Correlation between preS gene mutation of hepatitis B virus and liver cirrhosis after hepatitis B virus infection
XIE Jia-xin1, DING Yi-bo2, ZHANG Li1, WANG Fu-kun3, ZHANG Hai-pu2
1. The Third Military Medical University, Chongqing 400038, China; 2. The Second Military Medical University, Shanghai 2000433, China; 3. Bethune Hospital, Shijiazhuang, Hebei 050000, China
Abstract:Objective To explore the correlation of preS gene variation of hepatitis B virus (HBV) with the occurrence of liver cirrhosis (LC) after HBV infection. Methods A case-control study, including 50 patients with chronic hepatitis B (CHB) and 67 patients with LC after HBV infection, was designed. preS gene of serum HBV from all the subjects was amplified and sequenced. MEGA7 software was used to align the sequence. The correlation of mutations in HBV preS gene hot spots with LC was determined through univariate and multivariate analyses by using SPSS16.0 software. Results Univariate analysis indicated that HBV mutations in the preS region, including T3116m (χ2=8.470, P=0.004), A49m (χ2=4.939, P=0.026), T53m (χ2=6.683, P=0.010), A109m (χ2=5.868, P=0.015), and preS deletion (χ2=12.154, P=0.000) were significantly associated with the risks of LC. The frequency of preS deletion was significantly higher in decompensatory LC patients than in compensatory LC patients (63.16% vs. 31.03%, P=0.007). Multivariate analysis showed that advanced age (OR=1.07, 95%CI:1.02-1.11), T3116m (OR=4.18, 95%CI:1.39-12.61), and preS deletion (OR=7.20, 95%CI:2.09-24.80) were independent risk factors for LC. Conclusions HBV preS deletion and T3116m are the HBV mutations related to higher risk of progression from CHB to LC, which need to be validated in a larger sample size.
[1] Lok AS, McMahon BJ. Chronic hepatitis B: update 2009[J]. Hepatology, 2009, 50(3):661-662. [2] 中华医学会肝病学分会, 中华医学会感染病学分会. 慢性乙型肝炎防治指南(2015年版)[J]. 中华实验和临床感染病杂志(电子版), 2015,9(5):570-589. [3] Tseng TC, Liu CJ, Yang HC, et al. Higher proportion of viral basal core promoter mutant increases the risk of liver cirrhosis in hepatitis B carriers[J]. Gut, 2015, 64(2):292-302. [4] Chen QY, Harrison TJ, Sabin CA, et al. The effect of HBV genotype C on the development of HCC differs between wild-type viruses and those with BCP double mutations(T(1762)A(1764))[J]. Hepat Mon, 2014, 14(2):e16214. [5] Li YW, Yang FC, Lu HQ, et al. Hepatocellular carcinoma and hepatitis B surface protein[J]. World J Gastroenterol, 2016, 22(6):1943-1952. [6] Kim H, Kim BJ. Association of PreS/S mutations with occult hepatitis B virus(HBV) infection in South Korea:transmission potential of distinct occult HBV variants[J]. Int J Mol Sci, 2015, 16(6):13595-13609. [7] 谢佳新, 张海谱, 高秋菊, 等. 石家庄地区乙肝病毒基因型分布及其与疾病进展关联研究[J]. 现代预防医学, 2017, 44(7):1161-1165. [8] Xie J, Zhang Y, Zhang Q, et al. Interaction of signal transducer and activator of transcription 3 polymorphisms with hepatitis B virus mutations in hepatocellular carcinoma[J]. Hepatology, 2013, 57(6):2369-2377. [9] Levrero M, Zucman-Rossi J. Mechanisms of HBV-induced hepatocellular carcinoma[J]. J Hepatol. 2016, 64(1 Suppl):S84-101. [10] 蔡兰兰,祝玲玲. 乙肝HBV DNA荧光定量检测与乙肝五项及PreS1的相关性分析[J].实用预防医学, 2014, 21(10):1171-1173. [11] Li X, Qin Y, Liu Y, et al. PreS deletion profiles of hepatitis B virus(HBV) are associated with clinical presentations of chronic HBV infection[J]. J Clin Virol, 2016, 82:27-32. [12] Zhong YW, Di FL, Liu C, et al. Hepatitis B virus basal core promoter/precore mutants and association with liver cirrhosis in children with chronic hepatitis B virus infection[J]. Clin Microbiol Infect, 2016, 22(4):379.e1-8. [13] Shantakumar S, Landis S, Lawton A, et al. Prevalence and incidence of liver enzyme elevations in a pooled oncology clinical trial cohort[J]. Regul Toxicol Pharmacol, 2016, 77:257-262. [14] Yin J, Xie J, Liu S, et al. Association between the various mutations in viral core promoter region to different stages of hepatitis B, ranging of asymptomatic carrier state to hepatocellular carcinoma[J]. Am J Gastroenterol, 2011, 106(1):81-92. [15] Tian Q, Jia J. Hepatitis B virus genotypes:epidemiological and clinical relevance in Asia[J]. Hepatol Int, 2016, 10(6):854-860. [16] Huang Y, Deng H, Shan X, et al. Lower mutation frequency of BCP/precore regions in e antigen-negative chronic HBV-infected children instead of adults patients[J]. PLoS One, 2015, 10(3):e0120733. [17] Kao JH. Risk stratification of HBV infection in Asia-Pacific region[J]. Clin Mol Hepatol, 2014, 20(3):223-227. [18] Fattovich G, Bortolotti F, Donato F. Natural history of chronic hepatitis B:special emphasis on disease progression and prognostic factors[J]. J Hepatol, 2008, 48(2):335-352. [19] Pollicino T, Cacciola I, Saffioti F, et al. Hepatitis B virus PreS/S gene variants:pathobiology and clinical implications[J]. J Hepatol. 2014, 61(2):408-417. [20] Cheong JY, Um SH, Seo YS, et al. A practical scoring system for predicting cirrhosis in patients with chronic viral hepatitis[J]. Hepatogastroenterology, 2012, 59(120):2592-2597. [21] Xie JX, Zhao J, Yin JH, et al. Association of novel mutations and haplotypes in the PreS region of hepatitis B virus with hepatocellular carcinoma[J]. Front Med China, 2010, 4(4):419-429.