This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
结果: 在用拉米夫定治疗的142例CHB患者中, YMDD变异率为56.3%. HLA-B*58和DRB1*03等位基因分布频率在YMDD变异组与YMDD野生组比较有显著性降低(0.013 vs 0.094, P = 0.036; 0.000 vs 0.063, P = 0.024); HLA-A*30等位基因分布频率在YIDD组明显增高, 与YVDD组比较差异显著(0.158 vs 0.024, P = 0.034); HLA-A*33等位基因分布频率在YVDD变异组明显增高, 与YIDD变异组比较差异显著(0.119 vs 0.000, P = 0.028).
Correlation of hepatitis B virus YMDD mutations with the polymorphism of HLA alleles in patients with chronic hepatitis B virus infection
Shu-Yun Zhang, Xing-Ku Li, Guang-Lu Dong, Shu-Feng Yang, Hong-Xi Gu, Di Li, Qian Jin, Wei Liu, Bo Du, Bin Lu
Shu-Yun Zhang, Xing-Ku Li, Shu-Feng Yang, Qian Jin, Wei Liu, Bo Du, Bin Lu, Research Center, the Second Affiliated Hospital of Harbin Medical University, Harbin 150086, Heilongjiang Province, China
Guang-Lu Dong, Department of Tumor Radiotherapy, the Second Affiliated Hospital of Harbin Medical University, Harbin 150086, Heilongjiang Province, China
Hong-Xi Gu, Di Li, Department of Microbiology, Harbin Medical University, Harbin 150086, Heilongjiang Province, China
Supported by: the Natural Science Foundation of Heilongjiang Province, No. D0307, and the Fund from Health Department of Heilongjiang Province, No. 2005-311.
Correspondence to: Guang-Lu Dong, Department of Tumor Radiotherapy, the Second Affiliated Hospital of Harbin Medical University, Harbin 150086, Heilongjiang Province, China. dgl64@163.com
Received: July 2, 2006 Revised: August 1, 2006 Accepted: August 10, 2006 Published online: October 18, 2006
AIM: To investigate the relationship between HBV YMDD mutations and the polymorphism of human leukocyte antigen (HLA) alleles in patients with chronic hepatitis B virus (HBV) infection.
METHODS: Fluorescent hybridization biprobe PCR and melting curve assay (FH-PCR-MC) was used to determine HBV YMDD mutations in serum specimens from 142 patients with chronic HBV infection. HLA-A, B, and DRB1 alleles in peripheral blood mononuclear cells (PBMCs) were detected by polymerase chain reaction-sequence specific primer (PCR-SSP). The PBMCs were collected from 56 of the 142 patients.
RESULTS: YMDD mutations occurred in 56.3% of the 142 patients who received lumivudine treatment. The frequencies of HLA-B*58 and DRB1*03 alleles were significantly lower in YMDD mutation group in comparison with those in YMDD wild group (0.013 vs 0.094, P = 0.036; 0.000 vs 0.063, P = 0.024). The frequency of HLA-A*30 allele was markedly higher in YIDD group than that in YVDD group (0.158 vs 0.024, P = 0.034), while the frequency of HLA-A*33 allele was lower in YIDD group ( 0.119vs 0.000, P = 0.028).
CONCLUSION: YMDD mutation is associated with the polymorphism of HLA alleles in patients with chronic hepatitis B. Individuals with HLA-B*58 and DRB1*03 alleles may have resistance to YMDD mutation. Patients with HLA-A*30 allele may have a susceptibility to YIDD mutation, and those with HLA-A*33 allele are susceptible to YVDD mutation.
Citation: Zhang SY, Li XK, Dong GL, Yang SF, Gu HX, Li D, Jin Q, Liu W, Du B, Lu B. Correlation of hepatitis B virus YMDD mutations with the polymorphism of HLA alleles in patients with chronic hepatitis B virus infection. Shijie Huaren Xiaohua Zazhi 2006; 14(29): 2854-2859
在40例YMDD变异(YIDD或/和YVDD)患者中, HLA-B*58和DRB1*03等位基因分布频率明显降低, 与YMDD比较差异显著(0.013 vs 0.094, P = 0.036; 0.000 vs 0.063, P = 0.024); 虽然HLA-A*31和A*33均有2倍以上降低(OR<0.500), HLA-B*40, DRB1*07和DRB1*15等位基因频率均有2倍以上增高(OR>2.000), 但均没有统计学意义(P>0.05)(表2). 其他位点未见明显差异.
在YIDD组, HLA-A*30等位基因分布频率明显增高, 而HLA-A*33则明显降低, 与YVDD组比较差异显著(0.158 vs 0.024, P = 0.034和0.000 vs 0.119, P = 0.028); HLA-A*01和A*32在YIDD组也明显增高, 但与YVDD组比较统计学上均无显著差异(0.079 vs 0.000, P = 0.063); HLA-DRB1*09和DRB1*11在YIDD组均较YVDD组2倍以上增高(OR>2.000), HLA-A*24, B*15和B*35在YIDD组均较YVDD组2倍以上降低(OR<0.500), 但均没有统计学意义(P>0.05)(表3). 其他位点未见明显差异.
Ling R, Mutimer D, Ahmed M, Boxall EH, Elias E, Dusheiko GM, Harrison TJ. Selection of mutations in the hepatitis B virus polymerase during therapy of transplant recipients with lamivudine.Hepatology. 1996;24:711-713.
[PubMed] [DOI]
Tipples GA, Ma MM, Fischer KP, Bain VG, Kneteman NM, Tyrrell DL. Mutation in HBV RNA-dependent DNA polymerase confers resistance to lamivudine in vivo.Hepatology. 1996;24:714-717.
[PubMed] [DOI]
Allen MI, Deslauriers M, Andrews CW, Tipples GA, Walters KA, Tyrrell DL, Brown N, Condreay LD. Identification and characterization of mutations in hepatitis B virus resistant to lamivudine. Lamivudine Clinical Investigation Group.Hepatology. 1998;27:1670-1677.
[PubMed] [DOI]
Suzuki F, Tsubota A, Arase Y, Suzuki Y, Akuta N, Hosaka T, Someya T, Kobayashi M, Saitoh S, Ikeda K. Efficacy of lamivudine therapy and factors associated with emergence of resistance in chronic hepatitis B virus infection in Japan.Intervirology. 2003;46:182-189.
[PubMed] [DOI]
Liaw YF, Leung NW, Chang TT, Guan R, Tai DI, Ng KY, Chien RN, Dent J, Roman L, Edmundson S. Effects of extended lamivudine therapy in Asian patients with chronic hepatitis B. Asia Hepatitis Lamivudine Study Group.Gastroenterology. 2000;119:172-180.
[PubMed] [DOI]
Wang YG, Zhu WJ, Yang XL. Investigation of the relationships between HBV YMDD variation and its genotypes.Zhonghua Gan Zang Bing Za Zhi. 2005;13:193, 197.
[PubMed] [DOI]
Li D, Gu HX, Zhang SY, Zhong ZH, Zhuang M, Hattori T. YMDD mutations and genotypes of hepatitis B virus in northern China.Jpn J Infect Dis. 2006;59:42-45.
[PubMed] [DOI]
Song JW, Zhang G, Lin JG, Tang WX, Lin JS. Clinical study of lamivudine and interferon combinate administration to inhibit hepatitis B virus replication.Zhonghua Gan Zang Bing Za Zhi. 2004;12:593-596.
[PubMed] [DOI]
Lin CL, Tsai SL, Lee TH, Chien RN, Liao SK, Liaw YF. High frequency of functional anti-YMDD and -mutant cytotoxic T lymphocytes after in vitro expansion correlates with successful response to lamivudine therapy for chronic hepatitis B.Gut. 2005;54:152-161.
[PubMed] [DOI]
Wolters LM, Niesters HG, Hansen BE, van der Ende ME, Kroon FP, Richter C, Brinkman K, Meenhorst PL, de Man RA. Development of hepatitis B virus resistance for lamivudine in chronic hepatitis B patients co-infected with the human immunodeficiency virus in a Dutch cohort.J Clin Virol. 2002;24:173-181.
[PubMed] [DOI]
Seehofer D, Rayes N, Steinmuller T, Muller AR, Settmacher U, Neuhaus R, Radke C, Berg T, Hopf U, Neuhaus P. Occurrence and clinical outcome of lamivudine-resistant hepatitis B infection after liver transplantation.Liver Transpl. 2001;7:976-982.
[PubMed] [DOI]
Bock CT, Tillmann HL, Torresi J, Klempnauer J, Locarnini S, Manns MP, Trautwein C. Selection of hepatitis B virus polymerase mutants with enhanced replication by lamivudine treatment after liver transplantation.Gastroenterology. 2002;122:264-273.
[PubMed] [DOI]
Wang FS. Current status and prospects of studies on human genetic alleles associated with hepatitis B virus infection.World J Gastroenterol. 2003;9:641-644.
[PubMed] [DOI]
Kacprzak-Bergman I, Nowakowska B. Influence of genetic factors on the susceptibility to HBV infection, its clinical pictures, and responsiveness to HBV vaccination.Arch Immunol Ther Exp (Warsz). 2005;53:139-142.
[PubMed] [DOI]
He YL, Zhao YR, Zhang SL, Lin SM. Host susceptibility to persistent hepatitis B virus infection.World J Gastroenterol. 2006;12:4788-4793.
[PubMed] [DOI]
Wang C, Tang J, Song W, Lobashevsky E, Wilson CM, Kaslow RA. HLA and cytokine gene polymorphisms are independently associated with responses to hepatitis B vaccination.Hepatology. 2004;39:978-988.
[PubMed] [DOI]
Godkin A, Davenport M, Hill AV. Molecular analysis of HLA class II associations with hepatitis B virus clearance and vaccine nonresponsiveness.Hepatology. 2005;41:1383-1390.
[PubMed] [DOI]
Wu YF, Wang LY, Lee TD, Lin HH, Hu CT, Cheng ML, Lo SY. HLA phenotypes and outcomes of hepatitis B virus infection in Taiwan.J Med Virol. 2004;72:17-25.
[PubMed] [DOI]
Thio CL, Thomas DL, Karacki P, Gao X, Marti D, Kaslow RA, Goedert JJ, Hilgartner M, Strathdee SA, Duggal P. Comprehensive analysis of class I and class II HLA antigens and chronic hepatitis B virus infection.J Virol. 2003;77:12083-12087.
[PubMed] [DOI]
Han YN, Yang JL, Zheng SG, Tang Q, Zhu W. Relationship of human leukocyte antigen class II genes with the susceptibility to hepatitis B virus infection and the response to interferon in HBV-infected patients.World J Gastroenterol. 2005;11:5721-5724.
[PubMed] [DOI]
Chu RH, Ma LX, Wang G, Shao LH. Influence of HLA-DRB1 alleles and HBV genotypes on interferon-alpha therapy for chronic hepatitis B.World J Gastroenterol. 2005;11:4753-4757.
[PubMed] [DOI]
Perrillo RP, Lai CL, Liaw YF, Dienstag JL, Schiff ER, Schalm SW, Heathcote EJ, Brown NA, Atkins M, Woessner M. Predictors of HBeAg loss after lamivudine treatment for chronic hepatitis B.Hepatology. 2002;36:186-194.
[PubMed] [DOI]
Honkoop P, de Man RA, Zondervan PE, Schalm SW. Histological improvement in patients with chronic hepatitis B virus infection treated with lamivudine.Liver. 1997;17:103-106.
[PubMed] [DOI]