Kim Sang-Heon, Kim Yoon-Keun, Park Heung-Woo, Jee Young-Koo, Kim Sang-Hoon, Bahn Joon-Woo, Chang Yoon-Seok, Kim Seung-Hyun, Ye Young-Min, Shin Eun-Soon, Lee Jong-Eun, Park Hae-Sim, Min Kyung-Up
Department of Internal Medicine, Seoul National University College of Medicine, Korea.
Pharmacogenet Genomics. 2007 Apr;17(4):295-304. doi: 10.1097/01.fpc.0000239977.61841.fe.
Genetic predisposition is linked to the pathogenesis of aspirin-intolerant asthma. Most candidate gene approaches have focused on leukotriene-related pathways, whereas there have been relatively few studies evaluating the effects of polymorphisms in prostanoid receptor genes on the development of aspirin-intolerant asthma. Therefore, we investigated the potential association between prostanoid receptor gene polymorphisms and the aspirin-intolerant asthma phenotype.
We screened for genetic variations in the prostanoid receptor genes PTGER1, PTGER2, PTGER3, PTGER4, PTGDR, PTGIR, PTGFR, and TBXA2R using direct sequencing, and selected 32 tagging single nucleotide polymorphisms among the 77 polymorphisms with frequencies >0.02 based on linkage disequilibrium for genotyping. We compared the genotype distributions and allele frequencies of three participant groups (108 patients with aspirin-intolerant asthma, 93 patients with aspirin-tolerant asthma, and 140 normal controls).
Through association analyses studies of the 32 single nucleotide polymorphisms, the following single nucleotide polymorphisms were found to have significant associations with the aspirin-intolerant asthma phenotype: -616C>G (P=0.038) and -166G>A (P=0.023) in PTGER2; -1709T>A (P=0.043) in PTGER3; -1254A>G (P=0.018) in PTGER4; 1915T>C (P=0.015) in PTGIR; and -4684C>T (P=0.027), and 795T>C (P=0.032) in TBXA2R. In the haplotype analysis of each gene, the frequency of PTGIR ht3[G-G-C-C], which includes 1915T>C, differed significantly between the aspirin-intolerant asthma patients and aspirin-tolerant asthma patients (P=0.015).
These findings suggest that genetic polymorphisms in PTGER2, PTGER3, PTGER4, PTGIR, and TBXA2R play important roles in the pathogenesis of aspirin-intolerant asthma.
遗传易感性与阿司匹林不耐受性哮喘的发病机制相关。大多数候选基因研究都集中在白三烯相关途径，而评估前列腺素受体基因多态性对阿司匹林不耐受性哮喘发展影响的研究相对较少。因此，我们调查了前列腺素受体基因多态性与阿司匹林不耐受性哮喘表型之间的潜在关联。
我们使用直接测序法筛查前列腺素受体基因PTGER1、PTGER2、PTGER3、PTGER4、PTGDR、PTGIR、PTGFR和TBXA2R中的基因变异，并基于连锁不平衡从77个频率>0.02的多态性中选择32个标签单核苷酸多态性进行基因分型。我们比较了三组参与者（108例阿司匹林不耐受性哮喘患者、93例阿司匹林耐受性哮喘患者和140例正常对照）的基因型分布和等位基因频率。
通过对32个单核苷酸多态性的关联分析研究，发现以下单核苷酸多态性与阿司匹林不耐受性哮喘表型有显著关联：PTGER2中的-616C>G（P=0.038）和-166G>A（P=0.023）；PTGER3中的-1709T>A（P=0.043）；PTGER4中的-1254A>G（P=0.018）；PTGIR中的1915T>C（P=0.015）；以及TBXA2R中的-4684C>T（P=0.027）和795T>C（P=0.032）。在每个基因的单倍型分析中，包含1915T>C的PTGIR ht3[G-G-C-C]频率在阿司匹林不耐受性哮喘患者和阿司匹林耐受性哮喘患者之间有显著差异（P=0.015）。
这些发现表明，PTGER2、PTGER3、PTGER4、PTGIR和TBXA2R中的基因多态性在阿司匹林不耐受性哮喘的发病机制中起重要作用。
