HLA-DQ基因多态性与重症肌无力的相关性研究
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摘要
目的：通过人类白细胞共同抗原(HLA)DQA1.DQB1基因多态性分析探讨中国华东地区汉人重症肌无力(MG)患者的DQ等位基因和单倍型与发病年龄、临床亚型和乙酰胆碱受体(AChR)抗体水平的相关性,以期回答我国儿童型和眼肌型MG高发的原因。
方法：对196例华东汉族重症肌无力患者和100例同一地区汉族正常对照采用覆盖DQAl第1-4号外显子和DQBl第2、3号外显子的聚合酶链反应一直接测序分型法(PCR-SBT)进行分型。用酶联免疫吸附法测定133例患者血清AChR抗体。DQA1-DQB1单倍型频率用最大似然法估算(EM算法),病例组和对照组差异显著性用Fisher精确检验法检验,相对危险度用比数比(OR)表不。
结果与结论：1.单倍型DQA1*03:02-DQB1*03:03:02(DQ9)与儿童型MG显著相关(OR=4.6,p<0.001),在儿童型MG中携带该单倍型的患者比例(即表型频率)高达88%。
2.单倍型DQA1*03:01:01一DQB1*03:02:01(DQ8)和单倍型DQ9与眼肌型MG显著相关(DQ8:OR=3.4,p<0.01；DQ9:OR=3.5,p<0.001)。其中DQ8与成人晚发型(起病年龄>40岁)眼肌型MG显著相关,DQ9与儿童型(起病≤15岁)和成人早发型(16-40岁起病)眼肌型MG显著相关。
3.单倍型DQ9与MG伴发其它自身免疫病(AID)显著相关(表型频率67%,OR=3.9,p<0.01)。自身免疫性甲状腺疾病为最主要的MG伴发自身免疫病。伴发AlD者与不伴AID者相比在起病年龄、临床分型上并无显著差异,但AChR抗体水平显著降低,可能与DQ9的作用有关。
4.等位基因DQAl*03：02与DQBl*03：03：02呈紧密连锁不平衡,两者组成的单倍型DQ9在汉人中的频率明显高于西方人群。以DQ9为标志的亚洲人祖先单倍型可能是中国汉人儿童眼肌型MG高发的群体遗传基础。
Objectives:Childhood-onset and ocular myasthenia gravis (MG) are more common in Chinese compared to Caucasian populations. HLA-DQ was typed to investigated whether the polymorphism of HLA-DQ genes correlates with onset age of disease, MG clinical subgroups and acetylcholine receptor (AChR) antibody levels.
Methods:196 Chinese Han myasthenia gravis patients from East China and 100 healthy controls from the same region underwent high resolution HLA DQ analysis using polymerase chain reaction- sequence based typing (PCR-SBT) that covered exon 1-4 of DQA1 gene and exon 2 and 3 of DQB1 gene. Serum AChR antibody was determined by enzyme-linked immunosorbent assay in 133 patients before immunosupressive therapy or during clinical exacerbation. DQA1-DQB1 haplotype was estimated using maximum-likelyhood method (EM algorithm). Significancy of differences between case and control was tested by Fisher's exact test. Relative risk was represented by odd ratio (OR).
Results and Conclusions:
1) Haplotype frequency of DQA1*03:02-DQB1*03:03:02 (DQ9) was significantly higher in childhood-onset MG patients (OR=4.6, p<0.001). DQ9 was observed in 88% childhood-onset MG patients.
2) HLA haplotype DQA1*03:01:01-DQB1*03:02:01 (DQ8) and DQ9 frequencies were significantly increased in ocular MG (oMG) patients (OR=3.4, p<0.01; OR=3.5, p<0.001; respectively). DQ8 was assiociated with late-onset oMG (onset age> 40), while DQ9 was associated with early-onset oMG (onset age<= 40).
3) Haplotype frequency of DQ9 was also increased in MG patients with concurrent autoimmune diseases (OR=3.9, p<0.01). This MG subgroup was characterized by low AChR antibody levels, which might due to the effect of DQ9.
4) DQA1*03:02 allele is in high linkage disequilibrim with DQB1*03:03:02, both of which are part of the asian ancestral haplotype. DQ9's high haplotype frequency in Chinese and extremely low frequency in Caucasians is probably the reason underlies the ethnic differences of MG phenotypes.
方法：对196例华东汉族重症肌无力患者和100例同一地区汉族正常对照采用覆盖DQAl第1-4号外显子和DQBl第2、3号外显子的聚合酶链反应一直接测序分型法(PCR-SBT)进行分型。用酶联免疫吸附法测定133例患者血清AChR抗体。DQA1-DQB1单倍型频率用最大似然法估算(EM算法),病例组和对照组差异显著性用Fisher精确检验法检验,相对危险度用比数比(OR)表不。
结果与结论：1.单倍型DQA1*03:02-DQB1*03:03:02(DQ9)与儿童型MG显著相关(OR=4.6,p<0.001),在儿童型MG中携带该单倍型的患者比例(即表型频率)高达88%。
2.单倍型DQA1*03:01:01一DQB1*03:02:01(DQ8)和单倍型DQ9与眼肌型MG显著相关(DQ8:OR=3.4,p<0.01；DQ9:OR=3.5,p<0.001)。其中DQ8与成人晚发型(起病年龄>40岁)眼肌型MG显著相关,DQ9与儿童型(起病≤15岁)和成人早发型(16-40岁起病)眼肌型MG显著相关。
3.单倍型DQ9与MG伴发其它自身免疫病(AID)显著相关(表型频率67%,OR=3.9,p<0.01)。自身免疫性甲状腺疾病为最主要的MG伴发自身免疫病。伴发AlD者与不伴AID者相比在起病年龄、临床分型上并无显著差异,但AChR抗体水平显著降低,可能与DQ9的作用有关。
4.等位基因DQAl*03：02与DQBl*03：03：02呈紧密连锁不平衡,两者组成的单倍型DQ9在汉人中的频率明显高于西方人群。以DQ9为标志的亚洲人祖先单倍型可能是中国汉人儿童眼肌型MG高发的群体遗传基础。
Objectives:Childhood-onset and ocular myasthenia gravis (MG) are more common in Chinese compared to Caucasian populations. HLA-DQ was typed to investigated whether the polymorphism of HLA-DQ genes correlates with onset age of disease, MG clinical subgroups and acetylcholine receptor (AChR) antibody levels.
Methods:196 Chinese Han myasthenia gravis patients from East China and 100 healthy controls from the same region underwent high resolution HLA DQ analysis using polymerase chain reaction- sequence based typing (PCR-SBT) that covered exon 1-4 of DQA1 gene and exon 2 and 3 of DQB1 gene. Serum AChR antibody was determined by enzyme-linked immunosorbent assay in 133 patients before immunosupressive therapy or during clinical exacerbation. DQA1-DQB1 haplotype was estimated using maximum-likelyhood method (EM algorithm). Significancy of differences between case and control was tested by Fisher's exact test. Relative risk was represented by odd ratio (OR).
Results and Conclusions:
1) Haplotype frequency of DQA1*03:02-DQB1*03:03:02 (DQ9) was significantly higher in childhood-onset MG patients (OR=4.6, p<0.001). DQ9 was observed in 88% childhood-onset MG patients.
2) HLA haplotype DQA1*03:01:01-DQB1*03:02:01 (DQ8) and DQ9 frequencies were significantly increased in ocular MG (oMG) patients (OR=3.4, p<0.01; OR=3.5, p<0.001; respectively). DQ8 was assiociated with late-onset oMG (onset age> 40), while DQ9 was associated with early-onset oMG (onset age<= 40).
3) Haplotype frequency of DQ9 was also increased in MG patients with concurrent autoimmune diseases (OR=3.9, p<0.01). This MG subgroup was characterized by low AChR antibody levels, which might due to the effect of DQ9.
4) DQA1*03:02 allele is in high linkage disequilibrim with DQB1*03:03:02, both of which are part of the asian ancestral haplotype. DQ9's high haplotype frequency in Chinese and extremely low frequency in Caucasians is probably the reason underlies the ethnic differences of MG phenotypes.
引文
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