Genome-wide association analysis in asthma subjects identifies SPATS2L as a novel bronchodilator response gene.
Genome-wide association analysis in asthma subjects identifies SPATS2L as a novel bronchodilator response gene.
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DOI：
10.1371/journal.pgen.1002824
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发表时间：
2012-07
期刊：
影响因子：
4.5
通讯作者：
Weiss ST
中科院分区：
文献类型：
--
作者：
Himes BE;Jiang X;Hu R;Wu AC;Lasky-Su JA;Klanderman BJ;Ziniti J;Senter-Sylvia J;Lima JJ;Irvin CG;Peters SP;Meyers DA;Bleecker ER;Kubo M;Tamari M;Nakamura Y;Szefler SJ;Lemanske RF Jr;Zeiger RS;Strunk RC;Martinez FD;Hanrahan JP;Koppelman GH;Postma DS;Nieuwenhuis MA;Vonk JM;Panettieri RA Jr;Markezich A;Israel E;Carey VJ;Tantisira KG;Litonjua AA;Lu Q;Weiss ST
支气管扩张剂反应（BDR）是一种重要的哮喘表型，通过比较短效β2受体激动剂（治疗哮喘最常用的急救药物）给药前后的肺功能（即FEV 1）来测量气道阻塞的可逆性。BDR也可作为β2-激动剂功效的测试。BDR是一种复杂的性状，部分受遗传控制。对来自6项药物临床试验（CAMP、LOCCS、LODO、Sepracor、CARE和ACRN进行的药物试验）的1，644名非西班牙裔白色哮喘受试者进行了BDR全基因组关联研究（GWAS），定量为β2-激动剂给药后基线FEV 1的百分比变化。469，884个单核苷酸多态性（SNP）的数据用于使用线性回归模型测量SNP与BDR的关联，同时调整年龄，性别和身高。尝试在SARP的501例白色受试者和DAG的550例白色受试者中复制主要P值。通过siRNA敲除和Western印迹分析获得支持顶部基因的实验证据。SNP rs 295137的最低总体组合P值为9.7E-07，靠近SPATS 2L基因。在主要分析的受试者中，rs 295137 TT基因型受试者的中位BDR为16.0（IQR =[6.2，32.4]），而CC或TC基因型受试者的中位BDR为10.9（IQR =[5.0，22.2]）。 SPATS 2L mRNA敲低导致β2肾上腺素能受体水平升高。我们的研究结果表明，SPATS 2L可能是β2-肾上腺素能受体下调的重要调节因子，并且有希望通过GWAS更好地理解β2-激动剂差异反应的生物学机制。支气管扩张剂反应（BDR）是一种重要的哮喘表型，通过比较短效β2受体激动剂（哮喘治疗常用药物）给药前后的肺功能来衡量气道阻塞的可逆性。我们对来自6个药物临床试验的1,644名白色哮喘受试者进行了BDR的全基因组关联研究，并试图在来自两个独立队列的1,051名白色受试者中复制这些发现。最显著的相关变异位于SPATS 2L基因附近。我们在人气道平滑肌细胞中敲低SPATS 2L mRNA，发现β2-肾上腺素能受体水平增加，表明SPATS 2L可能是BDR的调节剂。我们的研究结果突出了追求GWAS结果的希望，这些结果不一定达到全基因组意义，并且是药物遗传学GWAS结果如何在功能上进行研究的一个例子。
Bronchodilator response (BDR) is an important asthma phenotype that measures reversibility of airway obstruction by comparing lung function (i.e. FEV1) before and after the administration of a short-acting β2-agonist, the most common rescue medications used for the treatment of asthma. BDR also serves as a test of β2-agonist efficacy. BDR is a complex trait that is partly under genetic control. A genome-wide association study (GWAS) of BDR, quantified as percent change in baseline FEV1 after administration of a β2-agonist, was performed with 1,644 non-Hispanic white asthmatic subjects from six drug clinical trials: CAMP, LOCCS, LODO, a medication trial conducted by Sepracor, CARE, and ACRN. Data for 469,884 single-nucleotide polymorphisms (SNPs) were used to measure the association of SNPs with BDR using a linear regression model, while adjusting for age, sex, and height. Replication of primary P-values was attempted in 501 white subjects from SARP and 550 white subjects from DAG. Experimental evidence supporting the top gene was obtained via siRNA knockdown and Western blotting analyses. The lowest overall combined P-value was 9.7E-07 for SNP rs295137, near the SPATS2L gene. Among subjects in the primary analysis, those with rs295137 TT genotype had a median BDR of 16.0 (IQR = [6.2, 32.4]), while those with CC or TC genotypes had a median BDR of 10.9 (IQR = [5.0, 22.2]). SPATS2L mRNA knockdown resulted in increased β2-adrenergic receptor levels. Our results suggest that SPATS2L may be an important regulator of β2-adrenergic receptor down-regulation and that there is promise in gaining a better understanding of the biological mechanisms of differential response to β2-agonists through GWAS. Bronchodilator response (BDR) is an important asthma phenotype that measures reversibility of airway obstruction by comparing lung function before and after the administration of short-acting β2-agonists, common medications used for asthma treatment. We performed a genome-wide association study of BDR with 1,644 white asthmatic subjects from six drug clinical trials and attempted to replicate these findings in 1,051 white subjects from two independent cohorts. The most significant associated variant was near the SPATS2L gene. We knocked down SPATS2L mRNA in human airway smooth muscle cells and found that β2-adrenergic receptor levels increased, suggesting that SPATS2L may be a regulator of BDR. Our results highlight the promise of pursuing GWAS results that do not necessarily reach genome-wide significance and are an example of how results from pharmacogenetic GWAS can be studied functionally.
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影响因子：
6.7
作者：
Drazen, JM;Silverman, EK;Lee, TH
通讯作者：
Lee, TH
DOI：
10.1016/j.cct.2004.03.002
发表时间：
2004-06-01
期刊：
CONTROLLED CLINICAL TRIALS
影响因子：
--
作者：
Guilbert, TW;Morgan, WJ;Martinez, FD
通讯作者：
Martinez, FD
DOI：
10.1164/ajrccm.162.1.9907092
发表时间：
2000-07-01
影响因子：
24.7
作者：
Israel, E;Drazen, JM;Yandava, CN
通讯作者：
Yandava, CN
影响因子：
3.7
作者：
Cooper PR;Mesaros AC;Zhang J;Christmas P;Stark CM;Douaidy K;Mittelman MA;Soberman RJ;Blair IA;Panettieri RA
通讯作者：
Panettieri RA
影响因子：
168.9
作者：
Israel, E;Chinchilli, VM;Drazen, JM
通讯作者：
Drazen, JM