CHRNA5-A3-B4基因簇多态性与烟草依赖易感性研究进展

Research progress on CHRNA5-A3-B4 gene cluster polymorphisms and susceptibility to tobacco dependence

烟草依赖又称尼古丁依赖,即对烟草中成瘾性物质尼古丁的依赖。尼古丁主要与烟碱型乙酰胆碱受体结合引起多巴胺释放继而导致吸烟成瘾。全基因组关联研究已确定了CHRNA5-A3-B4基因簇与吸烟严重程度和尼古丁依赖之间的关联,CHRNA5编码的α5亚基作为其他nAChRs亚基的“附件”,被证实参与尼古丁对多巴胺神经元的刺激作用,其基因多态性使CHRNA5蛋白序列改变而导致烟草依赖的发生。CHRNA3在大脑某些特定区域表达并在多巴胺神经元调节中发挥作用,其多个SNP位点通过调节mRNA而影响烟草依赖的发生。CHRNB4编码的β4亚基主要与α3亚基共组装共表达,具有缓慢脱敏和对尼古丁低亲和的特点。现综述CHRNA5-A3-B4基因簇多态性与烟草依赖的相关性,为烟草依赖的干预及靶向治疗提供新思路。

Tobacco dependence is also known as nicotine dependence,that is,dependence on nicotine,the addictive substance in tobacco.Nicotine binds primarily to nicotinic acetylcholine receptors and causes the release of dopamine,which leads to smoking addiction.Genome-wide association studies have identified associations between the CHRNA5-A3-B4 gene cluster and smoking severity and nicotine dependence.The alpha5 subunit encoded by CHRNA5,which acts as an accessory subunit to other nAChRs subunits,has been shown to be involved in nicotine stimulation of dopamine neurons.Its gene polymorphism can change CHRNA5 protein sequence and lead to tobacco dependence.CHRNA3 is expressed in some specific regions of the brain and plays a role in the regulation of dopamine neurons.Several SNPS of Chrna3 affect the occurrence of tobacco dependence by regulating mRNA.Theβ4 subunit encoded by CHRNB4 is predominantly coassembled and co-expressed with theα3 subunit for slow desensitization and low affinity for nicotine.This article reviews the correlation between CHRNA5-A3-B4 gene cluster polymorphisms and tobacco dependence,provides new insight for comprehensive intervention and treatment of tobacco dependence.