.G.G., S.H., M.L.); INSERM, Unité 946, Fondation Jean-Dausset-Centre d'Etude du Polymorphisme Humain (CEPH) (F.D., E.B.), Fondation Jean Dausset-CEPH (F.D., E.B., M.L.), and Université Paris Diderot Paris 7, Institut Universitaire d'Hématologie (F.D., E.B.) - all in Paris; University Children's Hospital, Asthma and Allergy Department, Ludwig Maximilians University, Munich, Germany (E.M.); and Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom (M.F.).
GABRIEL Consortium
Investigators
164 investigators, click to expand
Moffatt Miriam F
Gut Ivo G
Demenais Florence
Strachan David P
Bouzigon Emmanuelle
Heath Simon
Kumar Ashish
Burney Peter
Jarvis Debbie
Wjst Matthias
Kogevinas Manolis
Jogi Rain
Janson Christer
Franklin Karl A
Omenaas Ernst
Leynaert Benedicte
Pin Isabelle
Heinrich Joachim
Probst-Hensch Nicole M
Anto Josep M
Sunyer Jordi
Maldonado Jose-Antonio
Martinez-Moratalla Jesus
Urrutia Isabel
Payo Felix
Kauffmann Francine
Dizier Marie-Hélène
Siroux Valérie
Boznanski Andrzej
Braun-Fahrländer Charlotte
Genuneit Jon
Glas Juergen
Horak Elisabeth
Kabesch Michael
Pillai Sreekumar G
Helms Peter J
Carlsen Karin
Carlsen Kai-Håkon
Gerritsen Jorrit
Silverman Michael
Sly Peter
Tsanakas John
Von Berg Andrea
Whyte Moira
Blumenthal Malcolm
Imboden Medea
Rochat Thierry
Thun Gian Andri
Gerbase Margaret W
Curjuric Ivan
Gaspoz Jean-Michel
Liu Lee-Jane S
Wouters Inge M
Sigsgaard Torben
Heederik Dick
Basinas Ioannis
Schlunssen Vivi
Omland Øyvind
Cullinan Paul
Vermeulen Roel
Henderson John
Granell Raquel
McArdle Wendy L
Smith George Davey
James Alan L
Hui Jennie
Palmer Lyle J
Beilby John
Musk A William
Laprise Catherine
Hudson Thomas J
Lemire Mathieu
Daley Denise
Becker Allan
Chan-Yeung Moira
Sandford Andrew
Kozyrskyj Anita L
Paré Peter
Ferguson Alexander
Dimich-Ward Helen
Watson Wade T
Freidin Maxim B
Bragina Elena Iu
Deev Ivan A
Deeva Eugenia V
Kobyakova Olga S
Puzyrev Valery P
Ogorodova Ludmila M
Khusnutdinova Elza K
Karunas Alexandra S
Fedorova Yuliya Y
Hall Ian P
Sayers Ian
Tobin Martin D
Wan Yize I
Heaney Liam G
Al-Momani Basima A H
Mansur Adel H
Manney Sarah
Thomson Neil C
Chaudhuri Rekha
Brightling Christopher E
Bafadhel Mona
Singapuri Amisha
Niven Robert
Simpson Angela
Holloway John W
Howarth Peter H
Polonikov Alexey V
Ivanov Vladimir P
Solodilova Maria A
Melén Erik
Pershagen Göran
Bergström Anna
Kull Inger
Nyberg Fredrik
Wickman Magnus
Söderhäll Cilla
Kere Juha
Postma Dirkje S
Kerkhof Marjan
Brunekreef Bert
Smit Henriette A
de Jongste Johan C
Wijga Alet
Aalberse R C
Hoekstra Maarten O
Koppelman Gerard H
Binia Aristea
Chung Kian Fan
Bhavsar Pankaj
Chow Florence
Macedo Patricia
Menzies-Gow Andrew
van Stiphout Nicole
Bush Andrew
Lee Young-Ae
Esparza-Gordillo Jorge
Nickel Renate
Wahn Ulrich
Lau Susanne
Marenholz Ingo
Haahtela Tari
von Hertzen Leena
Jousilahti Pekka
Laatikainen Tiina
Mäkelä Mika J
Vartiainen Erkki
Laitinen Tarja
Balding David J
Peden John F
Corda Eve
Lechner Doris
Besse Cèline
Zelenika Diana
Boland Anne
Bacq Delphine
Demonchy Stephanie
Blanche Helene
Kamatani Yoichiro
von Mutius Erika
Farrall Martin
Lathrop Mark
Cookson William O C M
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Article Info
Journal
The New England journal of medicine
Abbr.
N Engl J Med
ISSN
1533-4406
DOI
10.1056/NEJMoa0906312
Published
2010-09-23
Pages
1211-1221
Language
English
Region
United States
NLM ID
0255562
PMCID
PMC4260321
Subset
IM
Grants
Wellcome Trust · 076113 · United Kingdom
Medical Research Council · G0401540 · United Kingdom
NIEHS NIH HHS · 5P30 ES07048 · United States
Medical Research Council · G0000934 · United Kingdom
NHLBI NIH HHS · R01 HL62633-01 · United States
CIHR · Canada
Medical Research Council · G0902125 · United Kingdom
Wellcome Trust · 077959 · United Kingdom
Wellcome Trust · 084703 · United Kingdom
Wellcome Trust · WT084703MA · United Kingdom
Wellcome Trust · 059168 · United Kingdom
Medical Research Council · MC_QA137934 · United Kingdom
Medical Research Council · G0800649 · United Kingdom
Medical Research Council · G0501942 · United Kingdom
Wellcome Trust · 068545/Z/02 · United Kingdom
Medical Research Council · G9815508 · United Kingdom
Corrections
CommentIn
PMID: 21208119
CommentIn
PMID: 26938664
External Links
PubMed source DOI: 10.1056/NEJMoa0906312 PMC Full Text View journal details
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