Yun Liao

Precore Mutation of Hepatitis B Virus May Contribute to Hepatocellular Carcinoma Risk: Evidence from an Updated Meta-Analysis

Background Studies focused on the correlation of mutations in the genome of Hepatitis B Virus (HBV) like Pre-S mutation, Basal Core promoter (BCP), Enhancer II (EnhII), especially Precore mutation, with the risk of hepatocellular carcinoma (HCC) have triggered stiff controversies. With an increasing number of studies in this field recently, we conducted this meta-analysis to appraise the correlations. Methods We searched the commonly used databases both in English and Chinese till February 1st, 2012. Meta-analysis was performed in fixed/random-effects models using STATA 10.0. Publication bias was examined through Eggers test and Beggs funnel plot. Results In total, 85 case-control studies were included involving 16745 HBV-infected patients, of whom 5781 had HCC. Statistically significant correlations were observed in Precore mutation G1896A (OR = 1.46, 95% confidence interval [CI] = 1.15–1.85, POR = 0.002), G1899A (OR = 3.13, 95%CI = 2.38–4.13, POR<0.001) and Pre-S mutation especially Pre-S1 deletion (OR = 2.94, 95%CI = 2.22 to 3.89) and Pre-S2 deletion (OR = 3.02, 95%CI = 2.03 to 4.50). Similar correlation existed between BCP double mutation A1762T/G1764A, T1753V, C1653T and HCC. In subgroup analysis, the Asians, genotype C or HBeAg positive patients with certain above mutations may be more susceptible to HCC. Besides, the mutations like G1896A and BCP double mutation may be associated with the progression of the liver diseases. Conclusions Precore mutation G1896A, G1899A, deletions in Pre-S region as well as the other commonly seen mutations correlated with the increased risk of HCC, especially in Asians and may predict the progression of the liver disease.

Meta-analysis of the effect of MDR1 C3435 polymorphism on tacrolimus pharmacokinetics in renal transplant recipients.

BACKGROUND The published data revealed conflicting results of the polymorphism of MDR1 exon 26 SNP C3435T on the pharmacokinetics of tacrolimus in different post transplant times; thus, the aim was to perform a meta-analysis of different post transplant times to investigate the influence of SNP C3435T on the tacrolimus pharmacokinetics. METHODS A literature search was conducted to locate the relevant papers by using the PUBMED and EMBASE electronic source until 2011. The pharmacokinetic parameters, including dose administration, concentration and concentration to dose ratio were extracted and a meta-analysis was performed by using STATA10.0. RESULTS A total of 13 papers concerning 1327 individuals were included in the meta-analysis. The overall results showed SNP C3435T could influence the pharmacokinetic parameters in different post transplant times, the subjects with CC genotype had lower concentration dose ratio and need higher tacrolimus dose than the CT and TT genotype. CONCLUSIONS Our meta-analysis of available studies has demonstrated a definite correlation between the SNP C3435T in MDR1 gene and pharmacokinetics of tacrolimus. However, additional studies with large sample size and better study designs are warranted to verify our finding.

Association analysis between SNPs in IL-28B gene and the progress of hepatitis B infection in Han Chinese.

Objective As a candidate gene association study, we investigated the genetic association of SNPs in IL-28B genes with different outcomes of HBV infection, including LC and HCC occurrence. Methods Chinese Han subjects were categorized into two groups: 406 LC caused by CHB and 406 HCC caused by CHB. Genomic DNA was isolated from whole blood samples, SNPs were detected using high resolution melting curve (HRM) method. PCR amplification was carried out under the same conditions in a 96-well plate in Real-Time PCR System. Then 341 LC and 356 HCC patients caused by HBV infection were analyzed as a verification by independent sample. 393 CHB patients and 244 health subjects were included as control. Results CHB patients who progress to LC or HCC showed a significant different frequency in rs12979860 (p = 0.046). Patients with HCC carried more frequently the T alleles in rs12979860 comparison to LC. Same results were found in the independent sample. Conclusion IL-28B rs12979860 C/T polymorphism T allele appears to be more prevalent in patients with HCC than in LC. Carriage of this allele seems to enhance the risk for developing HCC. Gene polymorphism of IL-28B may confer symptomatic specificity in progress and extent of hepatitis B infection.

Association of HLA-DP/DQ, STAT4 and IL-28B variants with HBV viral clearance in Tibetans and Uygurs in China

Several genome‐wide association studies have revealed that HLA‐DP/DQ, STAT4 and IL‐28B associated with liver diseases. But because of population heterogeneity, different races would have different causative polymorphisms. Therefore, in this study, we included Chinese Tibetans and Uygurs to examine the roles of these genes on HBV natural clearance.

Association of HLA-DP/DQ and STAT4 Polymorphisms with HBV Infection Outcomes and a Mini Meta-Analysis

Background Though HLA-DP/DQ is regarded to associate with HBV susceptibility and HBV natural clearance, its role in hepatocellular carcinoma (HCC) development is obscure. And the role of STAT4 in HBV susceptibility and clearance as well as HCC development is still contentious. Therefore, we conducted this study, aiming to clarify these obscure relationships. Methods We recruited 1312 Chinese Han subjects including healthy controls, HBV carriers and HCC patients in the experiment stage. The meta-analysis included 3467 HCC patients and 5821 HBV carriers to appraise the association with HCC development. Results Consistent with previous studies, HLA-DP/DQ associated with HBV susceptibility and HBV natural clearance (p<0.05). However, the experiment showed that HLA-DP rs3077, rs9277535 and rs7453920 did not associate with HCC development (dominant model, rs3077, OR = 0.86, 95%CI = 0.62–1.18; rs9277535, OR = 0.94, 95%CI = 0.68–1.30; rs7453920, OR = 0.75, 95%CI = 0.44–1.27). Meta-analysis again consolidated this conclusion (allele model, rs3077, OR = 0.94, 95%CI = 0.87–1.02; rs9277535, OR = 1.04, 95%CI = 0.97–1.11; rs7453920, OR = 0.89, 95%CI = 0.76–1.02). As for STAT4 rs7574865, we did not find any significant association with HBV susceptibility (OR = 0.91, 95%CI = 0.66–1.26) or HBV natural clearance (OR = 1.13, 95%CI = 0.86–1.49). Moreover, current data failed to acquire positive connection of rs7574865 with HCC development (experiment, OR = 0.86, 95%CI = 0.62–1.19; meta-analysis, OR = 0.87, 95%CI = 0.74–1.03), which may be due to the small sample size. Conclusions HLA-DP/DQ polymorphisms (rs3077, rs9277535, rs7453920) did not associate with HCC development, but did correlate with HBV susceptibility and HBV natural clearance. STAT4 rs7574865 seemed not to correlate with HBV susceptibility or natural clearance. And it seemed rather ambiguous in its role on HCC development at present.

Epidemiology study of HBV genotypes and antiviral drug resistance in multi-ethnic regions from Western China

Hepatitis B virus (HBV) infection is a critical global health issue and moderately epidemic in Western China, but HBV molecular epidemiology characteristics are still limited. We conducted this study to investigate HBV genotypes and antiviral resistant mutations in this multi-ethnic area. A total of 1316 HBV patients were recruited from four ethnic groups from 2011 to 2013. Genotypes and resistant mutations were determined by Sanger sequencing. Four genotypes (B, C, D and C/D) were identified. Genotype B and C were common in Han population, while genotype D was predominant in Uygurs. Genotype C was the major genotype in both Tibetans and Yis, and recombinant C/D was found in Tibetans only. Lamivudine resistance was common in all populations, especially in Hans with prevalence of 42.8%. Entecavir resistance was barely observed regardless of ethnicity. Genotype C isolates had higher rates of rtA181T/V than genotype B (13.5% vs. 5.1%, P < 0.001), in accordance with higher prevalence of resistance to adefovir (20.0% vs. 9.5%, P < 0.001). While incidence of resistant mutations to other drugs and clinical factors showed no difference among different genotypes. HBV genotypes and resistance-conferring mutations had different geographic and demographic distributions in Western China, which provided molecular epidemiology data for clinical management.

Incidence of natural resistance mutations in naïve chronic hepatitis B patients: A systematic review and meta‐analysis

Studies focused on the naturally occurring resistance mutation rate in treatment‐naïve chronic hepatitis B (CHB) patients have set off a furious dispute. We conduct this meta‐analysis to appraise the pooled incidence of spontaneous hepatitis B virus resistance mutations worldwide and its distribution.

Association of the gene polymorphisms in sodium taurocholate cotransporting polypeptide with the outcomes of hepatitis B infection in Chinese Han population

OBJECTIVE In recent years, sodium taurocholate cotransporting polypeptide (NTCP) was newly identified as a hepatitis B virus (HBV) receptor, which partly shed light on the reason for HBV hepatotropism and its host specificity. However, the related researches were limited to in vitro or animal experiments. Therefore, this study aimed to investigate the association of NTCP polymorphisms with HBV natural course in humans. METHODS According to their serological and clinical characteristics, 933 Chinese Han individuals were divided into two major groups, 352 viral clearance controls and 581 persistently infected patients. The latter one included 186 hepatocellular carcinoma (HCC) and 395 non-HCC subjects. A total of five single nucleotide polymorphisms (SNPs) were selected from HapMap dataset and genotyped by high resolution melting (HRM) curve method. RESULTS The rs7154439 AA genotype was observed slightly more common in viral clearance group than in persistently infected group [16 (4.5%) subjects vs. 10 (1.7%) subjects. p=0.008, adjusted odds ratio (AOR)=0.33, 95% confidence interval (CI)=0.15-0.75 in a codominant model; and p=0.006, AOR=0.32, 95% CI=0.14-0.72 in a recessive model]. While the rs4646287 AA genotype was observed slightly more frequent in HCC group than in non-HCC group [6 (3.2%) subjects vs. 1 (0.3%) subject. p=0.018, AOR=15.74, 95% CI=1.59-155.54 in a codominant model; and p=0.018, AOR=15.91, 95% CI=1.61-157.01 in a recessive model]. There were no statistically significant differences of allele or haplotype distribution between any two groups. CONCLUSIONS This study suggests that polymorphisms in the NTCP region may be associated with the natural course of HBV infection. The rs7154439 AA genotype was associated with HBV clearance, while the rs4646287 AA genotype was associated with HCC occurrence. However, considering the sample size is relatively small, larger studies, especially through multicenter collaboration will be needed to fully validate the significance of these findings.

Differential regulation of Tregs and Th17/Th1 cells by a sirolimus-based regimen might be dependent on STAT-signaling in renal transplant recipients☆

BACKGROUND Sirolimus (SRL), a mammalian target of rapamycin inhibitor, has been used as a de novo base therapy with steroids and mycophenolate mofetil to avoid the use of calcineurin inhibitors. Our aim was to determine whether immunoregulation is promoted after conversion from tacrolimus (TAC) to SRL. METHODS The study included 24 renal transplant recipients who converted from TAC to SRL therapy and 24 normal controls. The frequency of T helper (Th) cells and the presence of signal transducer and activator of transcription (STAT) proteins in peripheral blood were analyzed by flow cytometry before conversion and at 3 and 6 months after conversion. Plasma levels of interleukin (IL)-1β, interferon-γ (IFN-γ), IL-17, IL-6, and IL-10 were analyzed by the Bio-Plex® suspension array system before and at 3 months after conversion. RESULTS Renal transplant recipients who switched to SRL showed a significant increase in regulatory T cell (Treg) frequencies and better renal function compared with preconversion (P<0.05). The plasma concentrations of inflammatory cytokines IL-1β, IL-6, IL-17, and IFN-γ were significantly decreased after conversion to SRL. Furthermore, recipients who switched to SRL showed an increase in STAT5 activation and a decrease in STAT3 activation compared with the TAC group. CONCLUSION Our results indicate that conversion to SRL might both minimize calcineurin inhibitor toxicity and promote immune tolerance.

Association of T-cell immunoglobulin and mucin domain-containing molecule 3 (Tim-3) polymorphisms with susceptibility and disease progression of HBV infection.

Purpose T-cell immunoglobulin and mucin domain-containing molecule 3 (Tim-3) plays an important role in regulating T cells in hepatitis B virus (HBV) infection and hepatocellular carcinoma (HCC). However, few researches have reported the association of Tim-3 genetic variants with susceptibility and progression of HBV infection. In this study, we focused on the association of Tim-3 polymorphisms with HBV infection, HBsAg seroclearance and hepatocellular carcinoma. Methods A total of 800 subjects were involved in this study. Four groups were studied here, including HBV, HBsAg seroclearance, HBV-associated HCC and healthy controls. Three single-nucleotide polymorphisms (SNPs) of Tim-3, rs246871, rs25855 and rs31223 were genotyped to analyze the association of Tim-3 polymorphisms with susceptibility and disease progression of HBV infection. Results Our study found that rs31223 and rs246871 were associated with disease progression of HBV infection, while none of the three SNPs was relevant to HBV susceptibility. The minor allele “C” of rs31223 was found to be associated with an increased probability of HBsAg seroclearance (P = 0.033) and genotype “CC” of rs246871 to be associated with an increased probability of HBV-associated HCC (P = 0.007). In accordance, haplotypic analysis of the three polymorphisms also showed that the haplotype block CGC* and TGC* were significantly associated with HBsAg seroclearance (P<0.05) while haplotype block CAT*, CGT*, TAC* and TGT* were significantly associated with HBV-associated HCC (all P<0.05). Conclusions Genetic variants of Tim-3 have an important impact on disease progression of HBV infection. With specific Tim-3 polymorphisms, patients infected with HBV could be potential candidates of HCC and HBsAg seroclearance.