Research Center for Clinical and Translational Medicine

Beijing, China

Research Center for Clinical and Translational Medicine

Beijing, China
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Qiao Y.,Guilin Medical University | Qiao Y.,Research Center for Clinical and Translational Medicine | Xu Z.-H.,Research Center for Clinical and Translational Medicine | Lu S.-S.,Research Center for Clinical and Translational Medicine | And 7 more authors.
Medical Journal of Chinese People's Liberation Army | Year: 2016

Objective To investigate the association of additional N-glycosylation mutation in major hydrophilic region (MHR) of hepatitis B virus (HBV) S gene with the risk of hepatocellular carcinoma (HCC) in HBsAg and anti-HBs coexistent patients. Methods A total of 284 patients with coexistence of HBsAg and anti-HBs were enrolled in this study, who were admitted in 302 Hospital of PLA from July 2009 to June 2016. HBV DNA was extracted from serum samples and subjected to nested PCR for full-length S-gene sequencing. The association of MHR additional N-glycosylation mutation and clinical parameters with HCC occurrence risk was analyzed. Specifically, the additional N-glycosylation mutation was dynamically analyzed pre-and post-HCC occurrence for 18 patients. Results Multivariate analysis showed that age >40 years, HBsAg >median, HBeAg negativity, and additional N-glycosylation mutation in MHR were associated with HCC occurrence for the HBsAg and anti-HBs coexistent patients (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; and OR=4.381, 95%CI 1.842-10.417, P=0.001). In contrast, ALT, anti-HBs, anti-HBe, and HBV DNA levels had no significant association with HCC occurrence. Dynamical analysis showed that the additional N-glycosylation mutation had already developed 1-4 years prior to HCC occurrence in the 8 of 18 observed patients. Conclusion Additional N-glycosylation mutation in MHR of HBV S gene had close association with HCC occurrence in HBsAg and anti-HBs coexistent patients, suggesting that HBsAg and anti-HBs coexistence and additional N-glycosylation mutation together could serve as a predictive indicator for HCC occurrence in chronic HBV-infected patients. © 2016, People’s Military Medical Press. All rights reserved.


Lu S.-S.,Guilin Medical University | Li X.-D.,Research Center for Clinical and Translational Medicine | Luo S.-D.,Beijing Institute of Microbiology and Epidemiology | Qiao Y.,Guilin Medical University | And 5 more authors.
Medical Journal of Chinese People's Liberation Army | Year: 2016

Objective To analyze the characteristics of newly added N-glycosylation mutation in major hydrophilic region (MHR) of HBV S gene in patients with coexistence of HBsAg and antiHBs, and reveal the generation mechanism and clinical implications of the coexistence. Methods HBV S genes from 284 patients with HBsAg+antiHBs and 314 patients with single HBsAg were amplified respectively for sequence analysis. A chronic hepatitis B (CHB) patient with HBsAg+antiHBs in MHR was found to harbor a novel double N-glycosylation mutation and selected for further study. Recombinant vectors harboring the novel mutant or control PreS/S genes were constructed and transfected in HepG2 cells respectively for phenotypic analysis, and the effects of the mutations on HBV duplication and antigenicity were investigated. Results The detection rate of MHR N-glycosylation mutation was significantly higher in HBsAg+antiHBs group than in single HBsAg group (11.3% vs. 2.9%, P<0.01, respectively). In HBsAg+antiHBs cohort, the proportion of hepatocellular carcinoma (HCC) patients accounted for 46.9%(15/32) in patients with N-glycosylation mutation at the time of testing; by contrast, the number was 22.6%(57/252) in patients with non-N-glycosylation mutation (P<0.01). N-glycosylation mutational pattern of the novel strain was s116-118TST → NST+s131-133TSM → NST concomitant with sP120 deletion+G145D mutation. The novel mutants accounted for 98.0%, 2.0% and 2.5%, respectively, of viral clones in three sequential serum samples. Mutants with single N-glycosylation mutation s130-132GTS→NSS without sP120 deletion+G145D were detected in sample 2, accounting for 17.6% of viral clones. Compared to the wild-type, the novel mutant had an increase of 31% in replication capacity, but a decrease of 99% in HBsAg level. Immunofluorescence showed that elimination of the two additional N-glycosylation mutations only partly restored HBsAg detection by antiHBs, suggesting that sP120 deletion+G145D mutation also attenuated HBsAg antigenicity. Conclusions Additional N-glycosylation mutation in MHR of HBV S gene is associated with coexisting HBsAg+antiHBs, and the two parameters together might be a better risk factor for HCC occurrence. Combination of two additional N-glycosylation mutation, sP120 deletion and sG145D mutation may co-play a role in silence of HBsAg antigenicity. © 2016, People’s Military Medical Press. All rights reserved.

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