Allelic association and functional studies of promoter polymorphism in the leukotriene C4 synthase gene (LTC4S) in asthma
Allelic association and functional studies of promoter polymorphism in the leukotriene C4 synthase gene (LTC4S) in asthma
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DOI：
10.1136/thorax.58.5.417
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发表时间：
2003-05-01
期刊：
影响因子：
10
通讯作者：
Holgate, ST
中科院分区：
文献类型：
--
作者：
Sayers, I;Barton, S;Holgate, ST
背景：LTC4合成酶对半胱氨酰白三烯(Cys-LT)的产生是必不可少的，半胱氨酰白三烯是哮喘的关键介质。我们已经发现了一种新的启动子-1072(G/A)和-444(A/C)多态。方法：对341个白种人家系(两个哮喘兄弟姐妹)和184名非哮喘对照受试者进行基因分型，以验证基因与哮喘表型的相关性。使用病例对照和传递不平衡检验(TDT)分析来评估基因关联。结果：病例对照分析未发现LTC4S启动子荧光素酶基因与Hela和KU812F细胞的功能相关(-1072A，q=0.09；-444C，q=0.29)；TDT发现-444C等位基因与支气管乙酰甲胆碱的反应性存在边缘关联(p=0.065)。携带-444C等位基因的哮喘儿童1s基础用力呼气量较低(97.4vs92.7%，P=0.005)。LTC4S启动子荧光素酶分析没有证据表明这两种多态在决定基础转录中的功能作用。结论：这项研究不支持这些多态在哮喘遗传易感性中的作用，但提供了证据表明这些多态在决定肺功能参数中的作用。
Background: LTC4 synthase is essential for the production of cysteinyl leukotrienes (Cys-LT), critical mediators in asthma. We have identified a novel promoter polymorphism at position -1072 (G/A) and a - 444 (A/C) polymorphism has previously been reported. The role of these polymorphisms in the genetic susceptibility to asthma was examined.Methods: To test for genetic association with asthma phenotypes, 341 white families ( two asthmatic siblings) and 184 non-asthmatic control subjects were genotyped. Genetic association was assessed using case control and transmission disequilibrium test (TDT) analyses. LTC4S promoter luciferase constructs and transiently transfected human HeLa and KU812F cells were generated to determine the functional role of these polymorphisms on basal transcription.Results: No associations were observed in case control analyses ( - 1072 A, q=0.09; - 444 C, q=0.29); the TDT identified a borderline association between the - 444 C allele and bronchial responsiveness to methacholine ( p=0.065). Asthmatic children with the - 444 C allele had a lower mean basal forced expiratory volume in 1 second ( 97.4 v 92.7% predicted, p=0.005). LTC4S promoter luciferase analyses provided no evidence for a functional role of either polymorphism in determining basal transcription.Conclusion: This study does not support a role for these polymorphisms in genetic susceptibility to asthma but provides evidence to suggest a role in determining lung function parameters.