多发性硬化HLA-DQB1等位基因多态性及其与临床特征相关性的研究
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摘要
目的总结南方部分地区汉族人多发性硬化(multiple sclerosis,MS)患者的临床特点,并且对其脑脊液、诱发电位和影像学改变进行分析；探讨人类白细胞抗原(Human Leukocyte Antigen,HLA)-DQB1等位基因多态性与我国南方部分地区汉族人群MS的相关性。
方法从诱发因素、起病形式、病程分型、首发症状、累及部位、各项辅助检查情况等多方面对作者医院2004年8月至2010年2月住院和门诊的92例MS患者进行回顾性分析；采用基于测序的分型方法(SBT)对其中42例南方汉人MS患者及48名正常对照进行HLA-DQBl等位基因分型,并比较MS与对照组之间等位基因型频率的差异。
结果(1)临床分析：92例MS患者中,男女比为1：1-2；平均首发年龄(41.20±13.55)岁；起病形式：急性16.30%,.亚急性42.39%,慢性41.30%；病程：复发一缓解型占60.87%；首发症状：肢体无力54.35%,感觉异常38.04%,视力障碍26.09%。累及部位：大脑68.48%,视神经47.83%,脊髓38.04%,脑干26.09%,小脑14.13%。MRI：84例行磁共振检查,大脑发现病灶73.81%,脊髓占38.10%。VEP：阳性率为67.69%；BAEP:阳性率为55%。SEP：阳性率为66.67%。CSF：寡克隆区带检测13例,均为阴性；脑脊液蛋白正常者占51.79%。(2)HLA-DQB1多态性分析：共检测到15种HLA-DQB1等位基因片段,其中DQB1*0502的基因型频率在MS患者中(35.7%)高于正常人群(8.9%),差异有显著统计学意义(P=0.0018, PC=0.027,OR=4.29)。DQB1*0303的等位基因频率在MS患者中(19%)低于正常人群(39.6%)(P=0.04,OR=0.48),但此差异经校正后无统计学差异(Pc>0.05)。HLA-DQB1*0601和DQB1*0602的基因型频率在本组MS患者与正常对照之间差异均无统计学差异(均P>0.05)；(3)MS临床特征与HLA-DQB1等位基因的相关性研究：RR-MS组HLA-DQB1*0502基因型频率(38.9%)明显高于正常人群(8.3%)(P=0.001,),经校正后P值(PC)为0.015,差异有统计学意义,未发现与PP-MS相关的HLA-DQB1等位基因型。发现女性MS患者组DQB1*0502基因型频率(42.3%)明显高于正常女性人群(6.1%)(P=0.001,),经校正后P值(PC)为0.015,差异仍有统计学意义,而男性MS患者与正常男性人群间未发现MS的易感基因。
结论(1)MS病前多有诱因,以急性或亚急性起病为主,女性多见,病程多缓解-复发,首发症状以肢体无力或感觉异常多见,常累及大脑白质和视神经,MRI、EP、CSF检查有助于发现亚临床病变,提高诊断率。(2)我国南方汉族人群MS与HLA-DQB1基因多态的相关性与西方、日本人群者不同。南方汉族人MS与HLA-DQB1*0502相关,而与HLA-DQB1*0601和DQBl*0602无关。(3)RR-MS与HLA-DQB1*0502存在相关性,MS易感基因可能存在性别差异。
Objective To analyze the clinical features and laboratorial findings of multiple sclerosis (MS),and to examine the correlation between MS in Chinese Southern Han population and the polymorphism of HLA-DQB1 alleles.
Methods The clinical data of 92 MS patients admitted to the department of neurology of the Jiangxi Provincial People's Hospital was collected. The epidemiological data, early symptoms and signs, clinical progressive mode, course, and the localization of lesions were analyzed retrospectively. The HLA-DQB1 alleles of 42 subjects from 92 MS patients and 48 normal controls were determined by sequencing-based typing(PCR-SBT)method.The frequency of the HLA-DQB1 alleles were compared between MS subtypes and clinical features and controls byχ2 or Fisher exact probability test. The P values were corrected according to Bonferroni's method to calculate corrected P values (Pc).
Results(1)Clinical analysis:The ratio of male to female was 1:1.2 in 92 MS patients.The average onset age was 41.2 years.The clinical onset was acute in 16.30%, sub-acute in 42.39%,and chronic in 41.30% of the total patients.Sixty-one percent of patients with MS were relapsing and remitting type.The initial symptoms were weakness in 54.35%,abnormal sensation in 38.04%, visual disturbance in 26.09% of the total patients.The localization of lesions were cerebral in 68.48%, optic nerve in 47.83%,spinal cord in 38.04%, brain stem in 26.09%, cerebellum in 14.13%.The MRI data was available in 84 patients;of which 73.81% abnormal signals were found in cerebral and 38.10% were found in spinal cord.The positive rate of abnormal VEP was 67.69%, fifty-five percent patients had abnormal BAEP and sixty-seven percent patients had abnormal SEP.The OB was determined in 13 patients, but none of them were positive. (2) A total of 15 DQB1 alleles were identified in the MS patients and controls.The frequency of the DQB1*0502 allele was significantly higher in the MS patients(35.7%) than in the controls(8.3%) (P=0.0018,Pc=0.027, OR=429).In contrast, the frequency of the DQB1*0303 allele was lower in the MS patients(19%) than in the controls(39.6%)(P=0.04, OR=0.48),however, the difference was of no statistical significance since the corrected P values(PC) was>0.05.In addition,there was no correlation between the MS and HLA-DQB1*0601 or DQB1*0602(both P>0.1).(3)Association between clinical features and HLA-DQB1 alleles:The frequency of HLA-DQB1*0502(38.9%) is higher among RR-MS than controls(8.3%)(P=0.001, Pc=0,015).And the frequency of HLA-DQB1*0502(42.3%)also is higher among female MS than control(6.1%) (P=0.001,Pc=0,015).
Conclusions (1)Precipitating factors are often detected in clinical course.The MS patients were characterized by acute or sub-acute onset, female prepondence and high relapsing rate.Weakness or sensory abnormal were the most frequent initiatial symptoms in most MS patients.Optic nerve is frequently involved.The cerebral white matter lesions were found in nearly half of the MS patients.Some sub-clinical lesions in the CNS may be discovered by EP or MRI.(2) The correlation between the HLA-DQB1 allelic polymorphism and MS in Southern Chinese is different from that in the Westerners and Japanese.The susceptibility of MS in Southern Han Chinese is associated with the HLA-DQB1*0502 allele, but not with the DQB1*0301 or DQB1*0602 alleles.(3)The relapsing-remitting MS may be linked to HLA-DQB1 *0502.Overrepresentation of DQB1*0502 in females is seen in our study.
方法从诱发因素、起病形式、病程分型、首发症状、累及部位、各项辅助检查情况等多方面对作者医院2004年8月至2010年2月住院和门诊的92例MS患者进行回顾性分析；采用基于测序的分型方法(SBT)对其中42例南方汉人MS患者及48名正常对照进行HLA-DQBl等位基因分型,并比较MS与对照组之间等位基因型频率的差异。
结果(1)临床分析：92例MS患者中,男女比为1：1-2；平均首发年龄(41.20±13.55)岁；起病形式：急性16.30%,.亚急性42.39%,慢性41.30%；病程：复发一缓解型占60.87%；首发症状：肢体无力54.35%,感觉异常38.04%,视力障碍26.09%。累及部位：大脑68.48%,视神经47.83%,脊髓38.04%,脑干26.09%,小脑14.13%。MRI：84例行磁共振检查,大脑发现病灶73.81%,脊髓占38.10%。VEP：阳性率为67.69%；BAEP:阳性率为55%。SEP：阳性率为66.67%。CSF：寡克隆区带检测13例,均为阴性；脑脊液蛋白正常者占51.79%。(2)HLA-DQB1多态性分析：共检测到15种HLA-DQB1等位基因片段,其中DQB1*0502的基因型频率在MS患者中(35.7%)高于正常人群(8.9%),差异有显著统计学意义(P=0.0018, PC=0.027,OR=4.29)。DQB1*0303的等位基因频率在MS患者中(19%)低于正常人群(39.6%)(P=0.04,OR=0.48),但此差异经校正后无统计学差异(Pc>0.05)。HLA-DQB1*0601和DQB1*0602的基因型频率在本组MS患者与正常对照之间差异均无统计学差异(均P>0.05)；(3)MS临床特征与HLA-DQB1等位基因的相关性研究：RR-MS组HLA-DQB1*0502基因型频率(38.9%)明显高于正常人群(8.3%)(P=0.001,),经校正后P值(PC)为0.015,差异有统计学意义,未发现与PP-MS相关的HLA-DQB1等位基因型。发现女性MS患者组DQB1*0502基因型频率(42.3%)明显高于正常女性人群(6.1%)(P=0.001,),经校正后P值(PC)为0.015,差异仍有统计学意义,而男性MS患者与正常男性人群间未发现MS的易感基因。
结论(1)MS病前多有诱因,以急性或亚急性起病为主,女性多见,病程多缓解-复发,首发症状以肢体无力或感觉异常多见,常累及大脑白质和视神经,MRI、EP、CSF检查有助于发现亚临床病变,提高诊断率。(2)我国南方汉族人群MS与HLA-DQB1基因多态的相关性与西方、日本人群者不同。南方汉族人MS与HLA-DQB1*0502相关,而与HLA-DQB1*0601和DQBl*0602无关。(3)RR-MS与HLA-DQB1*0502存在相关性,MS易感基因可能存在性别差异。
Objective To analyze the clinical features and laboratorial findings of multiple sclerosis (MS),and to examine the correlation between MS in Chinese Southern Han population and the polymorphism of HLA-DQB1 alleles.
Methods The clinical data of 92 MS patients admitted to the department of neurology of the Jiangxi Provincial People's Hospital was collected. The epidemiological data, early symptoms and signs, clinical progressive mode, course, and the localization of lesions were analyzed retrospectively. The HLA-DQB1 alleles of 42 subjects from 92 MS patients and 48 normal controls were determined by sequencing-based typing(PCR-SBT)method.The frequency of the HLA-DQB1 alleles were compared between MS subtypes and clinical features and controls byχ2 or Fisher exact probability test. The P values were corrected according to Bonferroni's method to calculate corrected P values (Pc).
Results(1)Clinical analysis:The ratio of male to female was 1:1.2 in 92 MS patients.The average onset age was 41.2 years.The clinical onset was acute in 16.30%, sub-acute in 42.39%,and chronic in 41.30% of the total patients.Sixty-one percent of patients with MS were relapsing and remitting type.The initial symptoms were weakness in 54.35%,abnormal sensation in 38.04%, visual disturbance in 26.09% of the total patients.The localization of lesions were cerebral in 68.48%, optic nerve in 47.83%,spinal cord in 38.04%, brain stem in 26.09%, cerebellum in 14.13%.The MRI data was available in 84 patients;of which 73.81% abnormal signals were found in cerebral and 38.10% were found in spinal cord.The positive rate of abnormal VEP was 67.69%, fifty-five percent patients had abnormal BAEP and sixty-seven percent patients had abnormal SEP.The OB was determined in 13 patients, but none of them were positive. (2) A total of 15 DQB1 alleles were identified in the MS patients and controls.The frequency of the DQB1*0502 allele was significantly higher in the MS patients(35.7%) than in the controls(8.3%) (P=0.0018,Pc=0.027, OR=429).In contrast, the frequency of the DQB1*0303 allele was lower in the MS patients(19%) than in the controls(39.6%)(P=0.04, OR=0.48),however, the difference was of no statistical significance since the corrected P values(PC) was>0.05.In addition,there was no correlation between the MS and HLA-DQB1*0601 or DQB1*0602(both P>0.1).(3)Association between clinical features and HLA-DQB1 alleles:The frequency of HLA-DQB1*0502(38.9%) is higher among RR-MS than controls(8.3%)(P=0.001, Pc=0,015).And the frequency of HLA-DQB1*0502(42.3%)also is higher among female MS than control(6.1%) (P=0.001,Pc=0,015).
Conclusions (1)Precipitating factors are often detected in clinical course.The MS patients were characterized by acute or sub-acute onset, female prepondence and high relapsing rate.Weakness or sensory abnormal were the most frequent initiatial symptoms in most MS patients.Optic nerve is frequently involved.The cerebral white matter lesions were found in nearly half of the MS patients.Some sub-clinical lesions in the CNS may be discovered by EP or MRI.(2) The correlation between the HLA-DQB1 allelic polymorphism and MS in Southern Chinese is different from that in the Westerners and Japanese.The susceptibility of MS in Southern Han Chinese is associated with the HLA-DQB1*0502 allele, but not with the DQB1*0301 or DQB1*0602 alleles.(3)The relapsing-remitting MS may be linked to HLA-DQB1 *0502.Overrepresentation of DQB1*0502 in females is seen in our study.
引文
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