HLA-DQA1等位基因多态性与慢性丙型肝炎的相关性
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摘要
目的探讨人类白细胞抗原(HLA)-DQA1等位基因多态性与慢性丙型肝炎之间的相关性,并进一步明确HLA-DQA1与慢性丙型肝炎患者血清丙氨酸氨基转移酶(ALT)水平的关系以及与干扰素疗效的关系。方法采用序列特异性PCR(PCR-SSP)方法检测HLA-DQA1等位基因分型情况,比较171例慢性丙型肝炎患者(分为69例ALT正常组和102例ALT升高组)与162例健康对照组HLA-DQA1等位基因多态性差异。171例慢性丙型肝炎患者均采用聚乙二醇干扰素α-2a(PEG IFNα-2a)与利巴韦林(RBV)联合抗病毒治疗,治疗48周,随访6个月,以获得持续病毒学应答(SVR)为治疗有效,比较不同疗效组间HLA-DQA1等位基因频率分布。结果慢性丙型肝炎组HLA-DQA1*0103等位基因频率显著低于健康对照组(P <0. 05),HLA-DQA1*0101/0102/0104/0201/0301/0302/0401/0501/0601等位基因在两组间比较差异无统计学意义(P>0. 05);慢性丙型肝炎组患者中,ALT正常组HLA-DQA1*0501等位基因频率明显高于持续ALT升高组(P <0. 05),HLADQA1*0101/0102/0103/0104/0201/0301/0302/0401/0601等位基因差异无统计学意义(P> 0. 05);慢性丙型肝炎组患者中,获得SVR患者HLA-DQA1*0601等位基因频率明显高于未获得SVR患者(P <0. 05),HLA-DQA1*0101/0102/0103/0104/0201/0301/0302/0401/0501等位基因差异无统计学意义(P> 0. 05)。结论 HLA-DQA1*0103可能是慢性丙型肝炎的拮抗基因; HLA-DQA1*0501可能会抑制ALT升高,从而减缓病程发展和进行性肝损伤; HLA-DQA1*0601等位基因可能不利于PEG IFNα-2a和RBV联合抗病毒治疗的应答。
Objective To explore the relationship between HLA-DQA1 allele polymorphism and chronic hepatitis C,and to further clarify the relationship between HLA-DQA1 and serum alanine aminotransferase( ALT) level in patients with chronic hepatitis C and the efficacy of interferon. Methods The HLA-DQA1 allele genotyping was detected by PCR-SSP. The difference of HLA-DQA1 allele polymorphism between 171 patients with chronic hepatitis C( 69 normal ALT patients and 102 elevated ALT patients) and 162 healthy controls was compared. Totally 171 patients with chronic hepatitis C were treated with PEG interferon α-2 a( PEG IFN α-2 a)combined with ribavirin( RBV) for 48 weeks and followed up for 6 months. With sustained virological response( SVR) as effective in treatment,the allele frequencies of HLA-DQA1 among different therapeutic groups were compared. Results The frequency of HLADQA1* 0103 allele in chronic hepatitis C group was significantly lower than that in healthy control group( P < 0. 05),and there was no significant difference in other alleles between the two groups( P > 0. 05). In chronic hepatitis C patients,the frequency of HLA-DQA1* 0501 allele in ALT normal group was significantly higher than that in persistent ALT elevation group( P < 0. 05),but there was no significant difference in other alleles between the two groups( P > 0. 05). In chronic hepatitis C patients,the frequency of HLA-DQA1* 0601 allele in patients with SVR was significantly higher than that in patients without SVR( P < 0. 05),but there was no significant difference in other alleles( P > 0. 05). Conclusion HLA-DQA1 * 0103 may be an antagonistic gene of chronic hepatitis C. HLADQA1* 0501 may inhibit the elevation of ALT,so as to slow down the course of disease development and progressive liver injury.HLA-DQA1* 0601 allele may be detrimental to the response to combined antiviral therapy of PEG IFNα-2 a and RBV.
Objective To explore the relationship between HLA-DQA1 allele polymorphism and chronic hepatitis C,and to further clarify the relationship between HLA-DQA1 and serum alanine aminotransferase( ALT) level in patients with chronic hepatitis C and the efficacy of interferon. Methods The HLA-DQA1 allele genotyping was detected by PCR-SSP. The difference of HLA-DQA1 allele polymorphism between 171 patients with chronic hepatitis C( 69 normal ALT patients and 102 elevated ALT patients) and 162 healthy controls was compared. Totally 171 patients with chronic hepatitis C were treated with PEG interferon α-2 a( PEG IFN α-2 a)combined with ribavirin( RBV) for 48 weeks and followed up for 6 months. With sustained virological response( SVR) as effective in treatment,the allele frequencies of HLA-DQA1 among different therapeutic groups were compared. Results The frequency of HLADQA1* 0103 allele in chronic hepatitis C group was significantly lower than that in healthy control group( P < 0. 05),and there was no significant difference in other alleles between the two groups( P > 0. 05). In chronic hepatitis C patients,the frequency of HLA-DQA1* 0501 allele in ALT normal group was significantly higher than that in persistent ALT elevation group( P < 0. 05),but there was no significant difference in other alleles between the two groups( P > 0. 05). In chronic hepatitis C patients,the frequency of HLA-DQA1* 0601 allele in patients with SVR was significantly higher than that in patients without SVR( P < 0. 05),but there was no significant difference in other alleles( P > 0. 05). Conclusion HLA-DQA1 * 0103 may be an antagonistic gene of chronic hepatitis C. HLADQA1* 0501 may inhibit the elevation of ALT,so as to slow down the course of disease development and progressive liver injury.HLA-DQA1* 0601 allele may be detrimental to the response to combined antiviral therapy of PEG IFNα-2 a and RBV.
引文
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[4]Fitzmaurice K,Hurst J,Dring M,et al.Additive effects of HLAalleles and innate immune genes determine viral outcome in HCVinfection[J].Gut,2015,64(5):813-819.
[5]Samimi-Rad K,Sadeghi F,Amirzargar A,et al.Association of HLA classⅡalleles with hepatitis C virus clearance and persistence in thalassemia patients from Iran[J].Med Virol,2015,87(9):1565-1572.
[6]杨志明,丙型肝炎病毒感染和HLA-DQB1基因多态性的相关性研究[J].中国卫生检验杂志,2018,28(9):1057-1059.
[7]Messina JP,Humphreys I,Flaxman A,et al.Global distribution and prevalence of hepatitis C virus genotypes[J].Hepatology,2015,61(1):77-87.
[8]国家食品药品监督管理总局.世界卫生组织国际癌症研究机构致癌物清单[EB/OL].http://samr.cfda.gov.cn/WSO1/CL1991/215896.html,2017-12-30.
[9]杨永锐,李晖,沈凌.聚乙二醇干扰素α-2a加利巴韦林治疗慢性丙型肝炎的临床观察[J].昆明医科大学学报,2014,35(2):100-104.
[10]喻荣彬.HLA-DQA1、DQB1、DRB1基因多态性和慢性丙型肝炎的关系[D].南京:南京医科大学,2006.
[11]Esumi M,Ishibashi M,Yamaguchi H,et al.Transmembrane serine protease TMPRSS2 activates hepatitis C virus infection[J].Hepatology,2015,61:437-446.
[12]Ishibashi M,Yamaguchi H,Hirotani Y,et al.Contradictory intrahepatic immune responses activated in high-load hepatitis C virus livers compared with low-load livers[J].Arch Virol,2017,163:855-865.
[2]Lavanchy D.The global burden of hepatisC[J].Liver Int,2009,29(Suppl 1):74-81.
[3]中华医学会肝病学分会,中华医学会感染病学分会.丙型肝炎防治指南(2015更新版)[J].中华肝脏病杂志,2015,23(12):906-923.
[4]Fitzmaurice K,Hurst J,Dring M,et al.Additive effects of HLAalleles and innate immune genes determine viral outcome in HCVinfection[J].Gut,2015,64(5):813-819.
[5]Samimi-Rad K,Sadeghi F,Amirzargar A,et al.Association of HLA classⅡalleles with hepatitis C virus clearance and persistence in thalassemia patients from Iran[J].Med Virol,2015,87(9):1565-1572.
[6]杨志明,丙型肝炎病毒感染和HLA-DQB1基因多态性的相关性研究[J].中国卫生检验杂志,2018,28(9):1057-1059.
[7]Messina JP,Humphreys I,Flaxman A,et al.Global distribution and prevalence of hepatitis C virus genotypes[J].Hepatology,2015,61(1):77-87.
[8]国家食品药品监督管理总局.世界卫生组织国际癌症研究机构致癌物清单[EB/OL].http://samr.cfda.gov.cn/WSO1/CL1991/215896.html,2017-12-30.
[9]杨永锐,李晖,沈凌.聚乙二醇干扰素α-2a加利巴韦林治疗慢性丙型肝炎的临床观察[J].昆明医科大学学报,2014,35(2):100-104.
[10]喻荣彬.HLA-DQA1、DQB1、DRB1基因多态性和慢性丙型肝炎的关系[D].南京:南京医科大学,2006.
[11]Esumi M,Ishibashi M,Yamaguchi H,et al.Transmembrane serine protease TMPRSS2 activates hepatitis C virus infection[J].Hepatology,2015,61:437-446.
[12]Ishibashi M,Yamaguchi H,Hirotani Y,et al.Contradictory intrahepatic immune responses activated in high-load hepatitis C virus livers compared with low-load livers[J].Arch Virol,2017,163:855-865.