哮喘患者支气管扩张剂反应的全基因组关联研究。
A genome-wide association study of bronchodilator response in asthmatics.
作者信息
Duan Q L, Lasky-Su J, Himes B E, Qiu W, Litonjua A A, Damask A, Lazarus R, Klanderman B, Irvin C G, Peters S P, Hanrahan J P, Lima J J, Martinez F D, Mauger D, Chinchilli V M, Soto-Quiros M, Avila L, Celedón J C, Lange C, Weiss S T, Tantisira K G
机构信息
Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
1] Channing Division of Network Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA [2] Center for Genomic Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
出版信息
Pharmacogenomics J. 2014 Feb;14(1):41-7. doi: 10.1038/tpj.2013.5. Epub 2013 Mar 19.
Reversibility of airway obstruction in response to β2-agonists is highly variable among asthmatics, which is partially attributed to genetic factors. In a genome-wide association study of acute bronchodilator response (BDR) to inhaled albuterol, 534 290 single-nucleotide polymorphisms (SNPs) were tested in 403 white trios from the Childhood Asthma Management Program using five statistical models to determine the most robust genetic associations. The primary replication phase included 1397 polymorphisms in three asthma trials (pooled n=764). The second replication phase tested 13 SNPs in three additional asthma populations (n=241, n=215 and n=592). An intergenic SNP on chromosome 10, rs11252394, proximal to several excellent biological candidates, significantly replicated (P=1.98 × 10(-7)) in the primary replication trials. An intronic SNP (rs6988229) in the collagen (COL22A1) locus also provided strong replication signals (P=8.51 × 10(-6)). This study applied a robust approach for testing the genetic basis of BDR and identified novel loci associated with this drug response in asthmatics.
哮喘患者中，气道阻塞对β2受体激动剂的反应可逆性差异很大，部分原因是遗传因素。在一项关于吸入沙丁胺醇后急性支气管扩张反应（BDR）的全基因组关联研究中，利用五种统计模型，对来自儿童哮喘管理项目的403个白人三联体中的534290个单核苷酸多态性（SNP）进行了检测，以确定最可靠的遗传关联。主要复制阶段包括在三项哮喘试验中对1397个多态性进行检测（合并样本量n = 764）。第二个复制阶段在另外三个哮喘人群（样本量分别为n = 241、n = 215和n = 592）中对13个SNP进行了检测。位于10号染色体上的一个基因间SNP，rs11252394，靠近几个优秀的生物学候选基因，在主要复制试验中得到了显著的重复验证（P = 1.98×10−7）。胶原蛋白（COL22A1）基因座中的一个内含子SNP（rs6988229）也提供了强烈的重复验证信号（P = 8.51×10−6）。本研究采用了一种可靠的方法来检测BDR的遗传基础，并确定了与哮喘患者这种药物反应相关的新基因座。
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