Importin-13 genetic variation is associated with improved airway responsiveness in childhood asthma.
Importin-13 genetic variation is associated with improved airway responsiveness in childhood asthma.
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DOI：
10.1186/1465-9921-10-67
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发表时间：
2009-07-20
影响因子：
5.8
通讯作者：
Weiss ST
中科院分区：
文献类型：
--
作者：
Raby BA;Van Steen K;Lasky-Su J;Tantisira K;Kaplan F;Weiss ST
糖皮质激素的功能取决于糖皮质激素受体（GR）从细胞质到细胞核的有效易位。 Importin-13 (IPO13) 是一种核转运受体，介导 GR 进入核。在气道上皮细胞中，抑制 IPO13 表达可阻止 GR 进入核并消除糖皮质激素的抗炎作用。 GR 入核受损已在类固醇无反应性哮喘患者中得到证实。我们假设常见的 IPO13 遗传变异影响吸入皮质类固醇治疗哮喘的抗炎作用，通过乙酰甲胆碱气道高反应性 (AHR-PC20) 的变化来衡量。对参与儿童哮喘管理计划 (CAMP) 的 654 名轻度至中度哮喘儿童的 10 种多态性进行了评估，该计划是一项吸入抗炎药物（布地奈德和奈多罗米）的临床试验。使用混合模型进行基于人群的关联测试，并重复测量 PC20，并使用基于家庭的关联测试进行确认。在随机接受安慰剂或奈多罗米的参与者中，IPO13 多态性与 PC20 改善（即较少的 AHR）相关，携带次要等位基因的受试者在随机化后 8 个月时表现出平均 PC20 平均增加 1.51–2.17 倍，并持续了四年的观察（p = 0.01–0.005）。这种改善与长期吸入皮质类固醇治疗的儿童的改善相似。在接受吸入皮质类固醇治疗的儿童中，IPO13 变异体的 PC20 没有进一步改善。 IPO13 变异与哮喘儿童 AHR 改善相关。这种改善的程度与长期吸入皮质类固醇治疗观察到的相似，表明 IPO13 变异可能会改善内源性糖皮质激素的核生物利用度。
Glucocorticoid function is dependent on efficient translocation of the glucocorticoid receptor (GR) from the cytoplasm to the nucleus of cells. Importin-13 (IPO13) is a nuclear transport receptor that mediates nuclear entry of GR. In airway epithelial cells, inhibition of IPO13 expression prevents nuclear entry of GR and abrogates anti-inflammatory effects of glucocorticoids. Impaired nuclear entry of GR has been documented in steroid-non-responsive asthmatics. We hypothesize that common IPO13 genetic variation influences the anti-inflammatory effects of inhaled corticosteroids for the treatment of asthma, as measured by change in methacholine airway hyperresponsiveness (AHR-PC20). 10 polymorphisms were evaluated in 654 children with mild-to-moderate asthma participating in the Childhood Asthma Management Program (CAMP), a clinical trial of inhaled anti-inflammatory medications (budesonide and nedocromil). Population-based association tests with repeated measures of PC20 were performed using mixed models and confirmed using family-based tests of association. Among participants randomized to placebo or nedocromil, IPO13 polymorphisms were associated with improved PC20 (i.e. less AHR), with subjects harboring minor alleles demonstrating an average 1.51–2.17 fold increase in mean PC20 at 8-months post-randomization that persisted over four years of observation (p = 0.01–0.005). This improvement was similar to that among children treated with long-term inhaled corticosteroids. There was no additional improvement in PC20 by IPO13 variants among children treated with inhaled corticosteroids. IPO13 variation is associated with improved AHR in asthmatic children. The degree of this improvement is similar to that observed with long-term inhaled corticosteroid treatment, suggesting that IPO13 variation may improve nuclear bioavailability of endogenous glucocorticoids.
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影响因子：
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作者：
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通讯作者：
YAMAMOTO, KR
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DOI：
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DOI：
10.1165/ajrcmb.22.4.3929
发表时间：
2000-04-01
影响因子：
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