Kim S-H, Oh J-M, Kim Y-S, Palmer L J, Suh C-H, Nahm D-H, Park H-S
Department of Allergy and Rheumatology, Ajou University School of Medicine, Suwon, Korea.
Clin Exp Allergy. 2006 Apr;36(4):433-9. doi: 10.1111/j.1365-2222.2006.02457.x.
Cysteinyl leukotrienes (CysLTs) play important roles in the pathogenesis of eosinophilic airway inflammation characterized by bronchoconstriction, mucus secretion and airway hyper-responsiveness via cysteinyl leukotriene receptor 1 (CysLTR1)-mediated mechanism. CysLTR1-selective antagonists have anti-bronchoconstrictive and anti-inflammatory effects in asthma, particularly aspirin-intolerant asthma (AIA).
To investigate the association of CysLTR1 with AIA development, we identified three single nucleotide polymorphisms (SNPs), -634C>T, -475A>C, -336A>G, in the 5' upstream region of CysLTR1 gene using a direct sequencing method in 105 AIA patients, 110 ASA-tolerant asthma (ATA) patients and 125 normal healthy controls (NC).
Significant differences were observed in allele frequencies of the three SNPs within male subjects; Male AIA patients had higher frequencies of the minor alleles of these three SNPs than male control groups (P=0.03 for AIA vs. NC; P=0.02 for AIA vs. ATA). Moreover, three-SNP haplotype, ht2 [T-C-G], was associated with increased disease risk (odds ratio (OR)=2.71, P=0.03 for AIA vs. NC; OR=2.89, P=0.02 for AIA vs. ATA) in males. CysLTR1 haplotypes were also associated with altered gene expression; luciferase activity was significantly enhanced with the ht2 [T-C-G] construct in comparison with the ht1 [C-A-A] construct in human Jurkat cells (P=0.04).
These results suggest that genetic variants of CysLTR1 are associated with AIA in a Korean population, and may modulate CysLTR1 expression.
半胱氨酰白三烯（CysLTs）通过半胱氨酰白三烯受体1（CysLTR1）介导的机制，在以支气管收缩、黏液分泌和气道高反应性为特征的嗜酸性气道炎症发病机制中发挥重要作用。CysLTR1选择性拮抗剂在哮喘，尤其是阿司匹林不耐受性哮喘（AIA）中具有抗支气管收缩和抗炎作用。
为了研究CysLTR1与AIA发生之间的关联，我们采用直接测序法在105例AIA患者、110例阿司匹林耐受型哮喘（ATA）患者和125例正常健康对照者（NC）中，鉴定了CysLTR1基因5'上游区域的三个单核苷酸多态性（SNP），即-634C>T、-475A>C、-336A>G。
在男性受试者中观察到这三个SNP的等位基因频率存在显著差异；男性AIA患者中这三个SNP的次要等位基因频率高于男性对照组（AIA与NC相比，P = 0.03；AIA与ATA相比，P = 0.02）。此外，三SNP单倍型ht2 [T-C-G]与男性疾病风险增加相关（优势比（OR）= 2.71，AIA与NC相比，P = 0.03；OR = 2.89，AIA与ATA相比，P = 0.02）。CysLTR1单倍型也与基因表达改变相关；与人类Jurkat细胞中的ht1 [C-A-A]构建体相比，ht2 [T-C-G]构建体的荧光素酶活性显著增强（P = 0.04）。
这些结果表明，CysLTR1的基因变异与韩国人群中的AIA相关，并可能调节CysLTR1的表达。
