Variants of DENND1B Associated with Asthma in Children
Variants of DENND1B Associated with Asthma in Children
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DOI：
10.1056/nejmoa0901867
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发表时间：
2010-01-07
影响因子：
158.5
通讯作者：
Hakonarson, Hakon
中科院分区：
文献类型：
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作者：
Sleiman, Patrick M. A.;Flory, James;Hakonarson, Hakon
哮喘是一种复杂的疾病，有遗传和环境原因。与哮喘易感性相关的遗传因素在很大程度上仍然未知。METHODS我们进行了一项涉及哮喘儿童的全基因组关联研究。样本包括793名患有持续性哮喘的欧洲血统的北美儿童，他们需要每天吸入糖皮质激素治疗，以及1988名匹配的对照组（发现集）。我们还在一个由917名欧洲血统的哮喘患者和1546名匹配的对照（复制集）组成的独立队列中检测了全基因组关联。最后，我们在1667名患有哮喘的非洲血统的北美儿童和2045名血统匹配的对照者中检测了染色体1 q31处的20个单核苷酸多态性（SNP）与哮喘之间的关联。哮喘与先前报道的17 q21基因座上的SNPs之间的关系，以及1 q31上新基因座上的另外8个SNPs。与哮喘相关性最强的SNP是rs 2786098（P = 8.55 x 10（-9））。我们观察到哮喘与SNP rs 2786098的关联在欧洲血统的独立人群中重复出现（合并P = 9.3 x 10（-11））。染色体1 q31上的8个SNPs中的每一个的替代等位基因与非洲血统儿童的哮喘密切相关（所有样本的比较P = 1.6 x 10（-13））。1 q31基因座包含DENND 1B，一个基因，表达的自然杀伤细胞和树突状细胞，并编码一种蛋白质，与肿瘤坏死因子a receptor.CONCLUSIONSWe相互作用，我们已经确定了一个基因座包含DENND 1B染色体1q31.3，这是与哮喘的易感性。
BACKGROUNDAsthma is a complex disease that has genetic and environmental causes. The genetic factors associated with susceptibility to asthma remain largely unknown.METHODSWe carried out a genomewide association study involving children with asthma. The sample included 793 North American children of European ancestry with persistent asthma who required daily inhaled glucocorticoid therapy and 1988 matched controls (the discovery set). We also tested for genomewide association in an independent cohort of 917 persons of European ancestry who had asthma and 1546 matched controls (the replication set). Finally, we tested for an association between 20 single-nucleotide polymorphisms (SNPs) at chromosome 1q31 and asthma in 1667 North American children of African ancestry who had asthma and 2045 ancestrally matched controls.RESULTSIn our meta-analysis of all samples from persons of European ancestry, we observed an association, with genomewide significance, between asthma and SNPs at the previously reported locus on 17q21 and an additional eight SNPs at a novel locus on 1q31. The SNP most strongly associated with asthma was rs2786098 (P = 8.55 x 10(-9)). We observed replication of the association of asthma with SNP rs2786098 in the independent series of persons of European ancestry (combined P = 9.3 x 10(-11)). The alternative allele of each of the eight SNPs on chromosome 1q31 was strongly associated with asthma in the children of African ancestry (P = 1.6 x 10(-13) for the comparison across all samples). The 1q31 locus contains DENND1B, a gene that is expressed by natural killer cells and dendritic cells and that encodes a protein that interacts with the tumor necrosis factor a receptor.CONCLUSIONSWe have identified a locus containing DENND1B on chromosome 1q31.3 that is associated with susceptibility to asthma.