Genome-wide association study of asthma exacerbations despite inhaled corticosteroid use.
Genome-wide association study of asthma exacerbations despite inhaled corticosteroid use.
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DOI：
10.1183/13993003.03388-2020
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发表时间：
2021-05
期刊：
影响因子：
--
通讯作者：
PiCA and SysPharmPedia consortia
中科院分区：
文献类型：
--
作者：
Hernandez-Pacheco N;Vijverberg SJ;Herrera-Luis E;Li J;Sio YY;Granell R;Corrales A;Maroteau C;Lethem R;Perez-Garcia J;Farzan N;Repnik K;Gorenjak M;Soares P;Karimi L;Schieck M;Pérez-Méndez L;Berce V;Tavendale R;Eng C;Sardon O;Kull I;Mukhopadhyay S;Pirmohamed M;Verhamme KMC;Burchard EG;Kabesch M;Hawcutt DB;Melén E;Potočnik U;Chew FT;Tantisira KG;Turner S;Palmer CN;Flores C;Pino-Yanes M;Maitland-van der Zee AH;PiCA and SysPharmPedia consortia
吸入性皮质类固醇(ICS)对哮喘治疗的反应在个人和人群中有很大的差异，这表明遗传因素起到了作用。尽管如此，到目前为止，只发现了几个基因。我们的目标是确定与哮喘恶化相关的基因变异，尽管在欧洲儿童和年轻人中使用ICS，并验证在非欧洲人中的发现。此外，我们还探索了基因集浓缩分析是否可以提供潜在的哮喘治疗新方法。在8项研究中，对2681名接受ICS治疗的欧洲裔儿童进行了哮喘恶化的全基因组关联研究(GWAS)。在538名欧洲哮喘患者中，对暗示关联信号进行了重复跟踪。对1773名非欧洲人进行了进一步的评估。对已发表的GWAS揭示的变异进行了复制评估。此外，还进行了以药物为重点的基因集浓缩分析。有10个独立变异与哮喘加重有关，尽管ICS治疗处于发现阶段(p≤5×10−6)。其中，CACNA2D3-WNT5A基因座的一个变异在欧洲人中名义上是复制的(rs67026078，p=0.010)，但这在非欧洲人中没有得到证实。之前研究中与ICS反应相关的其他五个基因也被重复。此外，还发现曲古抑素A处理所调节的基因中的关联性丰富。CACNA2D3和Wnt5A的基因间隔区被发现是一个新的哮喘加重的基因位点，尽管在欧洲人群中接受了ICS治疗。相关基因与曲古抑素A相关，提示该药可能调节参与治疗反应的分子机制。
Substantial variability in response to asthma treatment with inhaled corticosteroids (ICS) has been described among individuals and populations, suggesting the contribution of genetic factors. Nonetheless, only a few genes have been identified to date. We aimed to identify genetic variants associated with asthma exacerbations despite ICS use in European children and young adults and to validate the findings in non-Europeans. Moreover, we explored whether a gene-set enrichment analysis could suggest potential novel asthma therapies. A genome-wide association study (GWAS) of asthma exacerbations was tested in 2,681 European-descent children treated with ICS from eight studies. Suggestive association signals were followed up for replication in 538 European asthma patients. Further evaluation was performed in 1,773 non-Europeans. Variants revealed by published GWAS were assessed for replication. Additionally, gene-set enrichment analysis focused on drugs was performed. Ten independent variants were associated with asthma exacerbations despite ICS treatment in the discovery phase (p≤5×10−6). Of those, one variant at the CACNA2D3-WNT5A locus was nominally replicated in Europeans (rs67026078, p = 0.010), but this was not validated in non-European populations. Five other genes associated with ICS response in previous studies were replicated. Additionally, an enrichment of associations in genes regulated by trichostatin A treatment was found. The intergenic region of CACNA2D3 and WNT5A was revealed as a novel locus for asthma exacerbations despite ICS treatment in European populations. Genes associated were related to trichostatin A, suggesting that this drug could regulate the molecular mechanisms involved in treatment response.
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来自1,092个人基因组的遗传变异的综合图。
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
2.1
作者：
Farzan, Niloufar;Vijverberg, Susanne J.;Maitland-van der Zee, Anke H.
通讯作者：
Maitland-van der Zee, Anke H.
影响因子：
1.9
作者：
Grossman, Nicole L.;Doros, Gheorghe D.;Israel, Elliot
通讯作者：
Israel, Elliot
影响因子：
9.6
作者：
Cerasoli, Franklin, Jr.
通讯作者：
Cerasoli, Franklin, Jr.
影响因子：
5.8
作者：
Kamat, Mihir A.;Blackshaw, James A.;Staley, James R.
通讯作者：
Staley, James R.