HBV母婴阻断失败儿童的HLA基因多态性研究——附12例报告
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摘要
目的探讨遗传因素对HBV母婴传播免疫阻断失败的影响。方法选择母亲血清HBs Ag阳性、经联合免疫后发生HBV阻断失败的12例婴儿为研究对象,7月龄时抽取肘静脉血,提取DNA,对其进行HLA-DPB1、HLA-DPB2等2个基因中3个单核苷酸多态性(SNP)位点(rs2281388、rs9277535、rs9366816)的PCR扩增测序,分析目的 SNP位点的碱基组成和等位基因比例,统计不同位点的基因频率,并与国际千人基因组计划中的中国南方人群比较。结果 12例HBV母婴阻断失败婴儿的rs9277535位点GA基因型频率与中国南方人群比较差异有统计学意义(P<0.05),且GA基因型与AA基因型相比,新生儿感染HBV的风险较低(OR=0.064,95%CI 0.006~0.641);rs9366816的C等位基因频率与中国南方人群比较差异有统计学意义(P<0.05),且C等位基因与T等位基因相比,新生儿感染HBV的风险较高(OR=2.585,95%CI 1.008~6.629);HBV母婴阻断失败婴儿的rs2281388各基因型及等位基因频率与中国南方人群比较差异无统计学意义(P均>0.05)。结论rs9277535(HLA-DPB1)的GA基因型可能是HBV母婴传播的保护性因素,rs9366816(HLA-DPB2)的C等位基因可能是HBV母婴传播的危险性因素。
Objective To investigate the effect of genetic factors on the failure of immune blockage of mother-to-child transmission of hepatitis B virus( HBV). Methods Twelve infants presenting with the failure of HBV transmission blockage after combined immunotherapy and positive serum HBs Ag of their mothers were recruited in this investigation. The venous blood samples were collected from the elbows of the 7-month-old infants. DNA extraction was performed. Three single nucleotide polymorphisms( SNPs,rs2281388,rs9277535 and rs9366816) at the HLA-DPB1 and HLA-DPB2 loci were subject to PCR amplification sequencing. The base composition and allele proportion of the target SNP sites were analyzed. The gene frequencies at different loci were statistically compared with those in the southern Chinese population recorded in the 1000 s Genomes Project. Results The frequencies of GA genotype of rs9277535 significantly differed between 12 infants with the failure of HBV transmission blockage and the population from southern China( P < 0. 05). The infants with GA genotype had a lower risk of HBV infection compared with their counterparts with AA genotype( OR =0. 064,95% CI: 0. 006-0. 641). The frequency of C allele of rs9366816 also significantly differed from that of the southern population( P < 0. 05). The infants with C allele had a higher risk of HBV infection compared with those with T allele( OR = 2. 585,95% CI: 1. 008-6. 629). However,there was no significant difference in the frequencies of rs2281388 genotypes and alleles between 12 infants and those from southern China( all P> 0. 05). Conclusion The GA genotype of rs9277535( HLA-DPB1) may be a protective factor,whereas the C allele of rs9366816( HLA-DPB2) is probably a risk factor of mother-to-child transmission of HBV.
Objective To investigate the effect of genetic factors on the failure of immune blockage of mother-to-child transmission of hepatitis B virus( HBV). Methods Twelve infants presenting with the failure of HBV transmission blockage after combined immunotherapy and positive serum HBs Ag of their mothers were recruited in this investigation. The venous blood samples were collected from the elbows of the 7-month-old infants. DNA extraction was performed. Three single nucleotide polymorphisms( SNPs,rs2281388,rs9277535 and rs9366816) at the HLA-DPB1 and HLA-DPB2 loci were subject to PCR amplification sequencing. The base composition and allele proportion of the target SNP sites were analyzed. The gene frequencies at different loci were statistically compared with those in the southern Chinese population recorded in the 1000 s Genomes Project. Results The frequencies of GA genotype of rs9277535 significantly differed between 12 infants with the failure of HBV transmission blockage and the population from southern China( P < 0. 05). The infants with GA genotype had a lower risk of HBV infection compared with their counterparts with AA genotype( OR =0. 064,95% CI: 0. 006-0. 641). The frequency of C allele of rs9366816 also significantly differed from that of the southern population( P < 0. 05). The infants with C allele had a higher risk of HBV infection compared with those with T allele( OR = 2. 585,95% CI: 1. 008-6. 629). However,there was no significant difference in the frequencies of rs2281388 genotypes and alleles between 12 infants and those from southern China( all P> 0. 05). Conclusion The GA genotype of rs9277535( HLA-DPB1) may be a protective factor,whereas the C allele of rs9366816( HLA-DPB2) is probably a risk factor of mother-to-child transmission of HBV.
引文
[1]Yin Y,Wu L,Zhang J,Zhou J,Zhang P,Hou H.Identification of risk factors associated with immunoprophylaxis failure to prevent the vertical transmission of hepatitis B virus.J Infect,2013,66(5):447-452.
[2]Han GR,Cao MK,Zhao W,Jiang HX,Wang CM,Bai SF,Yue X,Wang GJ,Tang X,Fang ZX.A prospective and open-label study for the efficacy and safety of telbivudine in pregnancy for the prevention of perinatal transmission of hepatitis B virus infection.J Hepatol,2011,55(6):1215-1221.
[3]Kamatani Y,Wattanapokayakit S,Ochi H,Kawaguchi T,Takahashi A,Hosono N,Kubo M,Tsunoda T,Kamatani N,Kumada H,Puseenam A,Sura T,Daigo Y,Chayama K,Chantratita W,Nakamura Y,Matsuda K.A genome-wide association study identifies variants in the HLA-DP locus associated with chronic hepatitis B in Asians.Nat Genet,2009,41(5):591-595.
[4]Mbarek H,Ochi H,Urabe Y,Kumar V,Kubo M,Hosono N,Takahashi A,Kamatani Y,Miki D,Abe H,Tsunoda T,Kamatani N,Chayama K,Nakamura Y,Matsuda K.A genome-wide association study of chronic hepatitis B identified novel risk locus in a Japanese population.Hum Mol Genet,2011,20(19):3884-3892.
[5]Wang L,Wu XP,Zhang W,Zhu DH,Wang Y,Li YP,Tian Y,Li RC,Li Z,Zhu X,Li JH,Cai J,Liu L,Miao XP,Liu Y,Li H.Evaluation of genetic susceptibility loci for chronic hepatitis B in Chinese:two independent case-control studies.PLo S One,2011,6(3):e17608.
[6]An P,Winkler C,Guan L,O’Brien SJ,Zeng Z,HBV Study Consortium.A common HLA-DPA1 variant is a major determinant of hepatitis B virus clearance in Han Chinese.J Infect Dis,2011,203(7):943-947.
[7]Li J,Yang D,He Y,Wang M,Wen Z,Liu L,Yao J,Matsuda K,Nakamura Y,Yu J,Jiang X,Sun S,Liu Q,Jiang X,Song Q,Chen M,Yang H,Tang F,Hu X,Wang J,Chang Y,He X,Chen Y,Lin J.Associations of HLA-DP variants with hepatitis B virus infection in southern and northern Han Chinese populations:a multicenter case-control study.PLo S One,2011,6(8):e24221.
[8]Chang SW,Fann CS,Su WH,Wang YC,Weng CC,Yu CJ,Hsu CL,Hsieh AR,Chien RN,Chu CM,Tai DI.A genomewide association study on chronic HBV infection and its clinical progression in male Han-Taiwanese.PLo S One,2014,9(6):e99724.
[9]Fan J,Huang X,Chen J,Cai Y,Xiong L,Mu L,Zhou L.Host genetic variants in HLA loci influence risk for hepatitis B virus infection in children.Hepat Mon,2016,16(8):e37786.
[10]Han GR,Xu CL,Zhao W,Yang YF.Management of chronic hepatitis B in pregnancy.World J Gastroenterol,2012,18(33):4517-4521.
[11]徐灵,张宇亮,吴成志,李仁杰,崔邦铨,董成林.不同感染时期慢性乙型肝炎患者表面抗原状况研究.临床和实验医学杂志,2015,14(10):822-824.
[12]WHO.Draft global health sector strategy on viral hepatitis 2016-2021.Geneva:World Health Orgnization,2015.
[13]黄柳,范祎,季冰,叶明.不同分娩方式与乙型肝炎病毒母婴垂直传播关系的研究——附290例分析.新医学,2012,43(4):247-249.
[14]Wen WH,Chen HL,Ni YH,Hsu HY,Kao JH,Hu FC,Chang MH.Secular trend of the viral genotype distribution in children with chronic hepatitis B virus infection after universal infant immunization.Hepatology,2011,53(2):429-436.
[15]尹玉竹,张培珍,腾奔琦,周瑾,侯红瑛.HBV基因型、前S/S基因突变与HBV母婴传播免疫预防失败的关系.中国病理生理杂志,2013,29(9):1615-1619.
[16]Yin Y,Wu L,Zhang J,Zhou J,Zhang P,Hou H.Identification of risk factors associated with immunoprophylaxis failure to prevent the vertical transmission of hepatitis B virus.J Infect,2013,66(5):447-452.
[2]Han GR,Cao MK,Zhao W,Jiang HX,Wang CM,Bai SF,Yue X,Wang GJ,Tang X,Fang ZX.A prospective and open-label study for the efficacy and safety of telbivudine in pregnancy for the prevention of perinatal transmission of hepatitis B virus infection.J Hepatol,2011,55(6):1215-1221.
[3]Kamatani Y,Wattanapokayakit S,Ochi H,Kawaguchi T,Takahashi A,Hosono N,Kubo M,Tsunoda T,Kamatani N,Kumada H,Puseenam A,Sura T,Daigo Y,Chayama K,Chantratita W,Nakamura Y,Matsuda K.A genome-wide association study identifies variants in the HLA-DP locus associated with chronic hepatitis B in Asians.Nat Genet,2009,41(5):591-595.
[4]Mbarek H,Ochi H,Urabe Y,Kumar V,Kubo M,Hosono N,Takahashi A,Kamatani Y,Miki D,Abe H,Tsunoda T,Kamatani N,Chayama K,Nakamura Y,Matsuda K.A genome-wide association study of chronic hepatitis B identified novel risk locus in a Japanese population.Hum Mol Genet,2011,20(19):3884-3892.
[5]Wang L,Wu XP,Zhang W,Zhu DH,Wang Y,Li YP,Tian Y,Li RC,Li Z,Zhu X,Li JH,Cai J,Liu L,Miao XP,Liu Y,Li H.Evaluation of genetic susceptibility loci for chronic hepatitis B in Chinese:two independent case-control studies.PLo S One,2011,6(3):e17608.
[6]An P,Winkler C,Guan L,O’Brien SJ,Zeng Z,HBV Study Consortium.A common HLA-DPA1 variant is a major determinant of hepatitis B virus clearance in Han Chinese.J Infect Dis,2011,203(7):943-947.
[7]Li J,Yang D,He Y,Wang M,Wen Z,Liu L,Yao J,Matsuda K,Nakamura Y,Yu J,Jiang X,Sun S,Liu Q,Jiang X,Song Q,Chen M,Yang H,Tang F,Hu X,Wang J,Chang Y,He X,Chen Y,Lin J.Associations of HLA-DP variants with hepatitis B virus infection in southern and northern Han Chinese populations:a multicenter case-control study.PLo S One,2011,6(8):e24221.
[8]Chang SW,Fann CS,Su WH,Wang YC,Weng CC,Yu CJ,Hsu CL,Hsieh AR,Chien RN,Chu CM,Tai DI.A genomewide association study on chronic HBV infection and its clinical progression in male Han-Taiwanese.PLo S One,2014,9(6):e99724.
[9]Fan J,Huang X,Chen J,Cai Y,Xiong L,Mu L,Zhou L.Host genetic variants in HLA loci influence risk for hepatitis B virus infection in children.Hepat Mon,2016,16(8):e37786.
[10]Han GR,Xu CL,Zhao W,Yang YF.Management of chronic hepatitis B in pregnancy.World J Gastroenterol,2012,18(33):4517-4521.
[11]徐灵,张宇亮,吴成志,李仁杰,崔邦铨,董成林.不同感染时期慢性乙型肝炎患者表面抗原状况研究.临床和实验医学杂志,2015,14(10):822-824.
[12]WHO.Draft global health sector strategy on viral hepatitis 2016-2021.Geneva:World Health Orgnization,2015.
[13]黄柳,范祎,季冰,叶明.不同分娩方式与乙型肝炎病毒母婴垂直传播关系的研究——附290例分析.新医学,2012,43(4):247-249.
[14]Wen WH,Chen HL,Ni YH,Hsu HY,Kao JH,Hu FC,Chang MH.Secular trend of the viral genotype distribution in children with chronic hepatitis B virus infection after universal infant immunization.Hepatology,2011,53(2):429-436.
[15]尹玉竹,张培珍,腾奔琦,周瑾,侯红瑛.HBV基因型、前S/S基因突变与HBV母婴传播免疫预防失败的关系.中国病理生理杂志,2013,29(9):1615-1619.
[16]Yin Y,Wu L,Zhang J,Zhou J,Zhang P,Hou H.Identification of risk factors associated with immunoprophylaxis failure to prevent the vertical transmission of hepatitis B virus.J Infect,2013,66(5):447-452.