HLA-DRB1*1101和HLA-DRB1*1201基因与乙肝疫苗无、弱应答及HBsAg阳性的关系
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摘要
目的:无、弱应答是乙肝预防中的一个重要问题,弄清乙肝疫苗接种后无、弱应答及HBsAg感染的发生原因及其影响因素,对提高乙肝疫苗的免疫效果具有十分重要的意义。本研究尝试探讨HLA-DRB1*1101、HLA-DRB1*1201基因与乙肝疫苗接种后无、弱应答及HBsAg感染之间的关系,为探索乙肝疫苗接种后无、弱应答及HBsAg感染的发生机制提供依据。
方法:选取全程接种乙肝疫苗后幼儿园在托幼儿无、弱应答者75人作为病例组, 485人有应答者作为对照组进行病例对照研究,对研究对象进行资料调查,并应用PCR-SSP技术检测研究对象的HLA-DRB1*1101基因和HLA-DRB1*1201基因。采用SPSS13.0软件对获取的研究数据进行单因素分析以及多因素非条件logistic回归分析。
另选取在托幼儿中HBsAg阳性37人作为病例组, HBsAg阴性幼儿591人作为对照组进行病例对照研究,对研究对象进行资料调查,并应用PCR-SSP技术检测研究对象的HLA-DRB1*1101基因和HLA-DRB1*1201基因。采用SPSS13.0软件对获取的研究数据进行单因素分析以及多因素非条件logistic回归分析。
结果单因素分析发现,与无、弱应答相关的因素为剂量10ug(OR=0.265, 95%CI 0.141～0.498 )。单因素分析还发现,携带HLA-DRB1*1201基因发生无、弱应答的风险为不携带此基因的6.037倍(95%CI 2.412~15.114);多因素非条件logistic回归分析,最终进入模型的有HLA-DRB1*1201基因(OR=4.612, 95%CI 1.55～13.726)和剂量10ug(OR=0.283, 95%CI 0.149～0.539 )。
单因素分析发现,与HBsAg感染相关的因素为抗-HBs(OR=0.128, 95%CI 0.064～0.256)、剂量10ug(OR=0.274, 95%CI 0.098～0.767);多因素非条件logistic回归分析,最终进入模型的是抗-HBs(OR=0.052, 95%CI 0.009～0.291)和HLA-DRB1*1101基因(OR=29.000 95%CI 1.803～466.413)。
结论:无、弱应答者的发生与HLA-DRB1*1201基因和剂量有关,HLA-DRB1*1201基因型容易导致乙肝疫苗无、弱应答。
HBsAg感染和HLA- DRB1*1101基因型和抗-HBsAb相关,HLA- DRB1*1101基因型容易导致HBsAg感染。
Objective: To primarily confirm the association between HBsAg infection, HLA-DRB1*1101, HLA-DQB1*1201 in combination with the non-or poor hyporesponsse to hepatitis B vaccine.
Methods : A study which included 75 non-or poor hyporesponders and 485 responders from 653 children who were subjected to a standard course of immunization with recombinant hepatitits B virus vaccine. All subjects were study with their health investigated file. Genes HLA-DRB1*1101 and HLA-DRB1*1201 were detected with ploymerse chain reaction-sequence specific primes(PCR-SSP). The data were analysed by SPSS 13.0 software.
A study about 628 children which included 37 HBsAg positive children. All subjects were subjected to a standard course of immunization with recombinant hepatitits B virus vaccine. All subjects were study with their health investigated file. Genes HLA-DRB1*1101 and HLA-DRB1*1201 were detected with ploymerse chain reaction-sequence specific primes(PCR-SSP). The data were analysed by SPSS 13.0 software.
Results: (1)Univariate analysis indicated that dosage 10ug(OR=0.265, 95%CI 0.141～0.498 ), and gene HLA-DRB1*1201 were associated with non-or poor hyporesponse.(2)The results of multivariate logistic regression also showed that dosage 10ug(OR=0.265, 95%CI 0.141～0.498 )and gene HLA-DRB1*1201(OR=4.612, 95%CI 1.55～13.726)were associated with non-or poor hyporesponse. (3)Univariate analysis indicated that HBsAb positive(OR=0.128, 95%CI 0.064～0.256) and dosage 10ug(OR=0.274, 95%CI 0.098～0.767)were associated with HBsAg infection . (4)The results of multivariate logistic regression showed that Gene HLA-DRB1*1101 and HBsAb positive(OR=0.128, 95%CI 0.064～0.256) were associated with HBsAg infection .
Conclusion: Gene HLA-DRB1*1201 was associated with non-or poor hyporesponse. Gene HLA-DRB1*1101 was associated with HBsAg infection .
方法:选取全程接种乙肝疫苗后幼儿园在托幼儿无、弱应答者75人作为病例组, 485人有应答者作为对照组进行病例对照研究,对研究对象进行资料调查,并应用PCR-SSP技术检测研究对象的HLA-DRB1*1101基因和HLA-DRB1*1201基因。采用SPSS13.0软件对获取的研究数据进行单因素分析以及多因素非条件logistic回归分析。
另选取在托幼儿中HBsAg阳性37人作为病例组, HBsAg阴性幼儿591人作为对照组进行病例对照研究,对研究对象进行资料调查,并应用PCR-SSP技术检测研究对象的HLA-DRB1*1101基因和HLA-DRB1*1201基因。采用SPSS13.0软件对获取的研究数据进行单因素分析以及多因素非条件logistic回归分析。
结果单因素分析发现,与无、弱应答相关的因素为剂量10ug(OR=0.265, 95%CI 0.141～0.498 )。单因素分析还发现,携带HLA-DRB1*1201基因发生无、弱应答的风险为不携带此基因的6.037倍(95%CI 2.412~15.114);多因素非条件logistic回归分析,最终进入模型的有HLA-DRB1*1201基因(OR=4.612, 95%CI 1.55～13.726)和剂量10ug(OR=0.283, 95%CI 0.149～0.539 )。
单因素分析发现,与HBsAg感染相关的因素为抗-HBs(OR=0.128, 95%CI 0.064～0.256)、剂量10ug(OR=0.274, 95%CI 0.098～0.767);多因素非条件logistic回归分析,最终进入模型的是抗-HBs(OR=0.052, 95%CI 0.009～0.291)和HLA-DRB1*1101基因(OR=29.000 95%CI 1.803～466.413)。
结论:无、弱应答者的发生与HLA-DRB1*1201基因和剂量有关,HLA-DRB1*1201基因型容易导致乙肝疫苗无、弱应答。
HBsAg感染和HLA- DRB1*1101基因型和抗-HBsAb相关,HLA- DRB1*1101基因型容易导致HBsAg感染。
Objective: To primarily confirm the association between HBsAg infection, HLA-DRB1*1101, HLA-DQB1*1201 in combination with the non-or poor hyporesponsse to hepatitis B vaccine.
Methods : A study which included 75 non-or poor hyporesponders and 485 responders from 653 children who were subjected to a standard course of immunization with recombinant hepatitits B virus vaccine. All subjects were study with their health investigated file. Genes HLA-DRB1*1101 and HLA-DRB1*1201 were detected with ploymerse chain reaction-sequence specific primes(PCR-SSP). The data were analysed by SPSS 13.0 software.
A study about 628 children which included 37 HBsAg positive children. All subjects were subjected to a standard course of immunization with recombinant hepatitits B virus vaccine. All subjects were study with their health investigated file. Genes HLA-DRB1*1101 and HLA-DRB1*1201 were detected with ploymerse chain reaction-sequence specific primes(PCR-SSP). The data were analysed by SPSS 13.0 software.
Results: (1)Univariate analysis indicated that dosage 10ug(OR=0.265, 95%CI 0.141～0.498 ), and gene HLA-DRB1*1201 were associated with non-or poor hyporesponse.(2)The results of multivariate logistic regression also showed that dosage 10ug(OR=0.265, 95%CI 0.141～0.498 )and gene HLA-DRB1*1201(OR=4.612, 95%CI 1.55～13.726)were associated with non-or poor hyporesponse. (3)Univariate analysis indicated that HBsAb positive(OR=0.128, 95%CI 0.064～0.256) and dosage 10ug(OR=0.274, 95%CI 0.098～0.767)were associated with HBsAg infection . (4)The results of multivariate logistic regression showed that Gene HLA-DRB1*1101 and HBsAb positive(OR=0.128, 95%CI 0.064～0.256) were associated with HBsAg infection .
Conclusion: Gene HLA-DRB1*1201 was associated with non-or poor hyporesponse. Gene HLA-DRB1*1101 was associated with HBsAg infection .
引文
[1] 中国疾病预防控制中心,全国人群乙肝血清流行病学调查结果.中国疾病预防控制中心网站,2008,4,23,网页链接:http://www.chinacdc.net.cn/n272442/n272530/n3246177/23316.html
[2] 广东省疾病预防控制中心,2006-2010年广东省乙型病毒性肝炎防治规划. 韩轲转载于广东省卫生厅网站, 2007年4月25日.网页链接:http://www.cdcp.org.cn/viewArticle.do?method=viewArticle&id=2c9087840e6513f5010e791e111b0038
[3] 吕茂利,何颖,袁利. 机体接种乙肝疫苗后无、弱应答的影响因素[J]. 现代预防医学,2007,34,(19):3689-3690.
[4]Alper Ca.The human immune response to hepatitis B surface antigen [J]. E xp C lin Imm unog enet,1995;12(3):171-181.
[5] 黄希田,江厦明,陈志明.乙肝疫苗效果及影响因素[J].浙江预防医学,1998,(10):583-584.
[6]姚文清,张玉宽,王凯.接种乙肝疫苗后影响人体免疫应答的因素分析[J].中国公共卫生.2004,20(7):858-859.
[7].尹爱红,张延学.乙型肝炎疫苗免疫后低应答和无应答影响因素的探讨[J].中国计划免疫.2002,8(2):104-106.7疾病监测,1998,13(12):447-450.
[8] U. Shankarkumar, K. Ghosh, S. Badakere, and D. Mohanty.Novel HLA Class I Alleles Associatedwith Indian Leprosy Patients[J].Journal of Biomedicine Biotechnology,2003,(3):(2003)208–211.
[9]卓金蓉.接种乙肝疫苗无、弱免疫应答与遗传因素[J].预防医学情报杂志,2002,18(4):298-299.
[10]Fu-Sheng Wang. Current status and prospects of studies on human genetic allelesassociated with hepatitis B virus infection[J]. World J Gastroenterol, 2003,9 .
[11] Wassim Y. Almawi, Marc Busson,Hala Tamim, etc. HLA Class II Profile and Distribution of HLA-DRB1 and HLA-DQB1Alleles and Haplotypes amongLebanese and Bahraini Arabs[J]. Clinical and Diagnostic Laboratory Immunology, 2004,11(4):770–774.
[12] J Pillot, T Poynard, A Elias, et al. Weak immunogenicity of thePre S2 sequence and lack of circumventing effect on the unrespornsiveness to the hepatitis B virus vaccine. Vaccine, 1995;13(3) 289-294.
[13]Fu-Sheng Wang. Current status and prospects of studies on human genetic allelesassociated with hepatitis B virus infection[J]. World J Gastroenterol, 2003,9 .
[14]曹孟德,秦东春,孙含笑. HLA分子生物学及临床应用〔M〕. 郑州:河南医科大学出版社,1998,44.
[15] 刘蓬勃,徐慧文,王学良.乙肝疫苗接种无、弱应答与遗传因素关系[J].第四军医大学学报,2000,21(1):30-33.
[16]钱毅,梁雪梅,邹东,等.乙肝疫苗无、弱应答与HLA-DR2、7、9相关性的研究[J].免疫学杂志,2001,17(6):463-465.
[17] 涂正坤,吴雄文,刘敏,等.湖北汉族人群对乙肝疫苗免疫应答能力与HLA-DRB1等位基因相关性的研究[J]. 免疫学杂志,2000,16(1):45-62.
[18] 袁振华,崔萌,孙成刚,等.HLA-DRB1*1201/*1501与HBV感染不同状态的相关性[J].山东大学学报,2005,43(5):428-431.
[19] 祜红瑞,范会兴,孙长宇,等. 河南汉族乙型肝炎e抗原阳性慢性乙型肝炎患者HLA-DRB1基因多态性测定[J]. 郑州大学学报医学版,2007,42,(6):1148-1150.
[20]胡章勇,毛笑难.乙肝疫苗免疫低无应答的原因及对策[J] . 实用肝脏杂志,2000,5,(4): 250.
[21]蒋业贵,王宇明. 乙型肝炎患者人类白细胞抗原-DRB1、-DQA1、-DQB1等位基因多态性分析[J]. 中华流行病学杂志, 2004,25,(4):337.
[22]蒋业贵,王宇明,刘同华. HLA2 Ⅱ类基因多态性与乙型肝炎转归的相关性[J]. 免疫学杂志,2006,22,(4):416.
[23] Mc Dermott AB, Zuckerman JN, Sabin CA, et al. Contribution of human leukocyte antigens to the antibody response to hepatitis B vaccination[J].Tissue Antigens. 1997,50(1):8-14.
[24] Desombere I,Willems A, Leroux-Roels G. Response to hepatitis B vaccine: multiple HLA genes are involved[J]. Tissue Antigens. 1998, 51(6):593-604.
[25] Alper CA, Kruskall M, Marcus-Bagley D, et al. Genetic prediction of nonresponse to hepatitis B vaccine[J]. N Engl J Med. 1989,321:708-712.
[26] Mc Dermott AB, Zuckerman JN, Sabin CA, et al. Contribution of human leukocyte antigens to the antibody response to hepatitis B vaccination[J]. Tissue Antigens. 1997,50(1):8-14.
[27] Desombere I,Willems A, Leroux-Roels G. Response to hepatitis B vaccine: multiple HLA genes are involved[J]. Tissue Antigens. 1998, 51(6):593-604.
[28] 黄德秋. 4573名儿童乙肝感染及免疫情况的分析[J].现代医学杂志,2003(5):12.
[29]马恒太,滕兆稳. 乙肝疫苗免疫无(弱)应答原因及对策[J].海峡预防医学杂志,2007,13,(3):35-36.
[30]林鸿滨,梅花.影响乙肝疫苗免疫应答的原因分析[J].中华中西医杂志,2004,5,(18) .
[31]陈仕珠, 韩永战.影响乙肝疫苗免疫效果的因素[J].世界华人消化杂志,2006,14,(27): 2701-2707.
[32] 大洋健康网http://health.dayoo.com/.乙肝接种必须打足剂量.网页链:http://health.dayoo.com/node_2640/node_2649/2007-11/19/1195443522233903.shtml
[33]李明月,黄尚志,曾宪嘉,等.乙型肝炎疫苗免疫不应答与HLA基因单体型的相关性研究[J].中华预防医学杂志,2002,(03):180-183.
[34]吴锋,杨志章,姜晓丹,等.湖北汉族人群对乙肝疫苗免疫应答能力与HLA-DRB1等位基因相关性的研究[J].免疫学杂志, 2000,16,(1):45-47.
[35]刘海英,孔北华,徐群,等.新生儿乙肝疫苗接种阻断HBV母婴传播与HLA-DR区域基因相关性的研究[J].山东大学学报,2003,41(4):378-381.
[36]Diepolder H M, Jung M C, Keller E, et al.A vigorous virus specific CD4 + T cell response may contribute to the association of HLA DR13 with viral clearance in hepatitis B[J].Clin Exp Immunol,1998,11(32):244-251.
[37]王德全,陈思东,周卫平,等. 乙肝疫苗接种后无(弱)应答状况及影响因素 [J].中国公共卫生.2006,22(6): 674-675.
[2] 广东省疾病预防控制中心,2006-2010年广东省乙型病毒性肝炎防治规划. 韩轲转载于广东省卫生厅网站, 2007年4月25日.网页链接:http://www.cdcp.org.cn/viewArticle.do?method=viewArticle&id=2c9087840e6513f5010e791e111b0038
[3] 吕茂利,何颖,袁利. 机体接种乙肝疫苗后无、弱应答的影响因素[J]. 现代预防医学,2007,34,(19):3689-3690.
[4]Alper Ca.The human immune response to hepatitis B surface antigen [J]. E xp C lin Imm unog enet,1995;12(3):171-181.
[5] 黄希田,江厦明,陈志明.乙肝疫苗效果及影响因素[J].浙江预防医学,1998,(10):583-584.
[6]姚文清,张玉宽,王凯.接种乙肝疫苗后影响人体免疫应答的因素分析[J].中国公共卫生.2004,20(7):858-859.
[7].尹爱红,张延学.乙型肝炎疫苗免疫后低应答和无应答影响因素的探讨[J].中国计划免疫.2002,8(2):104-106.7疾病监测,1998,13(12):447-450.
[8] U. Shankarkumar, K. Ghosh, S. Badakere, and D. Mohanty.Novel HLA Class I Alleles Associatedwith Indian Leprosy Patients[J].Journal of Biomedicine Biotechnology,2003,(3):(2003)208–211.
[9]卓金蓉.接种乙肝疫苗无、弱免疫应答与遗传因素[J].预防医学情报杂志,2002,18(4):298-299.
[10]Fu-Sheng Wang. Current status and prospects of studies on human genetic allelesassociated with hepatitis B virus infection[J]. World J Gastroenterol, 2003,9 .
[11] Wassim Y. Almawi, Marc Busson,Hala Tamim, etc. HLA Class II Profile and Distribution of HLA-DRB1 and HLA-DQB1Alleles and Haplotypes amongLebanese and Bahraini Arabs[J]. Clinical and Diagnostic Laboratory Immunology, 2004,11(4):770–774.
[12] J Pillot, T Poynard, A Elias, et al. Weak immunogenicity of thePre S2 sequence and lack of circumventing effect on the unrespornsiveness to the hepatitis B virus vaccine. Vaccine, 1995;13(3) 289-294.
[13]Fu-Sheng Wang. Current status and prospects of studies on human genetic allelesassociated with hepatitis B virus infection[J]. World J Gastroenterol, 2003,9 .
[14]曹孟德,秦东春,孙含笑. HLA分子生物学及临床应用〔M〕. 郑州:河南医科大学出版社,1998,44.
[15] 刘蓬勃,徐慧文,王学良.乙肝疫苗接种无、弱应答与遗传因素关系[J].第四军医大学学报,2000,21(1):30-33.
[16]钱毅,梁雪梅,邹东,等.乙肝疫苗无、弱应答与HLA-DR2、7、9相关性的研究[J].免疫学杂志,2001,17(6):463-465.
[17] 涂正坤,吴雄文,刘敏,等.湖北汉族人群对乙肝疫苗免疫应答能力与HLA-DRB1等位基因相关性的研究[J]. 免疫学杂志,2000,16(1):45-62.
[18] 袁振华,崔萌,孙成刚,等.HLA-DRB1*1201/*1501与HBV感染不同状态的相关性[J].山东大学学报,2005,43(5):428-431.
[19] 祜红瑞,范会兴,孙长宇,等. 河南汉族乙型肝炎e抗原阳性慢性乙型肝炎患者HLA-DRB1基因多态性测定[J]. 郑州大学学报医学版,2007,42,(6):1148-1150.
[20]胡章勇,毛笑难.乙肝疫苗免疫低无应答的原因及对策[J] . 实用肝脏杂志,2000,5,(4): 250.
[21]蒋业贵,王宇明. 乙型肝炎患者人类白细胞抗原-DRB1、-DQA1、-DQB1等位基因多态性分析[J]. 中华流行病学杂志, 2004,25,(4):337.
[22]蒋业贵,王宇明,刘同华. HLA2 Ⅱ类基因多态性与乙型肝炎转归的相关性[J]. 免疫学杂志,2006,22,(4):416.
[23] Mc Dermott AB, Zuckerman JN, Sabin CA, et al. Contribution of human leukocyte antigens to the antibody response to hepatitis B vaccination[J].Tissue Antigens. 1997,50(1):8-14.
[24] Desombere I,Willems A, Leroux-Roels G. Response to hepatitis B vaccine: multiple HLA genes are involved[J]. Tissue Antigens. 1998, 51(6):593-604.
[25] Alper CA, Kruskall M, Marcus-Bagley D, et al. Genetic prediction of nonresponse to hepatitis B vaccine[J]. N Engl J Med. 1989,321:708-712.
[26] Mc Dermott AB, Zuckerman JN, Sabin CA, et al. Contribution of human leukocyte antigens to the antibody response to hepatitis B vaccination[J]. Tissue Antigens. 1997,50(1):8-14.
[27] Desombere I,Willems A, Leroux-Roels G. Response to hepatitis B vaccine: multiple HLA genes are involved[J]. Tissue Antigens. 1998, 51(6):593-604.
[28] 黄德秋. 4573名儿童乙肝感染及免疫情况的分析[J].现代医学杂志,2003(5):12.
[29]马恒太,滕兆稳. 乙肝疫苗免疫无(弱)应答原因及对策[J].海峡预防医学杂志,2007,13,(3):35-36.
[30]林鸿滨,梅花.影响乙肝疫苗免疫应答的原因分析[J].中华中西医杂志,2004,5,(18) .
[31]陈仕珠, 韩永战.影响乙肝疫苗免疫效果的因素[J].世界华人消化杂志,2006,14,(27): 2701-2707.
[32] 大洋健康网http://health.dayoo.com/.乙肝接种必须打足剂量.网页链:http://health.dayoo.com/node_2640/node_2649/2007-11/19/1195443522233903.shtml
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