Miriam F Moffatt1, Ivo G Gut1, Florence Demenais1, David P Strachan1, Emmanuelle Bouzigon1, Simon Heath1, Erika von Mutius1, Martin Farrall1, Mark Lathrop1, William O C M Cookson1. 1. 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.).
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.)
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.)
Authors: Maxine Allen; Andrea Heinzmann; Emiko Noguchi; Gonçalo Abecasis; John Broxholme; Chris P Ponting; Sumit Bhattacharyya; Jon Tinsley; Youming Zhang; Richard Holt; E Yvonne Jones; Nick Lench; Alisoun Carey; Helene Jones; Nicholas J Dickens; Claire Dimon; Rosie Nicholls; Crystal Baker; Luzheng Xue; Elizabeth Townsend; Michael Kabesch; Stephan K Weiland; David Carr; Erika von Mutius; Ian M Adcock; Peter J Barnes; G Mark Lathrop; Mark Edwards; Miriam F Moffatt; William O C M Cookson Journal: Nat Genet Date: 2003-10-19 Impact factor: 38.330
Authors: D H Smith; D C Malone; K A Lawson; L J Okamoto; C Battista; W B Saunders Journal: Am J Respir Crit Care Med Date: 1997-09 Impact factor: 21.405
Authors: Jennifer M Taylor; Teresa L Street; Lizhong Hao; Richard Copley; Martin S Taylor; Patrick J Hayden; Gina Stolper; Richard Mott; Jotun Hein; Miriam F Moffatt; William O C M Cookson Journal: PLoS One Date: 2009-10-30 Impact factor: 3.240
Authors: Carole Ober; Zheng Tan; Ying Sun; Jennifer D Possick; Lin Pan; Raluca Nicolae; Sadie Radford; Rodney R Parry; Andrea Heinzmann; Klaus A Deichmann; Lucille A Lester; James E Gern; Robert F Lemanske; Dan L Nicolae; Jack A Elias; Geoffrey L Chupp Journal: N Engl J Med Date: 2008-04-09 Impact factor: 91.245
Authors: Paul Elliott; John C Chambers; Weihua Zhang; Robert Clarke; Jemma C Hopewell; John F Peden; Jeanette Erdmann; Peter Braund; James C Engert; Derrick Bennett; Lachlan Coin; Deborah Ashby; Ioanna Tzoulaki; Ian J Brown; Shahrul Mt-Isa; Mark I McCarthy; Leena Peltonen; Nelson B Freimer; Martin Farrall; Aimo Ruokonen; Anders Hamsten; Noha Lim; Philippe Froguel; Dawn M Waterworth; Peter Vollenweider; Gerard Waeber; Marjo-Riitta Jarvelin; Vincent Mooser; James Scott; Alistair S Hall; Heribert Schunkert; Sonia S Anand; Rory Collins; Nilesh J Samani; Hugh Watkins; Jaspal S Kooner Journal: JAMA Date: 2009-07-01 Impact factor: 56.272
Authors: Emmanouela Repapi; Ian Sayers; Louise V Wain; Paul R Burton; Toby Johnson; Ma'en Obeidat; Jing Hua Zhao; Adaikalavan Ramasamy; Guangju Zhai; Veronique Vitart; Jennifer E Huffman; Wilmar Igl; Eva Albrecht; Panos Deloukas; John Henderson; Raquel Granell; Wendy L McArdle; Alicja R Rudnicka; Inês Barroso; Ruth J F Loos; Nicholas J Wareham; Linda Mustelin; Taina Rantanen; Ida Surakka; Medea Imboden; H Erich Wichmann; Ivica Grkovic; Stipan Jankovic; Lina Zgaga; Anna-Liisa Hartikainen; Leena Peltonen; Ulf Gyllensten; Asa Johansson; Ghazal Zaboli; Harry Campbell; Sarah H Wild; James F Wilson; Sven Gläser; Georg Homuth; Henry Völzke; Massimo Mangino; Nicole Soranzo; Tim D Spector; Ozren Polasek; Igor Rudan; Alan F Wright; Markku Heliövaara; Samuli Ripatti; Anneli Pouta; Asa Torinsson Naluai; Anna-Carin Olin; Kjell Torén; Matthew N Cooper; Alan L James; Lyle J Palmer; Aroon D Hingorani; S Goya Wannamethee; Peter H Whincup; George Davey Smith; Shah Ebrahim; Tricia M McKeever; Ian D Pavord; Andrew K MacLeod; Andrew D Morris; David J Porteous; Cyrus Cooper; Elaine Dennison; Seif Shaheen; Stefan Karrasch; Eva Schnabel; Holger Schulz; Harald Grallert; Nabila Bouatia-Naji; Jérôme Delplanque; Philippe Froguel; John D Blakey; John R Britton; Richard W Morris; John W Holloway; Debbie A Lawlor; Jennie Hui; Fredrik Nyberg; Marjo-Riitta Jarvelin; Cathy Jackson; Mika Kähönen; Jaakko Kaprio; Nicole M Probst-Hensch; Beate Koch; Caroline Hayward; David M Evans; Paul Elliott; David P Strachan; Ian P Hall; Martin D Tobin Journal: Nat Genet Date: 2009-12-13 Impact factor: 38.330
Authors: Miriam F Moffatt; Michael Kabesch; Liming Liang; Anna L Dixon; David Strachan; Simon Heath; Martin Depner; Andrea von Berg; Albrecht Bufe; Ernst Rietschel; Andrea Heinzmann; Burkard Simma; Thomas Frischer; Saffron A G Willis-Owen; Kenny C C Wong; Thomas Illig; Christian Vogelberg; Stephan K Weiland; Erika von Mutius; Gonçalo R Abecasis; Martin Farrall; Ivo G Gut; G Mark Lathrop; William O C Cookson Journal: Nature Date: 2007-07-04 Impact factor: 49.962
Authors: Minna Anthoni; Guoying Wang; Marina S Leino; Antti I Lauerma; Harri T Alenius; Henrik J Wolff Journal: Int J Biol Sci Date: 2007-11-24 Impact factor: 6.580
Authors: Jared M Bischof; Christopher J Ott; Shih-Hsing Leir; Nehal Gosalia; Lingyun Song; Darin London; Terrence S Furey; Calvin U Cotton; Gregory E Crawford; Ann Harris Journal: Thorax Date: 2011-12-14 Impact factor: 9.139
Authors: Dara G Torgerson; Daniel Capurso; Rasika A Mathias; Penelope E Graves; Ryan D Hernandez; Terri H Beaty; Eugene R Bleecker; Benjamin A Raby; Deborah A Meyers; Kathleen C Barnes; Scott T Weiss; Fernando D Martinez; Dan L Nicolae; Carole Ober Journal: Am J Hum Genet Date: 2012-02-10 Impact factor: 11.025
Authors: Emma Lefrançais; Stephane Roga; Violette Gautier; Anne Gonzalez-de-Peredo; Bernard Monsarrat; Jean-Philippe Girard; Corinne Cayrol Journal: Proc Natl Acad Sci U S A Date: 2012-01-17 Impact factor: 11.205