A large-scale, consortium-based genomewide association study of asthma
A large-scale, consortium-based genomewide association study of asthma
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=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.
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. (Funded by the European Commission and others.)
1211-1221
Moffatt, Miriam F.
c8b85a3b-bc0e-47cf-b161-d64a197fe579
Gut, Ivo G.
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Demenais, Florence
624f1028-a62d-4ee5-8059-cce1fdb4cb05
Strachan, David P.
76ddbacc-b6cb-48db-8ab6-77f799c8d1c8
Bouzigon, Emmanuelle
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Heath, Simon
ca3090a2-64ac-4673-bb8e-c36eabeaae04
von Mutius, Erika
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Farrall, Martin
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Lathrop, Mark
ff1cfeeb-96fe-49dc-980f-595ce2f390fb
Cookson, William O.C.M.
f25b485f-af7a-499d-b522-169e5c991f18
Holloway, John
4bbd77e6-c095-445d-a36b-a50a72f6fe1a
23 September 2010
Moffatt, Miriam F.
c8b85a3b-bc0e-47cf-b161-d64a197fe579
Gut, Ivo G.
256d7f09-2976-4981-a1ca-8a68929dde08
Demenais, Florence
624f1028-a62d-4ee5-8059-cce1fdb4cb05
Strachan, David P.
76ddbacc-b6cb-48db-8ab6-77f799c8d1c8
Bouzigon, Emmanuelle
9c2b4d6f-4ccd-4036-bd52-db54e1d0be27
Heath, Simon
ca3090a2-64ac-4673-bb8e-c36eabeaae04
von Mutius, Erika
90135d3a-b0f8-4623-bc99-b68c65af422b
Farrall, Martin
0991d3b8-effa-4c97-8c62-76064361edb6
Lathrop, Mark
ff1cfeeb-96fe-49dc-980f-595ce2f390fb
Cookson, William O.C.M.
f25b485f-af7a-499d-b522-169e5c991f18
Holloway, John
4bbd77e6-c095-445d-a36b-a50a72f6fe1a
Moffatt, Miriam F., Gut, Ivo G. and Demenais, Florence et al.
(2010)
A large-scale, consortium-based genomewide association study of asthma.
New England Journal of Medicine, 363 (13), .
(doi:10.1056/NEJMoa0906312).
(PMID:21208119)
Abstract
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=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.
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. (Funded by the European Commission and others.)
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Published date: 23 September 2010
Organisations:
Human Development & Health
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Local EPrints ID: 177937
URI: http://eprints.soton.ac.uk/id/eprint/177937
PURE UUID: f9c374b6-3f44-425f-9016-d34a7b9640a0
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Date deposited: 27 Jan 2016 14:09
Last modified: 15 Mar 2024 02:56
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Contributors
Author:
Miriam F. Moffatt
Author:
Ivo G. Gut
Author:
Florence Demenais
Author:
David P. Strachan
Author:
Emmanuelle Bouzigon
Author:
Simon Heath
Author:
Erika von Mutius
Author:
Martin Farrall
Author:
Mark Lathrop
Author:
William O.C.M. Cookson
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