A large-scale, consortium-based genomewide association study of asthma.
A large-scale, consortium-based genomewide association study of asthma.
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DOI：
10.1056/nejmoa0906312
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发表时间：
2010-09-23
期刊：
影响因子：
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通讯作者：
GABRIEL Consortium
中科院分区：
文献类型：
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作者：
Moffatt MF;Gut IG;Demenais F;Strachan DP;Bouzigon E;Heath S;von Mutius E;Farrall M;Lathrop M;Cookson WOCM;GABRIEL Consortium
哮喘的易感性受基因和环境的影响；相关基因可能指示治疗干预的途径。遗传风险因素可能有助于确定哮喘的亚型，并确定中间表型，如血清总IgE水平的升高，是否与疾病有因果关系。我们进行了一项全基因组关联研究，对10,365名医生诊断为哮喘的患者和16,110名未受影响的人进行了基因分型，所有人的祖先都是匹配的。我们使用随机效应合并分析来测试整个研究人群和患有儿童期哮喘(定义为16岁之前发展的哮喘)、晚发型哮喘、重度哮喘和职业性哮喘的受试者的相关性。我们观察到哮喘与下列单核苷酸多态有关：位于第2染色体的rs3771166，涉及IL1RL1/IL18R1(P=3×10−9)；位于第6染色体的rs9273349，涉及人类白细胞抗原DQ(P=7×10−14)；位于第9染色体的rs1342326，位于IL33两侧(P=9×10−10)；位于SMAD3的第15染色体的rs744910(P=4×10−9)；以及位于22号染色体的rs2284033(P=1.1×10−8)。染色体17q21上的ORMDL3/GSDMB基因座与儿童发病有关(rs2305480，P=6×10−23)。只有人类白细胞抗原DR与血清总IgE浓度有显著的全基因组相关性，而与IgE水平密切相关的基因座与哮喘无关。哮喘在遗传上是异质性的。一些常见的等位基因在所有年龄段都与疾病风险相关。相关基因提示上皮损伤与适应性免疫系统之间的联系以及呼吸道炎症的激活。ORMDL3/GSDMB基因的变异只与儿童期发病有关。血清总IgE水平升高在哮喘的发生发展中起次要作用。(由欧盟委员会和其他机构提供资金。)
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.)