一项基于大型联盟的哮喘全基因组关联研究。
A large-scale, consortium-based genomewide association study of asthma.
机构信息
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.).
出版信息
N Engl J Med. 2010 Sep 23;363(13):1211-1221. doi: 10.1056/NEJMoa0906312.
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.)
背景
哮喘易感性受基因和环境影响；相关基因可能提示治疗干预途径。遗传风险因素可能有助于识别哮喘亚型，并确定血清总 IgE 水平升高等中间表型是否与疾病有因果关系。
方法
我们对 10365 名经医生诊断患有哮喘的患者和 16110 名未患病者进行了全基因组关联研究，所有患者均按祖源匹配。我们使用随机效应合并分析来检测整个研究人群以及儿童期起病哮喘（定义为 16 岁前发病）、晚发型哮喘、严重哮喘和职业性哮喘患者亚组中的关联。
结果
我们观察到哮喘与以下单核苷酸多态性之间存在全基因组显著关联：2 号染色体上的 rs3771166，提示 IL1RL1/IL18R1（P=3×10(−9)）；6 号染色体上的 rs9273349，提示 HLA-DQ（P=7×10(−14)）；9 号染色体上的 rs1342326，提示 IL33 侧翼（P=9×10(−10)）；15 号染色体上的 rs744910，提示 SMAD3（P=4×10(−9)）；22 号染色体上的 rs2284033，提示 IL2RB（P=1.1×10(−8)）。17q21 上的 ORMDL3/GSDMB 基因座与儿童期起病疾病的关联具有特异性（rs2305480，P=6×10(−23)）。仅 HLA-DR 与血清总 IgE 浓度存在全基因组显著关联，与 IgE 水平强烈相关的基因座与哮喘无关。
结论
哮喘具有遗传异质性。少数常见等位基因与所有年龄段的疾病风险相关。提示基因参与上皮损伤与适应性免疫系统的通讯以及气道炎症的激活。ORMDL3/GSDMB 基因座上的变异仅与儿童期起病疾病相关。血清总 IgE 水平升高在哮喘发病中的作用较小。（由欧盟委员会等资助）。
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