AQP4基因多态性与NMO临床表型的相关性分析及功能研究  

Correlation of AQP4 gene polymorphism with NMO clinical phenotypes and its underlying mechanism

作　　者：邱伟[1] 常艳宇 李蕊[1] 龙友明[2] 黄建华[3] 麦卫华[4] 孙晓渤[1] 陆正齐[1] 胡学强[1] 

机构地区：[1]中山大学附属第三医院神经科,广州510630 [2]广州医科大学附属第二医院神经科 [3]中山大学附属第三医院检验科,广州510630 [4]中山大学附属第五医院神经科

出　　处：《中华医学杂志》2015年第7期501-506,共6页National Medical Journal of China

基　　金：国家自然科学基金（81100886）

摘　　要：目的 探讨水通道蛋白4（AQP4）基因多态性与国人视神经脊髓炎（NMO）发病的遗传相关性及分子机制.方法 收集2010年1月至2014年1月在中山大学附属第三医院神经科就诊的血清AQP4抗体（NMO-IgG）阳性的NMO患者111例及NMO谱系疾病（NMOSD）患者97例和健康对照204名作为研究对象.首先,选择AQP4基因调控区的8个单核苷酸多态性位点（SNP）进行基因分型;之后,通过关联分析SNP基因基因型与NMO临床表型的相关性;最后,利用双荧光素酶检测技术验证3＇-非翻译区（3＇-UTR）SNP位点的碱基改变对小分子RNA （miRNA）调控作用的影响.结果 AQP4基因3 ＇-UTR区rs1058424的A/T基因型（50.61％比70.45％,OR=0.430,95％ CI 0.210～0.880）和rs3763043的C/T基因型（50.00％比68.18％,OR=0.467,95％ CI 0.231 ～0.994）与长节段脊髓炎,3＇-UTR区rs1058424的A/T基因型（46.72％比66.28％,OR=0.525,95％ CI0.276～0.999）、rs335929的A/C基因型（45.08％比58.14％,OR=0.527,95％ CI0.281 ～0.987）和启动子0区rs151244的C/T基因型（50.82％比69.77％,OR=0.450,95％ CI 0.230 ～0.881）与视神经炎,3＇-UTR区rs6508459及内含子区rs3763040基因型与合并系统性自身免疫性疾病存在相关性（P分别为0.012和0.023）;miRNA 323-3p对AQP4基因表达有调控作用,但3＇-UTR区rs1058424碱基改变并不影响miRNA 323-3p对AQP4基因的调控.结论 AQP4基因3＇-UTR区的SNP与国人NMO临床表型具有相关性.miRNA 323-3p可能通过与AQP4基因3＇-UTR区某一特定SNP位点结合起调节作用,从而参与NMO发病.Objective To explore the correlation between aquaporin-4 （AQP4） gene single nucleotide polymorphism （SNP） and clinical phenotypes of neuromyelitis optica （NMO） and its underlying mechanism.Methods Eight SNPs in AQP4 gene regulatory region were selected and genotyped for 208 antiAQP4 autoantibodies （NMO-IgG） seropositive cases during January 2010 to January 2014 and 200 healthy subjects.Then the correlation was further analysed between genotypes and NMO phenotypes.And the effect of microRNA （miRNA） on the expression of AQP4 gene was examined by dual-luciferase reporter technique.Results The A/Tgenotypeofrs1058424 （50.61％ vs70.45％,OR=0.430,95％CI0.210-0.880） and C/T （50.00％ vs 68.18％,OR =0.467,95％ CI 0.231-0.994） genotype of rs3763003 in 3＇-UTR were correlated with longitudinal extensive transverse myelitis; the A/T genotype of rs1058424 （46.72％ vs 66.28％,OR =0.525,95％ CI 0.276-0.999） and A/C genotype of rs335929 （45.08％ vs 58.14％,OR =0.527,95％ CI 0.281-0.987） in 3＇-UTR as well as C/T genotype of rs151244 （50.82％ vs 69.77％,OR =0.450,95％ CI 0.230-0.881） in promoter 0 region were correlated with optic neuritis.The polymorphism of rs6508459 in 3＇-UTR and rs3763040 in intron region were correlated with concurrent systemic autoimmune diseases （P =0.012 and 0.023 respectively）.miRNA 323-3p could regulate AQP4 gene expression.However,variation in SNP rs1058424 failed to affect this regulation.Conclusion SNP in 3＇-UTR of AQP4 gene may be associated with NMO phenotypes,miRNA 323-3p may participate in the pathogenesis of NMO by binding to certain SNP sites in 3＇-UTR of AQP4 gene and regulating its expression.

关 键 词：视神经脊髓炎 水通道蛋白4基因 3'-非翻译区 小分子RNA 

分 类 号：R744.52[医药卫生—神经病学与精神病学]