Polymorphism at the glutathione S-transferase GSTP1 locus -: A new marker for bronchial hyperresponsiveness and asthma
Polymorphism at the glutathione S-transferase GSTP1 locus -: A new marker for bronchial hyperresponsiveness and asthma
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DOI：
10.1164/ajrccm.161.5.9903006
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发表时间：
2000-05-01
影响因子：
24.7
通讯作者：
Spiteri, MA
中科院分区：
文献类型：
--
作者：
Fryer, AA;Bianco, A;Spiteri, MA
大多数哮喘的遗传学研究集中在染色体11 q和5 q上的基因及其与支气管高反应性（BHR）和特应性的关键哮喘相关表型的关联。虽然哮喘的特征是气道炎症，其中一个关键组成部分是氧化应激，很少有数据存在的基因参与保护免受这种侮辱。我们描述了一项关联研究，旨在研究谷胱甘肽-S-转移酶GSTP 1位点的等位基因变异是否影响哮喘中BHR和特应性表型的表达。由GSTP 1编码的酶利用氧化应激的多种脂质和DNA产物，并且该基因的多态性变体与该酶的改变的催化功能相关。哮喘组CSTP 1瓦尔（105）/Va（105）频率显著低于对照组。事实上，这种基因型的存在使哮喘的风险比GSTP 1 Ile（105）/Ile（105）低6倍。值得注意的是，校正特应性指数、年龄和性别后，Va（105）纯合子的哮喘风险进一步降低（9倍）。根据支气管反应性/阻塞程度分层后的趋势分析显示，GST 1瓦尔（105）/Va（105）的频率与气道功能障碍的严重程度降低相关。此外，具有GST 1瓦尔（105）/瓦尔（105）的受试者表现出由皮肤试验阳性和IgE水平定义的特应性的风险分别降低4倍和10倍。这些数据表明CSTP 1多态性与哮喘及相关表型密切相关，并为染色体11 q13与BHR和特应性的连锁提供了另一种解释。
Most genetic studies of asthma have concentrated on genes on chromosomes 11q and 5q and their association with the key asthma-related phenotypes of bronchial hyperresponsiveness (BHR) and atopy. Although asthma is characterized by airway inflammation, a critical component of which is oxidative stress, few data exist on genes involved in protecting against this insult. We describe an association study designed to examine whether allelic variation at the glutathione-S-transferase GSTP1 locus influences expression of the BHR and atopy phenotypes in asthma. The enzyme encoded by GSTP1 utilizes a variety of lipid and DNA products of oxidative stress, and polymorphic variants of this gene are associated with altered catalytic function of this enzyme. We found that the frequency of CSTP1 Val(105)/Va(105) was significantly lower in asthmatic than in control subjects. Indeed, the presence of this genotype conferred a sixfold lower risk of asthma than did GSTP1 Ile(105)/Ile(105). Remarkably, asthma risk in Va(105) homozygotes was further reduced (by ninefold) after correction for atopic indices, age, and gender. Trend analysis after stratification according to the degree of bronchial reactivity/obstruction showed that the frequency of GSTP1 Val(105)/Va(105) correlates with decreasing severity of airway dysfunction. Furthermore, subjects with GSTP1 Val(105)/Val(105) have four- and 10-fold lower risks, respectively, of exhibiting atopy defined by skin test positivity and IgE level. These data show that CSTP1 polymorphism is strongly associated with asthma and related phenotypes, and provide an alternative explanation for the linkage of chromosome 11q13 with BHR and atopy.