From gene identifications to therapeutic targets for asthma:Focus on great potentials of TSLP,ORMDL3,and GSDMB

Asthma is a chronic respiratory disease,and clinically,asthma exacerbations remain difficult to treat.The disease is caused by combinations of and interactions between genetic and environmental factors.Genomic and genetic approaches identified many novel genes to treat asthma and brought new insights into the disease.The products of the genes have functional roles in regulating physiological or pathophysiological processes in airway structural cells and immune system cells.Genetic factors also interact with environmental factors such as air pollutants,and bacterial and viral infections to trigger the disease.Thymic stromal lymphopoietin(TSLP),orosomucoid-like 3(ORMDL3),and gasdermin B(GSDMB)are three genes identified by genetic studies to have a great potential as therapeutic targets of asthma.TSLP is an important driver of type 2 inflammation.ORMDL3 mediates cell stress,sphingolipid synthesis,and viral and bacterial infections.GSDMB regulates cell pyroptosis through its N and C terminals and can bind sulfatides to influence inflammatory response.Investigating inhibitors or modulators for these pathways would bring a new landscape for therapeutics of asthma in future.

中国南方汉族人群哮喘与GSDMB/ORMDL3基因多态性

目的研究GSDMB/ORMDL3基因相关单核苷酸多态性位点(SNP)与中国广东人群哮喘发病、吸烟行为的相关性。方法于2014年3月—2015年3月对广东医学院附属医院就诊的394例哮喘患者、395名健康成人进行血样采集和问卷调查,用SNa Pshot技术检测GSDMB/ORMDL 3基因单核苷酸多态性(SNP)rs7216389、rs4794820、rs11650680基因型,并分析SNP变异与哮喘风险及吸烟因素的相关性。结果 SNP位点rs7216389C-T和rs4794820 A-G变异增加哮喘发病风险(OR分别为1.8和1.7,均为P<0.000 1),而rs11650680 C-T位点变异与哮喘风险无明显相关性(OR=0.8,P=0.170 0);吸烟哮喘患者rs7216389 T/T和rs11650680 C/C高于戒烟与非吸烟组,而rs4794820 A/A低于非吸烟组(均为P<0.000 1)。结论 rs7216389 C-T、rs4794820 A-G位点变异与哮喘发病风险明显相关,吸烟增加rs7216389 C-T、rs4794820 A-G、rs11650680 T-C位点的变异风险。

ORM DL3/GSDM B基因多态性与儿童支气管哮喘遗传易感性的 M eta分析

目的 探讨ORMDL3/GSDMB基因（rs7216389）多态性与儿童支气管哮喘（哮喘）易感性的关系。方法 检索PubMed数据库、万方数据库、中国知网全文数据库、维普数据库、中国生物医学文献数据库发表的有关ORMDL3/GSDMB 基因多态性与儿童哮喘的病例对照研究的文献，OR值及95% CI为效应指标，采用固定或随机效应模型进行合并分析，并进行偏倚评估。应用Review manager5.0软件进行统计学处理。结果 共纳入文献6篇，包含哮喘病例3289例，对照3391例。与野生基因型 CC相比，TT合并的 OR值（95% CI）为1.86（1.58～2.20），TT＋TC合并的OR值（95% CI）为1.56（1.35～1.80），按人群进行分层分析，亚洲人群TT、TT＋TC的OR值（95% CI）分别为1.51（1.15～1.98）、1.50（1.15～1.96），欧洲人群 TT、TT ＋TC的 OR值（95% CI）分别为 2.11（1.71～2.61）、1.69（1.42～2.02）。结论 ORMDL3/GSDMB基因（rs7216389）多态性与儿童哮喘易感性相关，与欧洲人群相比，亚洲人群易感性相对较低。