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目的探讨临床HBs Ag和抗HBs双阳性(简称双阳性)慢性HBV感染患者病毒S基因主要亲水区(MHR)新增N-糖基化突变与肝细胞癌(HCC)发生的相关性。方法纳入2009年7月-2015年6月在解放军302医院就诊的284例双阳性慢性HBV感染患者,通过巢式PCR方法扩增血清样本HBV S基因全序列并进行测序,分析MHR新增糖基化突变和其他临床指标与HCC发生的相关性并动态分析18例双阳性HCC患者临床确诊HCC前后S区新增N-糖基化的突变情况。结果多因素分析表明,患者年龄>40岁、HBs Ag>中位数、HBe Ag阴性和MRH新增N-糖基化突变是双阳性慢性HBV感染患者发展为HCC的危险因素(分别为OR=4.281,95%CI 1.843~9.941,P=0.001;OR=3.146,95%CI 1.633~6.060,P=0.001;OR=2.097,95%CI 1.010~4.357,P=0.047;OR=4.381,95%CI 1.842~10.417,P=0.001),而丙氨酸氨基转移酶(ALT)、抗HBs>中位数、抗HBe阳性和HBV DNA水平与HCC发生均无显著相关性。动态研究结果表明,18例双阳性HCC患者样本中有8例在发生HCC 1~4年前已携有新增N-糖基化突变。结论在双阳性患者中HBV S基因MHR区新增N-糖基化突变与HCC发生密切相关,HBs Ag和抗HBs双阳性叠加MHR新增糖基化突变可作为慢性HBV感染患者HCC发生风险的预测指标。
Objective To investigate the relationship between N-glycosylation mutations and hepatocellular carcinoma (HCC) in the major hydrophilic region (MHR) of viral S gene in clinical HBs Ag and anti-HBs double positive (double positive) chronic HBV infection. Methods A total of 284 patients with double-positive chronic HBV infection who visited the 302 Hospital of Chinese People’s Liberation Army from July 2009 to June 2015 were enrolled in this study. The complete sequence of HBV S gene was amplified by nested PCR and sequenced. Mutation and other clinical indicators and the occurrence of HCC and dynamic analysis of 18 cases of double positive HCC patients with clinically diagnosed HCC before and after the S district N-glycosylation mutations. Results Multivariate analysis showed that patients aged> 40 years old, HBsAg> median, HBe Ag negative and MRH N-glycosylation mutations were risk factors for developing HCC in patients with double positive chronic HBV infection (OR = 4.281, 95% CI 1.843-9.941, P = 0.001; OR = 3.146,95% CI 1.633-6.060, P = 0.001; OR = 2.097,95% CI 1.010-4.357, P = 0.047; OR = 4.381,95% CI 1.842 ~ 10.417, P = 0.001). However, there was no significant correlation between alanine aminotransferase (ALT), anti-HBs> median, anti-HBe positive and HBV DNA levels. Dynamic studies showed that eight of the 18 double positive HCC patients had already had a new N-glycosylation mutation 1 to 4 years prior to HCC. Conclusions The newly increased N-glycosylation mutations in the MHR region of HBV S gene are closely related to the occurrence of HCC in double-positive patients. The newly-added glycosylation mutations of MHR double-positive HBs Ag and anti-HBs may be used as risk factors for HCC in patients with chronic HBV infection Predictors.