HLA-DRB1等位基因多态性和乙肝病毒基因型与慢性乙型肝炎α-干扰素抗病毒治疗应答的相关性研究
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摘要
目的:
探讨山东省乙肝病毒基因型的分布情况及其与慢性乙型肝炎α-干扰素抗病毒治疗应答的相关性。
方法:
1.研究对象 249例慢性HBV-DNA阳性者均为我院2002年2月至2003年10月门诊和住院病人,男186例,女63例,平均年龄33.8±14.6岁,其中无症状携带者(ASC)53例,慢性肝炎(CAH)126例,肝硬化(LC)38例,重型肝炎(FHF)32例,所有病例和对照均为山东地区的华人汉族人,诊断均符合2000年全国病毒性肝炎会议制定的标准。通过适当的临床和实验室方法排除所有引起慢性肝病的其他因素,如HCV感染、自身免疫性肝炎、酒精性肝炎和代谢失调。所有病例均无抑郁症病史、免疫缺陷病毒感染、应用干扰素史、化疗或其他可影响治疗结果的试剂、甲状腺功能异常等。
α-干扰素治疗组包括126例慢性乙型肝炎患者(男性94例,女性32例,平均年龄:33.2±13.3岁)。
2.血清学检验 血清用来检测肝功能、乙肝五项病毒学指标(HBsAg、抗-HBs、HBeAg、抗-HBe、抗-HBe)及HBV-DNA,剩余血清在-70℃保存备用。
3.HBV基因分型HBV-DNA应用直接煮沸法从200μL血清样本中提取,用巢式PCR扩增,引物均参考文献。第一轮PCR在一含40 μL反应缓冲液的试管中进行,包含4μL HBV-DNA,4μL 10×buffer,4μL浓度为15mM的MgCl2,4μL浓度为10mM的dNTPs,0.2μL浓度为5U/μL的Taq聚合酶,浓度为12.5μg/
Aims:To investigate the distribution of HBV genotypes in Shandong Province and influence of HBV genotypes on response to interferon- α therapy in chronic hepatitis B. Methods:1. SubjectsHBV genotypes were determined by the nested-PCR analysis using type-specific primers in 249 randomly selected HBV-DNA positive patients, including 53 asymptomatic HBV carriers(ASC), 126 chronic active hepatitis(CAH)(including mild、 moderate and severe hepatitis), 38 liver cirrhosis(LC),and 32 fulminant hepatic failure(FHF) in Shandong area. All the patients were Chinese Han people from Shandong area. The diagnosis of all the cases was made according to the criteria established on the Viral Hepatitis Conference held in 2000. All causes of chronic liver disease other than HBV, such as HCV infection, auto-immune hepatitis and metabolic disorders, were excluded by appropriate clinical and laboratory evaluations. They did not have a history of malignancy or depression, immunodeficiency virus infection, prior use of IFN- α preparation, chemotherapy, or other agents that could influence treatment outcomes, or thyroid abnormality in which normal thyroid function could not be maintained by medication.2. Serological testsSera were tested for ALT, HBeAg, anti-HBeAg, as well as HBV-DNA. The remaining sera were stored at -70 ℃. 3.Genotyping of HBV
The nucleic acid of HBV was extracted from 200μl serum samples by heating in one hundred degrees for ten minutes and the HBV genome was amplified by nested PCR using universal primers for the outer primers, followed by two different mixtures containing type-specific inner primers. The first PCR was carried out in a tube containing 40μl of a reaction buffer made up of the following components: 4μl of HBV-DNA, 4 μl of 10xbuffer, 4μl of MgC12(15 mM), 4μl of dNTPs(10 mM), 0.2μl of Taq polymerase (5U/μl, 4μl of each outer primer(12.5μg/ml), and 15.8μl of demonized H2O. The thermocycler was programmed to first incubate the samples for 2 min at 94 ℃, followed by 35 cycles: 94℃ for 15sec, 58℃ for 30sec, 72℃ for 30sec, and final extension at 72 ℃ for 7min. Two second-round PCRs were performed for each sample, with the common universal antisense primer for mixA which is for types A through C, and the common universal antisense primer for mixB which is for types D through F. 2μl of the first PCR product was added to two tubes containing the second sets of each of the inner primer pairs, each of the deoxynucleotides, Taq polymerase and PCR buffer, as in the first reaction. These were amplified with the following parameters: preheating at 94℃ for 2min, then followed by 35 cycles: 94℃ for 15sec, 60℃ for 30sec ,72 ℃ for 30sec, and final extension at 72 ℃ for 7min.PCR products were separately electrophoresed on a 2% agarose gel, stained with ethidium bromide, and evaluated under ultraviolet light. The sizes of PCR products were estimated according to the pUC19 DNA/MspI(HpaII) Marker, 23.4. Antiviral therapyThe 126 patients were administered treatment subcutaneously at a dose of 3 MU three times weekly for 24 weeks. The response to IFN- α therapy was defined as loss of HBeAg, seroconversion to anti-HBe and normalization of serum ALT levels and HBV-DNA(-).The patients with a response are described as "responders" and the other patients as "non-responders" in this report.5. Statistical analysisData were analyzed using SPSS version 10.0 software package. Categorical variables were compared by Chi-square test. Continuous data were compared by Student's t-test. Tendency test were used to analyse the correlation between ages and
HBeAg positivities. Statistical significance was taken as P < 0.05. ResultsOf the 249 patients 84(33.7%) were genotype B, 124(49.8%) were genotype C, and 41(16.5%) were mixed genotype B + C, no genotypes D, E, F was found. Genotype C and genotype B were the major genotypes in this area. There was a statistical significance in the distribution of genotype B between active liver diseases and ASC(P<0.05). HBV-DNA and ALT level were higher in group genotype C than that in group genotype B(P<0.01, respectively).The HBeAg positivity was significant(P<0.01) among the three groups,but was of no significance(P>0.05) between males and females among the three groups. The rate of HBeAg positivity in genotype C group was higher than that in other two groups(P<0.01).The prevalence of HBeAg gradually decreased with age in patients with all groups.There was no statistical significance in age and gender among the three groups. ALT level of genotype B group was lower than that of genotype C group(P<0.01).There was significant difference in HBV-DNA level among the three groups(P<0.01).Response was significantly better in patients with genotype B infections(50%) than in patients with genotype C (13.0%) and genotype B+C(26.3%)(P < 0.005). Response was higher in females than in males(P<0.01), and the patients with higherALT level(≥200IU/L) had a higher response than those with lower ALT level(P < 0.05), the higher HBV-DNA level(>105copies/ml) had a lower response to antiviral than lower level(P < 0.05). DiscussionOur study indicate that genotype B 、 genotype C and genotype B+C exist in Shandong area .Genotype C was the major genotype and was associated with the development of severe liver diseases. Genotype B was associated with ASC.There was no correlation between gender age and genotypes.Genotype B was associated with response to IFN-α therapy. These data indicate that HBV genotyping
may have prognostic relevance in the response to r-IFN- α therapy in patients with chronic HBV infection. HBV genotype C was associated with lower response to interferon- α therapy than genotype B. Patients with HBV genotype C had a significantly lower rate of antiviral response to IFN- α , only 13% versus 50% among patients with genotype B and 26.3% with genotype B+C(x2=17.3, p<0.005) .Females, lower HBV-DNA level、 higher ALT level and genotype B were all important predictive factors of higher response to antiviral therapy. Thus,early analysis of the factors above before antiviral therapy was important for selection of cases and judgement of progonosis in patients with chronic HBV infection.
探讨山东省乙肝病毒基因型的分布情况及其与慢性乙型肝炎α-干扰素抗病毒治疗应答的相关性。
方法:
1.研究对象 249例慢性HBV-DNA阳性者均为我院2002年2月至2003年10月门诊和住院病人,男186例,女63例,平均年龄33.8±14.6岁,其中无症状携带者(ASC)53例,慢性肝炎(CAH)126例,肝硬化(LC)38例,重型肝炎(FHF)32例,所有病例和对照均为山东地区的华人汉族人,诊断均符合2000年全国病毒性肝炎会议制定的标准。通过适当的临床和实验室方法排除所有引起慢性肝病的其他因素,如HCV感染、自身免疫性肝炎、酒精性肝炎和代谢失调。所有病例均无抑郁症病史、免疫缺陷病毒感染、应用干扰素史、化疗或其他可影响治疗结果的试剂、甲状腺功能异常等。
α-干扰素治疗组包括126例慢性乙型肝炎患者(男性94例,女性32例,平均年龄:33.2±13.3岁)。
2.血清学检验 血清用来检测肝功能、乙肝五项病毒学指标(HBsAg、抗-HBs、HBeAg、抗-HBe、抗-HBe)及HBV-DNA,剩余血清在-70℃保存备用。
3.HBV基因分型HBV-DNA应用直接煮沸法从200μL血清样本中提取,用巢式PCR扩增,引物均参考文献。第一轮PCR在一含40 μL反应缓冲液的试管中进行,包含4μL HBV-DNA,4μL 10×buffer,4μL浓度为15mM的MgCl2,4μL浓度为10mM的dNTPs,0.2μL浓度为5U/μL的Taq聚合酶,浓度为12.5μg/
Aims:To investigate the distribution of HBV genotypes in Shandong Province and influence of HBV genotypes on response to interferon- α therapy in chronic hepatitis B. Methods:1. SubjectsHBV genotypes were determined by the nested-PCR analysis using type-specific primers in 249 randomly selected HBV-DNA positive patients, including 53 asymptomatic HBV carriers(ASC), 126 chronic active hepatitis(CAH)(including mild、 moderate and severe hepatitis), 38 liver cirrhosis(LC),and 32 fulminant hepatic failure(FHF) in Shandong area. All the patients were Chinese Han people from Shandong area. The diagnosis of all the cases was made according to the criteria established on the Viral Hepatitis Conference held in 2000. All causes of chronic liver disease other than HBV, such as HCV infection, auto-immune hepatitis and metabolic disorders, were excluded by appropriate clinical and laboratory evaluations. They did not have a history of malignancy or depression, immunodeficiency virus infection, prior use of IFN- α preparation, chemotherapy, or other agents that could influence treatment outcomes, or thyroid abnormality in which normal thyroid function could not be maintained by medication.2. Serological testsSera were tested for ALT, HBeAg, anti-HBeAg, as well as HBV-DNA. The remaining sera were stored at -70 ℃. 3.Genotyping of HBV
The nucleic acid of HBV was extracted from 200μl serum samples by heating in one hundred degrees for ten minutes and the HBV genome was amplified by nested PCR using universal primers for the outer primers, followed by two different mixtures containing type-specific inner primers. The first PCR was carried out in a tube containing 40μl of a reaction buffer made up of the following components: 4μl of HBV-DNA, 4 μl of 10xbuffer, 4μl of MgC12(15 mM), 4μl of dNTPs(10 mM), 0.2μl of Taq polymerase (5U/μl, 4μl of each outer primer(12.5μg/ml), and 15.8μl of demonized H2O. The thermocycler was programmed to first incubate the samples for 2 min at 94 ℃, followed by 35 cycles: 94℃ for 15sec, 58℃ for 30sec, 72℃ for 30sec, and final extension at 72 ℃ for 7min. Two second-round PCRs were performed for each sample, with the common universal antisense primer for mixA which is for types A through C, and the common universal antisense primer for mixB which is for types D through F. 2μl of the first PCR product was added to two tubes containing the second sets of each of the inner primer pairs, each of the deoxynucleotides, Taq polymerase and PCR buffer, as in the first reaction. These were amplified with the following parameters: preheating at 94℃ for 2min, then followed by 35 cycles: 94℃ for 15sec, 60℃ for 30sec ,72 ℃ for 30sec, and final extension at 72 ℃ for 7min.PCR products were separately electrophoresed on a 2% agarose gel, stained with ethidium bromide, and evaluated under ultraviolet light. The sizes of PCR products were estimated according to the pUC19 DNA/MspI(HpaII) Marker, 23.4. Antiviral therapyThe 126 patients were administered treatment subcutaneously at a dose of 3 MU three times weekly for 24 weeks. The response to IFN- α therapy was defined as loss of HBeAg, seroconversion to anti-HBe and normalization of serum ALT levels and HBV-DNA(-).The patients with a response are described as "responders" and the other patients as "non-responders" in this report.5. Statistical analysisData were analyzed using SPSS version 10.0 software package. Categorical variables were compared by Chi-square test. Continuous data were compared by Student's t-test. Tendency test were used to analyse the correlation between ages and
HBeAg positivities. Statistical significance was taken as P < 0.05. ResultsOf the 249 patients 84(33.7%) were genotype B, 124(49.8%) were genotype C, and 41(16.5%) were mixed genotype B + C, no genotypes D, E, F was found. Genotype C and genotype B were the major genotypes in this area. There was a statistical significance in the distribution of genotype B between active liver diseases and ASC(P<0.05). HBV-DNA and ALT level were higher in group genotype C than that in group genotype B(P<0.01, respectively).The HBeAg positivity was significant(P<0.01) among the three groups,but was of no significance(P>0.05) between males and females among the three groups. The rate of HBeAg positivity in genotype C group was higher than that in other two groups(P<0.01).The prevalence of HBeAg gradually decreased with age in patients with all groups.There was no statistical significance in age and gender among the three groups. ALT level of genotype B group was lower than that of genotype C group(P<0.01).There was significant difference in HBV-DNA level among the three groups(P<0.01).Response was significantly better in patients with genotype B infections(50%) than in patients with genotype C (13.0%) and genotype B+C(26.3%)(P < 0.005). Response was higher in females than in males(P<0.01), and the patients with higherALT level(≥200IU/L) had a higher response than those with lower ALT level(P < 0.05), the higher HBV-DNA level(>105copies/ml) had a lower response to antiviral than lower level(P < 0.05). DiscussionOur study indicate that genotype B 、 genotype C and genotype B+C exist in Shandong area .Genotype C was the major genotype and was associated with the development of severe liver diseases. Genotype B was associated with ASC.There was no correlation between gender age and genotypes.Genotype B was associated with response to IFN-α therapy. These data indicate that HBV genotyping
may have prognostic relevance in the response to r-IFN- α therapy in patients with chronic HBV infection. HBV genotype C was associated with lower response to interferon- α therapy than genotype B. Patients with HBV genotype C had a significantly lower rate of antiviral response to IFN- α , only 13% versus 50% among patients with genotype B and 26.3% with genotype B+C(x2=17.3, p<0.005) .Females, lower HBV-DNA level、 higher ALT level and genotype B were all important predictive factors of higher response to antiviral therapy. Thus,early analysis of the factors above before antiviral therapy was important for selection of cases and judgement of progonosis in patients with chronic HBV infection.
引文
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