Park Jong Sook, Chang Hun Soo, Park Choon-Sik, Lee June-Hyuk, Lee Yong Mok, Choi Jung Hee, Park Hae-Sim, Kim Lyoung Hyo, Park Byung Lae, Choi Yoo Hyun, Shin Hyoung Doo
Asthma Genome Research Group, Soonchunhyang University Hospital, Seoul, Korea.
Pharmacogenet Genomics. 2005 Jul;15(7):483-92. doi: 10.1097/01.fpc.0000166456.84905.a0.
The cysteinyl leukotriene receptor 2 (CYSLTR2) gene on chromosome 13q14.12-q21.1 encodes a receptor for CYSLTs, potent biological mediators in the pathogenesis of asthma, particularly that associated with aspirin intolerance (AIA). In an effort to discover additional polymorphism(s), the variant(s) of which have been implicated in asthma and aspirin intolerance, we scrutinized genetic polymorphisms of the CYSLTR2 gene, and evaluated this locus as a potential candidate for asthma.
DNA sequencing in 24 Koreans of the 5-kb region of the CYSLTR2 gene, including the approximately 1500-bp promoter region, revealed four sequence variants: one in the 5'-flanking region (c.-819T>G), two in the 3'-flanking region (c.2078C>T and c.2534A>G), and one downstream of the gene (c.2545+297A>G). The SNP frequencies were 0.499 (c.-819T>G), 0.351 (c.2078C>T), 0.429 (c.2534A>G), and 0.088 (c.2545+297A>G), and five haplotypes were constructed. The SNPs and haplotypes were not associated with risk of asthma development, but were significantly associated with aspirin intolerance. The frequencies of rare alleles on c.-819T>G, c.2078C>T, and c.2534A>G were higher in subjects with AIA than in subjects with aspirin-tolerant asthma (P=0.013-0.031). Asthmatics who had rare alleles for c.-819T>G, c.2078C>T or c.2534A>G exhibited a more pronounced fall in FEV1 after aspirin provocation than did those who carried the common allele (P=0.03-0.009). Asthmatics carrying ht2 (TTGA) also showed a more pronounced decrease in FEV1% after aspirin provocation than those carrying ht1 (GCGA) (P=0.006). These associations were even stronger when combined with LTC4S polymorphisms (-444A>C [c.-444A>C]) gene.
CYSLTR2 polymorphisms are associated with aspirin intolerance in asthmatics.
位于13q14.12 - q21.1染色体上的半胱氨酰白三烯受体2（CYSLTR2）基因编码一种白三烯（CYSLTs）受体，白三烯是哮喘发病机制中重要的生物介质，尤其是与阿司匹林不耐受（AIA）相关的发病机制。为了发现更多与哮喘和阿司匹林不耐受相关的多态性，我们仔细研究了CYSLTR2基因的遗传多态性，并将该基因座评估为哮喘的潜在候选基因。
对24名韩国人CYSLTR2基因5kb区域（包括约1500bp的启动子区域）进行DNA测序，发现了四个序列变异：一个在5'侧翼区域（c.-819T>G），两个在3'侧翼区域（c.2078C>T和c.2534A>G），一个在基因下游（c.2545+297A>G）。单核苷酸多态性（SNP）频率分别为0.499（c.-819T>G）、0.351（c.2078C>T）、0.429（c.2534A>G）和0.088（c.2545+297A>G），并构建了五种单倍型。这些SNP和单倍型与哮喘发病风险无关，但与阿司匹林不耐受显著相关。在AIA患者中，c.-819T>G、c.2078C>T和c.2534A>G上罕见等位基因的频率高于阿司匹林耐受型哮喘患者（P = 0.013 - 0.031）。携带c.-819T>G、c.2078C>T或c.2534A>G罕见等位基因的哮喘患者在阿司匹林激发后FEV1下降比携带常见等位基因的患者更明显（P = 0.03 - 0.009）。携带ht2（TTGA）的哮喘患者在阿司匹林激发后FEV1%下降也比携带ht1（GCGA）的患者更明显（P = 0.006）。当与白三烯C4合成酶（LTC4S）多态性（-444A>C [c.-444A>C]）基因联合分析时，这些关联更强。
CYSLTR2基因多态性与哮喘患者的阿司匹林不耐受相关。
