Functional polymorphism in the suppressor of cytokine signaling 1 gene associated with adult asthma
Functional polymorphism in the suppressor of cytokine signaling 1 gene associated with adult asthma
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DOI：
10.1165/rcmb.2006-0090oc
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发表时间：
2007-04-01
影响因子：
6.4
通讯作者：
Tamari, Mayumi
中科院分区：
文献类型：
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作者：
Harada, Michishige;Nakashima, Kazuko;Tamari, Mayumi
细胞因子信号传导抑制因子（SOCS）1是IFN-γ信号传导的重要生理调节因子，其对于引起适当的免疫应答至关重要，并且IFN-γ产生受损被认为是特应性疾病的标志。最近的研究表明，SOCS 1在减弱1型IFN信号传导和限制宿主对病毒感染的反应中也是至关重要的。临床和实验证据表明呼吸道病毒感染在哮喘的发展中起重要作用。为了评估SOCS 1基因功能变异与日本成人哮喘易感性和临床表型的关系，我们对462名成人哮喘患者和639名对照者进行了相关性和单倍型分析。筛选多态性后，我们确定了共13个变种和特点的连锁不平衡（LD）基因定位。选择三种变异体进行LD模式的基因分型，我们发现SOCS 1启动子多态性-1478CAdel与成人哮喘之间存在显著相关性（P = 0.0063）。使用这三个多态性的SOCS 1的三个位点单倍型也显示与单倍型T-C-del（-5388T、-3969C和-1478 del; P = 0.0097）正相关。此外，报告基因分析显示，相关的启动子变体-1478 del增强了SOCS 1在人肺上皮细胞中的转录水平，并诱导了更高水平的SOCS 1蛋白表达和更低水平的STAT 1磷酸化。这些结果表明，SOCS 1基因可能通过功能遗传多态性参与成人哮喘的发生。
Suppressor of cytokine signaling (SOCS) 1 is an essential physiologic regulator of the IFN-gamma signaling that is crucial to lead appropriate immune responses, and impaired IFN-gamma production is considered a hallmark of atopic diseases. Recent study has shown that SOCS1 is also crucial in attenuating type 1 IFN signaling and in limiting the host response to viral infection. Clinical and experimental evidence suggest an important role for respiratory viral infections in the development of asthma. To assess genetic functional variants of SOCS1 related to susceptibility and clinical phenotypes in adult asthma in a Japanese population, we conducted association and haplotype analyses of 462 subjects with adult asthma and 639 control subjects. After screening for polymorphisms, we identified a total of 13 variants and characterized the linkage disequilibrium (LD) mapping of the gene. Three variants were selected for genotyping with regard to the LD pattern, and we found a significant association between an SOCS1 promoter polymorphism -1478CA del and adult asthma (P = 0.0063). The three-locus haplotype of SOCS1 using these three polymorphisms also showed a positive association with a haplotype T-C-del (-5388T, -3969C, and -1478 del; P = 0.0097). Furthermore, reporter gene analysis revealed that related promoter variant -1478 del enhanced the transcriptional level of SOCS1 in human lung epithelial cells, and induced higher levels of protein expression of SOCS1 and lower phosphorylation of STAT1 stimulated with IFN-beta. These findings suggest that the SOCS1 gene might be involved in the development of adult asthma through functional genetic polymorphism.