Genetic variants regulating ORMDL3 expression contribute to the risk of childhood asthma
Genetic variants regulating ORMDL3 expression contribute to the risk of childhood asthma
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DOI：
10.1038/nature06014
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发表时间：
2007-07-26
期刊：
影响因子：
64.8
通讯作者：
Cookson, William O. C.
中科院分区：
文献类型：
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作者：
Moffatt, Miriam F.;Kabesch, Michael;Cookson, William O. C.
哮喘是由遗传和环境因素的结合所引起的（1，2）。我们系统地绘制了单核苷酸多态性（SNPs）对儿童期哮喘发病的影响，通过全基因组关联。我们使用家庭和病例参考小组，对994名儿童发作哮喘患者和1，243名非哮喘患者的DNA中超过317，000个SNP进行了特征分析。在此，我们发现染色体17 q21上的多个标记物与家族和病例参照组中的儿童期发作的哮喘有很强的可重复的相关性，组合P值为P < 10（-12）。在独立的重复研究中，17 q21位点与来自德国儿童队列的2，320名受试者（P=0.0003）和来自英国1958年出生队列的3，301名受试者（P=0.0005）的儿童哮喘诊断密切相关。我们系统地评估了17 q21基因座标记物与EB-巴尔病毒（EBV）转化的淋巴母细胞样细胞系中基因转录水平之间的关系，这些细胞系来自我们关联研究中使用的哮喘家族组中的儿童。与儿童哮喘相关的SNP与ORMDL 3的转录水平顺式一致且强烈相关（P < 10（-22）），ORMDL 3是编码锚定在内质网中的跨膜蛋白的基因家族成员（3）。结果表明，调节ORMDL 3表达的遗传变异是儿童哮喘易感性的决定因素。
Asthma is caused by a combination of poorly understood genetic and environmental factors(1,2). 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 reticulum(3). The results indicate that genetic variants regulating ORMDL3 expression are determinants of susceptibility to childhood asthma.