生物谷報(bào)道：兒童哮喘診斷率在上升：美國(guó)6%的兒童是這種疾病的患者。遺傳因素和環(huán)境因素顯然都很重要,。為了發(fā)現(xiàn)更多關(guān)于遺傳因素的線索,，Moffatt等人在一項(xiàng)在整個(gè)基因組范圍內(nèi)尋找疾病關(guān)聯(lián)基因的研究工作中對(duì)與哮喘有關(guān)的基因進(jìn)行了搜索。初患哮喘的年齡在7歲以下的兒童中超過三分之一在第17號(hào)染色體上的ORMDL3基因的表達(dá)上表現(xiàn)出差異,。類似的基因也見于酵母和其他原始生物,，說明它們可能是一個(gè)古老的、在演化過程中保留下來的免疫機(jī)制的構(gòu)成部分,。
原始出處:
Nature 448, 470-473 (26 July 2007) | doi:10.1038/nature06014; Received 24 April 2007; Accepted 14 June 2007; Published online 4 July 2007
Genetic variants regulating ORMDL3 expression contribute to the risk of childhood asthma
Miriam F. Moffatt1,16, Michael Kabesch2,16, Liming Liang3,16, Anna L. Dixon4, David Strachan5, Simon Heath6, Martin Depner2, Andrea von Berg7, Albrecht Bufe8, Ernst Rietschel9, Andrea Heinzmann10, Burkard Simma11, Thomas Frischer12, Saffron A. G. Willis-Owen1, Kenny C. C. Wong1, Thomas Illig13, Christian Vogelberg14, Stephan K. Weiland15, Erika von Mutius2, Gonçalo R. Abecasis3, Martin Farrall4, Ivo G. Gut6, G. Mark Lathrop6 & William O. C. Cookson1
National Heart and Lung Institute, Imperial College, London SW3 6LY, UK
University Children's Hospital, Ludwig Maximilians University, D80337 Munich, Germany
Center for Statistical Genetics, Department of Biostatistics, SPH II, Ann Arbor, Michigan 48109-2029, USA
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK
Division of Community Health Science, St George's, University of London, London SW17 0RE, UK
Centre National de Génotypage, Institut Génomique, Commissariat à l'Énergie Atomique, 91057 Evry, France
Research Institute for the Prevention of Allergic Diseases, Children's Department, Marien-Hospital, D46483 Wesel, Germany
Department of Experimental Pneumology, Ruhr-University, D44789 Bochum, Germany
University Children's Hospital, University of Cologne, D50924 Cologne, Germany
University Children's Hospital, Albert Ludwigs University, D79106 Freiburg, Germany
Children's Department, Feldkirch Hospital, A6800 Feldkirch, Austria
University Children's Hospital Vienna, A1090 Vienna, Austria
Institute of Epidemiology, GSF-Research Centre for Environment and Health, D85764 Neuherberg, Germany
University Children's Hospital, Technical University Dresden, D01307 Dresden, Germany
Institute of Epidemiology, Ulm University, D89081 Germany
These authors contributed equally to this work.
Correspondence to: William O. C. Cookson1 Correspondence and requests for materials should be addressed to W.O.C.C. (Email: [email protected]).
Asthma is caused by a combination of poorly understood genetic and environmental factors1, 2. We have systematically mapped the effects of single nucleotide polymorphisms (SNPs) on the presence of childhood onset asthma by genome-wide association. We characterized more than 317,000 SNPs in DNA from 994 patients with childhood onset asthma and 1,243 non-asthmatics, using family and case-referent panels. Here we show multiple markers on chromosome 17q21 to be strongly and reproducibly associated with childhood onset asthma in family and case-referent panels with a combined P value of P < 10-12. In independent replication studies the 17q21 locus showed strong association with diagnosis of childhood asthma in 2,320 subjects from a cohort of German children (P = 0.0003) and in 3,301 subjects from the British 1958 Birth Cohort (P = 0.0005). We systematically evaluated the relationships between markers of the 17q21 locus and transcript levels of genes in Epstein–Barr virus (EBV)-transformed lymphoblastoid cell lines from children in the asthma family panel used in our association study. The SNPs associated with childhood asthma were consistently and strongly associated (P < 10-22) in cis with transcript levels of ORMDL3, a member of a gene family that encodes transmembrane proteins anchored in the endoplasmic reticulum3. The results indicate that genetic variants regulating ORMDL3 expression are determinants of susceptibility to childhood asthma.
