中国北方汉族人群TNF-α-238G/A、HLA-DRB1及HLA-DQA1基因多态性与HBV感染不同结局的关联研究
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摘要
人类感染乙型肝炎病毒(hepatitis B virus，HBV)后临床结局不同，其原因之一可能与宿主遗传因素密切相关。T细胞介导的免疫反应在HBV感染的病毒清除和发病机制中起主导作用，人类白细胞抗原(Human leucocyte antigen，HLA)可能参与免疫应答的遗传控制，肿瘤坏死因子(tumor necrosis factor，TNF)-α与HBV病毒清除以及宿主对病毒的免疫反应过程有关。本研究应用病例对照研究方法，在中国北方汉族人群中选取207例慢性乙型肝炎患者、212例无症状HBV长期携带者(HBV携带者)和148例HBV自限性感染者作为研究对象，采用限制性片段长度多态性和序列特异引物法检测其TNF-α-238G／A、HLA-DRB1和HLA-DQA1的基因多态性，分析遗传因素与环境因素的交互作用，以探讨其与HBV感染结局的关系。主要结果如下：
1、TNF-α-238GG基因型的频率在慢性乙型肝炎、HBV携带和HBV自限性感染组的频率分别为98.07％、91.98％和93.24％，G等位基因的频率分别为99.03％、95.99％和96.62％。等位基因G的频率在慢性乙型肝炎组明显高于HBV携带者(x~2=7.94，P=0.0048)和自限性感染组(x~2=5.20，P=0.0226)。HBV携带组和HBV自限性感染组等位基因G的频率分布无明显统计学意义(x~2=0.19，P=0.6610)。
2、HLA-DRB1*01等位基因在HBV自限性感染组的频率为5.41％，显著高于HBV携带组的2.36％(x~2=4.65，P=0.0311)；HLA-DRB1*12在慢性乙型肝炎组的频率为17.32％，明显高于HBV携带组的12.03％(x~2=4.67，P=0.0307)；HLA-DRB1*09在HBV携带组的频率为20.52％，明显高于慢性乙型肝炎组的13.66％(x~2=6.91，P=0.0086)。
3、慢性乙型肝炎组HLA-DQA1*0301等位基因频率(14.81％)显著低于HBV携带组(25.24％)和HBV自限性感染组(25.00％)(x~2=14.16，P=0.0002；x~2=11.60，P=0.0007)；HBV自限性感染组HLA-DQA1*0102等位基因频率(8.78％)显著高于HBV携带组(1.89％)和慢性乙型肝炎组(2.18％)(x~2=15.96，P=0.0007；x~2=18.43，P＜0.0001)；HBV自限性感染组HLA-DQA1*0302等位基因频率(4.05％)显著低于HBV慢性乙型肝炎组(11.41％)和携带组(8.73％)(x~2=12.19，P=0.0005；x~2=6.00，P=0.0143)。
The clinical outcomes of HBV infection are extremely variable, and might be associated with the genetic factors. Immune reaction initiated by the T-cell response to viral antigens is supposed to play a fundamental and important role for viral clearance and disease pathogenesis in HBV infection. Human leucocytes antigen (HLA) may be associated with the control of immune reaction. Tumor necrosis factor-α (TNF-α) may play an important role in HBV elimination and the immune reaction of host responding to HBV. A case-control study was used to analyze the relationship between gene polymorphisms and outcomes of HBV infection, the gene-environment interaction and its effects on the outcomes of HBV infection. This study included 207 chronic HB patients, 212 chronic asymptomatic HBV carriers (HBV carrier) and 148 self-limited HBV infection individuals. The polymorphisms of TNF-α -238, HLA-DRB1 and HLA-DQA1 gene were detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and PCR-sequence special primers (PCR-SSP) in genomic DNA. The results of the study are as follows:
1. The frequency of TNF-α-238GG genotype was 98.07% in chronic HB patients, 91.98% in HBV carriers and 93.24% in self-limited HBV infection subjects, respectively. The frequency of the G allele in patients with chronic HB was significantly higher than that in subjects with HBV carriers (x~2=7.94, P=0.0048) and self-limited HBV infection subjects (x~2=5.20, P=0.0226). There was no significant difference of G allele frequency between HBV carriers and self-limited HBV infection subjects (x~2=0.19, P=0.6610).
2. The frequency of HLA-DRB1*01 in self-limited HBV infection subjects (5.41%) was higher than in HBV carriers (2.36%) (x~2=4.65, P=0.0311), and the frequency of HLA-DRB1*12 in chronic HB patients (17.32%) was higher than that in HBV carriers (12.03%) (x~2=4.67, P=0.0307). The frequency of HLA-DRB1*09 in HBV carriers (20.52%) was much higher than that in chronic HB patients (13.66%) (x~2=6.91,
1、TNF-α-238GG基因型的频率在慢性乙型肝炎、HBV携带和HBV自限性感染组的频率分别为98.07％、91.98％和93.24％，G等位基因的频率分别为99.03％、95.99％和96.62％。等位基因G的频率在慢性乙型肝炎组明显高于HBV携带者(x~2=7.94，P=0.0048)和自限性感染组(x~2=5.20，P=0.0226)。HBV携带组和HBV自限性感染组等位基因G的频率分布无明显统计学意义(x~2=0.19，P=0.6610)。
2、HLA-DRB1*01等位基因在HBV自限性感染组的频率为5.41％，显著高于HBV携带组的2.36％(x~2=4.65，P=0.0311)；HLA-DRB1*12在慢性乙型肝炎组的频率为17.32％，明显高于HBV携带组的12.03％(x~2=4.67，P=0.0307)；HLA-DRB1*09在HBV携带组的频率为20.52％，明显高于慢性乙型肝炎组的13.66％(x~2=6.91，P=0.0086)。
3、慢性乙型肝炎组HLA-DQA1*0301等位基因频率(14.81％)显著低于HBV携带组(25.24％)和HBV自限性感染组(25.00％)(x~2=14.16，P=0.0002；x~2=11.60，P=0.0007)；HBV自限性感染组HLA-DQA1*0102等位基因频率(8.78％)显著高于HBV携带组(1.89％)和慢性乙型肝炎组(2.18％)(x~2=15.96，P=0.0007；x~2=18.43，P＜0.0001)；HBV自限性感染组HLA-DQA1*0302等位基因频率(4.05％)显著低于HBV慢性乙型肝炎组(11.41％)和携带组(8.73％)(x~2=12.19，P=0.0005；x~2=6.00，P=0.0143)。
The clinical outcomes of HBV infection are extremely variable, and might be associated with the genetic factors. Immune reaction initiated by the T-cell response to viral antigens is supposed to play a fundamental and important role for viral clearance and disease pathogenesis in HBV infection. Human leucocytes antigen (HLA) may be associated with the control of immune reaction. Tumor necrosis factor-α (TNF-α) may play an important role in HBV elimination and the immune reaction of host responding to HBV. A case-control study was used to analyze the relationship between gene polymorphisms and outcomes of HBV infection, the gene-environment interaction and its effects on the outcomes of HBV infection. This study included 207 chronic HB patients, 212 chronic asymptomatic HBV carriers (HBV carrier) and 148 self-limited HBV infection individuals. The polymorphisms of TNF-α -238, HLA-DRB1 and HLA-DQA1 gene were detected by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and PCR-sequence special primers (PCR-SSP) in genomic DNA. The results of the study are as follows:
1. The frequency of TNF-α-238GG genotype was 98.07% in chronic HB patients, 91.98% in HBV carriers and 93.24% in self-limited HBV infection subjects, respectively. The frequency of the G allele in patients with chronic HB was significantly higher than that in subjects with HBV carriers (x~2=7.94, P=0.0048) and self-limited HBV infection subjects (x~2=5.20, P=0.0226). There was no significant difference of G allele frequency between HBV carriers and self-limited HBV infection subjects (x~2=0.19, P=0.6610).
2. The frequency of HLA-DRB1*01 in self-limited HBV infection subjects (5.41%) was higher than in HBV carriers (2.36%) (x~2=4.65, P=0.0311), and the frequency of HLA-DRB1*12 in chronic HB patients (17.32%) was higher than that in HBV carriers (12.03%) (x~2=4.67, P=0.0307). The frequency of HLA-DRB1*09 in HBV carriers (20.52%) was much higher than that in chronic HB patients (13.66%) (x~2=6.91,
引文
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