Genome-Wide Association Study of Short-Acting β2-Agonists A Novel Genome-Wide Significant Locus on Chromosome 2 near ASB3
Genome-Wide Association Study of Short-Acting β2-Agonists A Novel Genome-Wide Significant Locus on Chromosome 2 near ASB3
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DOI：
10.1164/rccm.201408-1426oc
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发表时间：
2015-03-01
影响因子：
24.7
通讯作者：
Tantisira, Kelan G.
中科院分区：
文献类型：
--
作者：
Israel, Elliot;Lasky-Su, Jessica;Tantisira, Kelan G.
原理：[β(2) - 激动剂是治疗哮喘最常见的形式，但对这些药物的反应存在显著差异。这种反应性的很大一部分可能是可遗传的。目的：研究全基因组关联研究（GWAS）是否能在哮喘中识别新的药物遗传学位点。方法：我们对吸入β(2) - 激动剂的急性支气管扩张剂反应（BDR）进行了一项GWAS。在来自单核苷酸多态性健康关联资源（SHARe）哮喘资源项目（SHARP）的724名个体中，共检测了444,088个单核苷酸多态性（SNPs）。排名前50的SNPs在444名个体的人群中进行了验证。测量和主要结果：在对多重比较进行校正后，4个SNPs的综合P值达到了全基因组统计学意义。rs350729、rs1840321、rs1384918和rs1319797的综合P值分别为2.21×10⁻¹⁰、5.75×10⁻⁸、9.3×10⁻⁸、3.95×10⁻⁸。这些显著的变异都定位在2号染色体上靠近ASB3基因的一个新的基因区域，该区域与平滑肌增殖有关。与野生型相比，在原始人群中，次要等位基因的存在使BDR程度降低了20%，在验证人群中降低的百分比相似。结论：这些针对哮喘患者BDR的GWAS研究结果表明，一个与平滑肌增殖相关的基因可能影响哮喘中发生的一部分平滑肌松弛。
Rationale: [beta(2)-Agonists are the most common form of treatment of asthma, but there is significant variability in response to these medications. A significant proportion of this responsiveness may be heritable.Objectives: To investigate whether a genome-wide association study (GWAS) could identify novel pharmacogenetic loci in asthma.Methods: We performed a GWAS of acute bronchodilator response (BDR) to inhaled beta(2)-agonists. A total of 444,088 single-nucleotide polymorphisms (SNPs) were examined in 724 individuals from the SNP Health Association Resource (SHARe) Asthma Resource Project (SHARP). The top 50 SNPs were carried forward to replication in a population of 444 individuals.Measurements and Main Results: The combined P value for four SNPs reached statistical genome-wide significance after correcting for multiple comparisons. Combined P values for rs350729, rs1840321, rs1384918, and rs1319797 were 2:21 X 10(-10), 5.75 X 10(-8), 9.3 X 10(-8), 3.95 X 10(-8), respectively. The significant variants all map to a novel genetic region on chromosome 2 neat the ASB3 gene, a region associated with smooth muscle proliferation. As compared with the wild type, the presence of the minor alleles reduced the degree of BDR by 20% in the original population and by a similar percentage in the confirmatory population.Conclusions: These GWAS findings for BDR in subjects with asthma suggest that a gene associated with smooth muscle proliferation may influence a proportion of the smooth muscle relaxation that occurs in asthma.