The role of LTA4H and ALOX5AP polymorphism in asthma and allergy susceptibility
The role of LTA4H and ALOX5AP polymorphism in asthma and allergy susceptibility
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DOI：
10.1111/j.1398-9995.2008.01667.x
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发表时间：
2008-08-01
期刊：
影响因子：
12.4
通讯作者：
Sayers, I.
中科院分区：
文献类型：
--
作者：
Holloway, J. W.;Barton, S. J.;Sayers, I.
背景：白三烯（LTs）已被确定为哮喘和过敏的中枢介质。药物抑制半胱氨酸- lt活性可改善哮喘症状和控制。越来越多的证据表明，二羟基白三烯LTB4在气道疾病中的作用。LTA(4)水解酶和5-脂氧合酶激活蛋白在LTB4的产生中起关键作用。跨越LTA4H和ALOX5AP基因的单核苷酸多态性（snp）和单倍型与LTB4的产生和心肌梗死（MI）有关。目的：探讨LTA4H和ALOX5AP多态性与哮喘和过敏易感性的关系。方法：对341个高加索家庭（2个哮喘兄弟姐妹）进行基因分型，分析了8个跨越ALOX5AP的snp和5个跨越LTA4H的snp。使用基于家族的关联测试对哮喘和相关表型（总IgE、特应性、支气管高反应性、FEV1）进行关联分析。结果：单点分析发现snp SG13S114、SG13S89、SG13S41 （ALOX5AP）、rs1978331 （LTA4H）与哮喘和/或相关表型之间存在相关性（P < 0.05）。使用所有LTA4H snp的单倍型分析确定了哮喘发展的单一关键风险单倍型（P = 0.006）和相关表型（P = 0.042-0.005）。使用所有ALOX5AP snp进行单倍型分析，确定了几种哮喘和特应性风险和保护性单倍型。这两种基因与先前确定的心肌梗死风险单倍型的相关性有限。ALOX5AP SG13S41和LTA4H rs1978331等位基因携带者患哮喘的风险增加（OR 2.17, CI 1.41-3.32）。结论：这些数据为跨越ALOX5AP和LTA4H基因的snp在高加索人群哮喘和特应性易感性中的作用提供了证据，并支持LTB4在疾病发病机制中的作用。
Background: Leukotrienes (LTs) have been identified as central mediators in asthma and allergy. Pharmacological inhibition of cysteinyl-LT activity improves asthma symptoms and control. Accumulating evidence suggests a role for the dihydroxy leukotriene LTB4 in airway disease. LTA(4) hydrolase and 5-lipoxygenase activating protein have key roles in LTB4 production. Single nucleotide polymorphism (SNPs) and haplotypes spanning the LTA4H and ALOX5AP genes have been associated with LTB4 production and myocardial infarction (MI).Objective: To assess the contribution of LTA4H and ALOX5AP polymorphism to asthma and allergy susceptibility.Methods: Three hundred and forty-one Caucasian families (two asthmatic siblings) were genotyped for eight SNPs spanning ALOX5AP and five SNPs spanning LTA4H. Association analyses of asthma and related phenotypes (total IgE, atopy, bronchial hyper-responsiveness, FEV1) were undertaken using the Family Based Association Test.Results: Single point analyses identified association (P < 0.05) between SNPs SG13S114, SG13S89, SG13S41 (ALOX5AP), rs1978331 (LTA4H) and asthma and/or related phenotypes. Haplotype analyses using all LTA4H SNPs identified a single key risk haplotype for the development of asthma (P = 0.006) and related phenotypes (P = 0.042-0.005). Haplotype analyses using all ALOX5AP SNPs identified several asthma and atopy risk and protective haplotypes. There was limited correlation with previously identified MI risk haplotypes in both genes. Carriers of both ALOX5AP SG13S41 and LTA4H rs1978331 alleles had an increased risk of developing asthma (OR 2.17, CI 1.41-3.32).Conclusions: These data provide evidence for the role of SNPs spanning the ALOX5AP and LTA4H genes in asthma and atopy susceptibility in the Caucasian population and support a role for LTB4 in disease pathogenesis.