Sayers I, Barton S, Rorke S, Sawyer J, Peng Q, Beghé B, Ye S, Keith T, Clough J B, Holloway J W, Sampson A P, Holgate S T
Divisions of Human Genetics Infection, Inflammation and Repair, University of Southampton School of Medicine, Southampton General Hospital, Tremona Road, Southampton, UK.
Clin Exp Allergy. 2003 Aug;33(8):1103-10. doi: 10.1046/j.1365-2222.2003.01733.x.
5-Lipoxygenase (5-LO) and 5-lipoxygenase-activating protein (FLAP) are essential for cysteinyl-leukotriene (cys-LT) production, critical mediators in asthma.
We sought to identify novel promoter polymorphisms within the FLAP (ALOX5AP) gene promoter and test the role of these and the previously identified 5-LO (ALOX5) Sp1 promoter polymorphism in asthma susceptibility.
To assess genetic association with asthma phenotypes, we genotyped 341 Caucasian families (containing two asthmatic siblings) and non-asthmatic control subjects (n=184). Genetic association was determined by case-control and transmission disequilibrium test (TDT) analyses. To determine the functional role of polymorphisms on basal transcription, we generated ALOX5AP-promoter-luciferase constructs and transiently transfected human HeLa cells.
A novel G/A substitution at -336 bp and a poly(A) repeat (n=19 or 23) at position -169 to -146 bp were identified in the ALOX5AP promoter. Genotyping found the -336 A and poly(A19) alleles at frequencies of q=0.06 and 0.12, respectively. No ALOX5AP allele was associated with asthma or asthma-related phenotypes in case-control or TDT analyses. ALOX5AP-promoter-luciferase analyses did not support a functional role of the -336 or poly(A) polymorphism in determining basal transcription. The ALOX5 Sp1 polymorphism was predominantly homozygous wild-type 5/5 (frequency q=0.70) and heterozygous 4/5 (q=0.23) genotypes and no allele was associated with asthma or asthma-related phenotypes.
Taken together, these data do not support a significant role for these polymorphisms in genetic susceptibility to asthma in the Caucasian population.
5-脂氧合酶（5-LO）和5-脂氧合酶激活蛋白（FLAP）是半胱氨酰白三烯（cys-LT）生成所必需的，而cys-LT是哮喘中的关键介质。
我们试图鉴定FLAP（ALOX5AP）基因启动子内的新型启动子多态性，并测试这些多态性以及先前鉴定的5-LO（ALOX5）Sp1启动子多态性在哮喘易感性中的作用。
为了评估与哮喘表型的遗传关联，我们对341个白种人家庭（包含两名哮喘患者同胞）和非哮喘对照受试者（n = 184）进行了基因分型。通过病例对照和传递不平衡检验（TDT）分析确定遗传关联。为了确定多态性对基础转录的功能作用，我们构建了ALOX5AP启动子-荧光素酶构建体，并瞬时转染人HeLa细胞。
在ALOX5AP启动子中鉴定出-336 bp处的新型G/A替换以及-169至-146 bp处的poly(A)重复序列（n = 19或23）。基因分型发现-336 A和poly(A19)等位基因的频率分别为q = 0.06和0.12。在病例对照或TDT分析中，没有ALOX5AP等位基因与哮喘或哮喘相关表型相关。ALOX5AP启动子-荧光素酶分析不支持-336或poly(A)多态性在确定基础转录中的功能作用。ALOX5 Sp1多态性主要是纯合野生型5/5（频率q = 0.70）和杂合4/5（q = 0.23）基因型，没有等位基因与哮喘或哮喘相关表型相关。
综上所述，这些数据不支持这些多态性在白种人群体哮喘遗传易感性中起重要作用。
