【摘要翻译】 胸腺基质淋巴生成素( TSLP) 触发树突状细胞介导的Th2 型炎症反应。一个位于TSLP 基因启动子区域的rs3806933 位点的单核苷酸多态性能产生转录因子激活蛋白( AP) -1 的结合位点。这种变异增强了AP-1 结合到调控元件的能力, 并增强聚肌苷酸胞苷酸刺激人类正常支气管上皮细胞时TSLP 启动子-报告子反应活性。我们研究了这种包括rs3806933 位点的多态性是否影响支气管哮喘的易感性和临床表型。我们选择了三个具有代表性的单核苷酸多态位点进行TSLP 基因相关性研究, 对象为两个独立的人群( 其中一个为693 例儿童特应性哮喘患者和838 例对照者, 另一个为641 例成年哮喘患者和376 名对照者) 。我们进一步检测了糖皮质激素和长效β2 受体激动剂( 沙美特罗) 对聚肌苷酸胞苷酸刺激的人类正常支气管上皮细胞TSLP 基因表达的影响。我们发现启动子多态性位点rs3806933、rs2289276 与儿童特应性哮喘和成人哮喘的易感性均显著相关。功能单核苷酸多态性位点rs3806933 与哮喘相关( Meta 分析, P = 0. 000056; 比值比, 1. 29; 95% 可信区间, 1. 14 ～1. 47) 。Rs2289278 的基因型和肺功能相关。并且, 糖皮质激素和沙美特罗可协同性地抑制聚肌苷酸胞苷酸刺激导致人类正常支气管上皮细胞TSLP mRNA 及蛋白的上调表达。TSLP 多态性变异与支气管哮喘和肺功能显著相关。因此, TSLP可能作为联合治疗的分子靶点。【述评】 越来越多的研究表明哮喘是一种环境和遗传因素相互作用的疾病。本研究不但发现TSLP 启动子多态rs3806933、rs2289276 与儿童特应性哮喘和成人哮喘的易感性均显著相关, 并研究了其导致哮喘炎症反应可能与该多态性位点产生激活蛋白( AP) -1 的转录因子的结合位点。这种变异增强了AP-1 结合到调控元件从而导致基因表达异常。同时, 作者还发现临床常用的哮喘治疗药物ICS 与LABA 的联合制剂可调节TSLP 表达。这些数据表明TSLP在哮喘发病中起重要作用, 并进一步阐明ICS 与LABA 联合治疗的分子机制。该研究不但从分子遗传和分子生物学的角度阐明TSLP多态性在哮喘发病中的分子机制, 并从分子药理层面进一步证实目前常用哮喘治疗方案的合理性, 研究较为深入。
Objective To investigate the tumor suppressor genes of phlegm DNA in smokers, and analyze the correlation between methylation level of tumor suppressor gene promoter and chronic mucus hypersecretion (CMH). Methods The study recruited the patients who were admitted in the respiratory department during 2013-2016 in this hospital, including 700 cases of urban smokers and 380 cases of rural smokers. Eleven genes commonly silenced by promoter methylation in lung cancer and associated with cancer risk were selected. Methylation specific PCR (MSP) was used in the sputum sample of 700 individuals in the urban smokers cohort. Replication was performed in 380 individuals from the rural smokers cohort. Results CMH was significantly associated with an overall increased number of methylated genes, with SULF2 methylation demonstrating the most consistent association. The association between SULF2 methylation and CMH was significantly increased in males but not in females both in the urban and rural groups (OR=2.73, 95%CI 1.53-4.93, P=0.001; OR=2.96, 95%CI 1.47-5.94, P=0.002, respectively). Furthermore, the association between methylation and CMH was more obvious among 139 male former smokers with persistent CMH compared with current smokers (SULF2, OR=3.64, 95%CI 1.57-8.35, P=0.002). Conclusion These findings demonstrate that especially male former smokers with persistent CMH have markedly increased promoter methylation of lung cancer risk genes and potentially could be at increased risk for lung cancer.