重症肌无力患者HLA-DRB1易感基因的多态性研究
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摘要
目的探讨HLA-DRB1基因多态性在重症肌无力(MG)发病中的作用。方法选择新疆地区MG患者120例作为MG组、120例健康体检者为对照组。运用聚合酶链反应方法-直接测序分型法(PCR-SBT)进行HLA-DRB1等位基因分型。直接计数法计算HLA-DRB1各等位基因频率AF,MG患者组与对照组之间基因频率差异分析采用χ2检验,相对危险度采用比数比(OR)。结果 MG患者与健康对照组DRB1*07、DRB1*15与MG正相关(P <0. 05,OR=3. 653,3. 365,P <0. 05),DRB1*11、DRB1*13、DRB1*08与MG负相关(OR=0. 386、0. 272、0. 216,P <0. 05)。DRB1*09与早发眼肌型MG正相关(OR=22. 565、11. 059,P <0. 05)。DRB1*07与晚发型MG伴有胸腺瘤患者正相关(OR=0. 930、2. 493,P <0. 05)。结论 DRB1*07、DRB1*15与MG易感性有关,MG患者中缺少DRB1*11、DRB1*13,、DRB1*08可能在MG人群中起保护作用。
Objective To explore the effects of HLA-DRB1 gene polymorphism in the pathogenesis of myasthenia gravis(MG). Methods A total of 120 patients with MG in Xinjiang area were enrolled as MG group,and 120 healthy subjects were enrolled as control group. HLA-DRB1 allele typing was performed by polymerase chain reaction method-direct sequencing method(PCR)-SBT). The direct counting method was used to calculate HLA-DRB1 allele frequency AF,and gene frequency differences between MG group and control group were analyzed by using χ2 test,odds ratio(OR) was used to analyze the relative risk. Results The DRB1*07,DRB1*15 were positively correlated with Mg in both groups(P <0. 05),however,DRB1*11,DRB1*13,DRB1*08 were negatively correlated with MG(P < 0. 05). Moreover DRB1*09 was positively correlated with early-onset ocular type MG(P < 0. 05),and DRB1*07 was positively correlated with late-onset MG complicated by thymoma(P < 0. 05). Conclusion DRB1*07,DRB1*15 are correlated with Mgsusceptivity,and the patients with MG lack DRB1*11,DRB1*13,and DRB1*08,which may play a protective role in MG population.
Objective To explore the effects of HLA-DRB1 gene polymorphism in the pathogenesis of myasthenia gravis(MG). Methods A total of 120 patients with MG in Xinjiang area were enrolled as MG group,and 120 healthy subjects were enrolled as control group. HLA-DRB1 allele typing was performed by polymerase chain reaction method-direct sequencing method(PCR)-SBT). The direct counting method was used to calculate HLA-DRB1 allele frequency AF,and gene frequency differences between MG group and control group were analyzed by using χ2 test,odds ratio(OR) was used to analyze the relative risk. Results The DRB1*07,DRB1*15 were positively correlated with Mg in both groups(P <0. 05),however,DRB1*11,DRB1*13,DRB1*08 were negatively correlated with MG(P < 0. 05). Moreover DRB1*09 was positively correlated with early-onset ocular type MG(P < 0. 05),and DRB1*07 was positively correlated with late-onset MG complicated by thymoma(P < 0. 05). Conclusion DRB1*07,DRB1*15 are correlated with Mgsusceptivity,and the patients with MG lack DRB1*11,DRB1*13,and DRB1*08,which may play a protective role in MG population.
引文
1中华医学会神经病学分会神经免疫学组.中国重症肌无力诊断和治疗指南2015.中华神经科杂志,2015,48:934-940.
2中华医学会神经病学分会神经免疫学组重症肌无力诊断和治疗中国专家共识2012.中国神经免疫学和神经病学,2012,11:401-408.
3孙雪松,张荟雪,王娜,等.重症肌无力的分子遗传学研究进展.中华神经科杂志,2013,46:625-629.
4 Donmez B,Ozakbas S,Oktem MA,et al.HLA genotypes in Turkish patients with myasthenia gravis:comparison with multiple sclerosis patients on the basis of clinical subtypes and demographic features.Hum Immunol,2004,65:752-757.
5赵桐茂主编.HLA分型原理和应用.第1版.上海:上海科技出版社,1984.155-157,208.
6 Yang X,Zheng J,Tian S,et al.HLA-DRA/HLA-DRB5 polymorphism affects risk of sporadic ALS and survival in a southwest Chinese cohort.Journal of the Neurological Sciences,2017,373:124.
7李虹霞,郭丽萍,张君,等.CD40、HLA-DR在自身免疫性肝病Kupffer细胞的表达变化.中国实验诊断学,2017,21:1350-1353.
8陈文娟,顾俊瑛,龚瑜,等.活化抗原CD69、HLA-DR在寻常性银屑病外周血单一核细胞和皮损中的表达.中华皮肤科杂志,2015,63:625-628.
9 Nakajima J,Okumura M,Yano M,et al.Myasthenia graviswith thymic epithelial tumour:a retrospective analysis of a Japanesedatabase.Eur JCardiothorac Surg,2016,49:1510-1515.
10 Zhang X,Yang M,Xu J,et al.Clinical and serological study of myasthenia gravis in HuBei Province,China.Neurol Neurosurg Psychiatry,2007,78:386-390.
11 Wong V,Hawkins BR,Yu YL.Myasthenia gravis in Hong Kong Chinese 2 Paediatricdisease.Acta Neurol Scand,1992,86:68-72.
12 Maniaol AH,Elsais A,Lorentzen AR,et al.Late onset myasthenia gravis is a-ssociated with HLA DRB1*15:01 in the Norwegian population.PLo S One,2012,7:e36603.
13 Nikolic AV,Andric ZP,Simonovic RB,et al.High frequency of DQB1*05 and absolute absence of DRB1*13 in muscle-specific tyrosine kinase positive myasthenia gravis.Eur J Neurol,2014,135-138.
14 Fekih-Mrissa N,Klai S,Zaouali J,et al.Association of HLA-DR/DQpolymorphism with myasthenia gravis in Tunisian patients.Clin Neurol Neurosurg,2013,115:32-36.
15 Xie YC,Qu Y,Sun L,et al.Association between HLA-DRB1 and myastheniagravis in a northern Han Chinese population.Clin Neurosci,2011,18:1524-1527.
2中华医学会神经病学分会神经免疫学组重症肌无力诊断和治疗中国专家共识2012.中国神经免疫学和神经病学,2012,11:401-408.
3孙雪松,张荟雪,王娜,等.重症肌无力的分子遗传学研究进展.中华神经科杂志,2013,46:625-629.
4 Donmez B,Ozakbas S,Oktem MA,et al.HLA genotypes in Turkish patients with myasthenia gravis:comparison with multiple sclerosis patients on the basis of clinical subtypes and demographic features.Hum Immunol,2004,65:752-757.
5赵桐茂主编.HLA分型原理和应用.第1版.上海:上海科技出版社,1984.155-157,208.
6 Yang X,Zheng J,Tian S,et al.HLA-DRA/HLA-DRB5 polymorphism affects risk of sporadic ALS and survival in a southwest Chinese cohort.Journal of the Neurological Sciences,2017,373:124.
7李虹霞,郭丽萍,张君,等.CD40、HLA-DR在自身免疫性肝病Kupffer细胞的表达变化.中国实验诊断学,2017,21:1350-1353.
8陈文娟,顾俊瑛,龚瑜,等.活化抗原CD69、HLA-DR在寻常性银屑病外周血单一核细胞和皮损中的表达.中华皮肤科杂志,2015,63:625-628.
9 Nakajima J,Okumura M,Yano M,et al.Myasthenia graviswith thymic epithelial tumour:a retrospective analysis of a Japanesedatabase.Eur JCardiothorac Surg,2016,49:1510-1515.
10 Zhang X,Yang M,Xu J,et al.Clinical and serological study of myasthenia gravis in HuBei Province,China.Neurol Neurosurg Psychiatry,2007,78:386-390.
11 Wong V,Hawkins BR,Yu YL.Myasthenia gravis in Hong Kong Chinese 2 Paediatricdisease.Acta Neurol Scand,1992,86:68-72.
12 Maniaol AH,Elsais A,Lorentzen AR,et al.Late onset myasthenia gravis is a-ssociated with HLA DRB1*15:01 in the Norwegian population.PLo S One,2012,7:e36603.
13 Nikolic AV,Andric ZP,Simonovic RB,et al.High frequency of DQB1*05 and absolute absence of DRB1*13 in muscle-specific tyrosine kinase positive myasthenia gravis.Eur J Neurol,2014,135-138.
14 Fekih-Mrissa N,Klai S,Zaouali J,et al.Association of HLA-DR/DQpolymorphism with myasthenia gravis in Tunisian patients.Clin Neurol Neurosurg,2013,115:32-36.
15 Xie YC,Qu Y,Sun L,et al.Association between HLA-DRB1 and myastheniagravis in a northern Han Chinese population.Clin Neurosci,2011,18:1524-1527.