Man Li

Cytotoxic T-lymphocyte associated antigen-4 gene polymorphisms and primary biliary cirrhosis: a systematic review.

Background and Aim:  The cytotoxic T‐lymphocyte antigen 4 (CTLA4) is an inhibitory receptor expressed on activated and regulatory T lymphocytes. Polymorphisms could have remarkable effects on susceptibility to autoimmunity. However, the associations between CTLA‐4 polymorphisms and primary biliary cirrhosis (PBC) remain ambiguous. The aim of this meta‐analysis is to determine more precise estimations of the relationship.

HLA-DQ polymorphisms with HBV infection: different outcomes upon infection and prognosis to lamivudine therapy.

Two recent genome‐wide studies showed that the single‐nucleotide polymorphisms in the HLA‐DQ region (rs2856718 and rs9275572) were associated with chronic hepatitis B virus infection and chronic hepatitis C virus‐associated hepatocellular carcinoma in Japanese patients. We tested the effects of the two single‐nucleotide polymorphisms for all major HBV outcomes and lamivudine treatment in Han Chinese. A total of 1649 samples were enrolled, and peripheral blood samples were collected in this study. The single‐nucleotide polymorphisms in the HLA‐DQ region were genotyped using matrix‐assisted laser desorption/ionization time of flight mass spectrometry. Our study demonstrated the clear relevance of HLA‐DQ rs2856718 and rs9275572 with HBV susceptibility, natural clearance and HBV‐associated HCC. HLA‐DQ rs2856718G and rs9275572A were strongly associated with decreased risk of chronic HBV infection (odds ratio = 0.641; P = 2.64 × 10−4; odds ratio = 0.627, P = 7.22 × 10−5) and HBV natural clearance (odds ratio = 0.610; P = 4.80 × 10−4; odds ratio = 0.714, P = 0.013). Moreover, rs9275572A was also associated with development of cirrhosis and hepatocellular carcinoma (odds ratio = 0.632, P = 0.008). In addition, we showed for the first time to our knowledge that rs9275572 was a predictor for lamivudine therapy (viral response: odds ratio = 2.599, P = 4.43 × 10−4; biochemical response: odds ratio = 2.279, P = 4.23 × 10−4). Our study suggested that HLA‐DQ loci were associated with both HBV clearance and HBV‐related diseases and outcomes of lamivudine treatment in Han Chinese.

Association of the rs3077 and rs9277535 polymorphisms in HLA-DP with hepatitis B virus infection and spontaneous clearance: A meta-analysis

Abstract Purpose. Owing to inconsistent observations in the literature of an association between HLA-DP polymorphisms (rs3077 and rs9277535) and hepatitis B virus (HBV) infection and spontaneous clearance, there is an urgent need for a comprehensive and reliable understanding of this subject. This meta-analysis was performed to quantitatively summarise the evidence for the relevance of these HLA-DP polymorphisms to HBV infection and spontaneous clearance. Methods. A meta-analysis was conducted with the data from eight relevant papers published from April 2009 to March 2012, following strict selection. The pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated for alleles, co-dominant, dominant and recessive genotype models of the rs3077 and rs9277535 loci. Results. Our analysis indicated a significant association of rs3077 and rs9277535 in HLA-DP with HBV infection, suggesting that these HLA-DP polymorphisms act beneficially against HBV infection (for rs3077, AG vs. GG: OR = 0.522, 95% CI = 0.485–0.561; AA vs. GG: OR = 0.350, 95% CI = 0.311–0.393; for rs9277535, AG vs. GG: OR = 0.542, 95% CI = 0.506–0.579; AA vs. GG: OR = 0.371, 95% CI = 0.336–0.409). Additionally, these HLA-DP polymorphisms served as protective factors in the spontaneous clearance of HBV (for rs3077, AG vs. GG: OR = 0.600, 95% CI = 0.464–0.775; AA vs. GG: OR = 0.420, 95% CI = 0.299–0.590; for rs9277535, AG vs. GG: OR = 0.623, 95% CI = 0.570–0.681 and AA vs. GG: OR = 0.464, 95% CI = 0.386–0.556) with similar results for both dominant and recessive genotype models. Conclusions. Our results demonstrated that the rs3077 and rs9277535 HLA-DP polymorphisms reduced HBV infection and increased the likelihood of spontaneous viral clearance in some Asian populations.

HLA-DR polymorphism and primary biliary cirrhosis: evidence from a meta-analysis.

BACKGROUND AND AIMS We undertook this study to review and quantitatively analyze the association between human leukocyte antigen (HLA) DR polymorphisms and susceptibility of primary biliary cirrhosis (PBC). METHODS All relevant publications on the association between HLA-DR polymorphisms and PBC were searched through June 2013. Odds ratios (OR) and confidence intervals (CI) for the comparisons between case and control group were calculated. Statistical analysis was performed using Stata 11.0 software. RESULTS Nineteen articles (or 20 studies including the substudies) were identified. For DR*7 allele, the ORs (95% CIs) were 1.530 (1.310, 1.788), 1.757 (1.285, 2.403) and 1.495 (1.211, 1.845) in overall, Asian and European populations, respectively. For DR*8 alleles, the ORs (95% CIs) were 3.158 (1.822, 5.475), 2.803 (2.420, 3.247) and 3.056 (2.573, 3.629) in Asian, American and European subgroups, respectively. The subgroup analysis for DR*11 and DR*13 showed a significant association in Asian and European population. For DR*12 and *15 alleles, the overall ORs (95% CIs) were 0.551 (0.404, 0.753) and 0.721 (0.607, 0.857). However, in subgroup analysis for DR*12 allele, the association was only found in Asian population. In addition, statistical significance exists in American and European populations in the subgroup analysis for DR*15 allele. CONCLUSION Our meta-analysis suggested that HLA-DR *7 and *8 allele polymorphisms contributed to the susceptibility of PBC, whereas DR*11, *12, *13 and *15 allele polymorphisms are protective factors in certain population.

IL28B rs12980275 variant as a predictor of sustained virologic response to pegylated-interferon and ribavirin in chronic hepatitis C patients: A systematic review and meta-analysis.

BACKGROUND AND OBJECTIVE The IL-28B rs12979860 CC and rs8099917 TT genotypes were proved to be predictor for pegylated-interferon (PEG-IFN)/ribavirin (RBV)-treated hepatitis C virus (HCV) patients. However, there were no identical conclusions on rs12980275 polymorphism. Our aim is to perform a meta-analysis in order to determine the association between rs12980275 polymorphism of IL28B and the sustain viral response (SVR) of HCV patients with PEG-IFN/RBV therapy. METHODS Studies were retrieved from PubMed and Chinese China National Knowledge Infrastructure (CNKI). Data were extracted by two investigators and analyzed using Stata 11.0 software. RESULTS Sixteen articles, containing 19 independent studies were included in the analysis. The results showed that patients with AA genotype of rs12980275 achieved higher SVR than patients with AG/GG genotypes. The overall OR (95% CI) was 3.118 (2.146, 4.529). In subgroup analysis by ethnicity, the ORs (95% CIs) were 3.084 (1.454, 6.542) and 2.736 (1.863, 4.018) in Asian and Caucasian population, respectively. Another subgroup analysis by HCV genotype, the ORs (95% CIs) were 3.976 (2.568, 6.158), 1.462 (0.504, 4.240) and 1.489 (0.916, 2.421) in patients with HCV genotype 1/4, mix genotype, and HCV genotype 2/3, respectively. CONCLUSION AA genotype of rs12980275 was a predictive factor for SVR in HCV patients with PEG-IFN/RBV treatment, especially in HCV genotype 1/4.

Mortality analysis on wastewater exposure in Shijiazhuang, Hebei, China, from 2007 to 2011

The study investigated the age-adjusted mortality rate and disease odds among deceased residents living in areas exposed to wastewater and cleanwater from 2007 to 2011, in Shijiazhuang, China. Mortality data for eight villages exposed to wastewater and 16 villages not exposed to wastewater were collected and crosschecked from multiple sources. Overall mean age-adjusted mortality rate for wastewater areas was 798/105 (95 % Confidence Interval (CI) = ± 68), insignificantly higher than the mean mortality rate for cleanwater area, 726/105 (95 % CI = ± 46), p > 0.05. Malignant neoplasms and respiratory mortality and disease odds were higher in wastewater areas than in cleanwater areas, OR = 1.7 (95 % CI = 1.3–2.2, p < 0.01) and OR = 1.9 (95 % CI = 1.1–3.4, p < 0.05), respectively. Wastewater area mortality and disease odds for Lung and Stomach cancers after adjustments were OR = 1.6 (95 % CI = 1.1–2.4, p < 0.05) and OR = 1.8 (95 % CI = 1.2–2.7, p < 0.01), respectively, significantly higher than those of cleanwater areas. There is a possibility that exposure to wastewater might be associated with cancer and respiratory disease mortality. The study recommends that the use of wastewater be limited, discouraged, or discontinued.

eRF3b, a Biomarker for Hepatocellular Carcinoma, Influences Cell Cycle and Phosphoralation Status of 4E-BP1

Background Hepatitis B virus (HBV) infection and its sequelae are now recognized as serious problems globally. Our aime is to screen hepatocellular carcinoma (HCC) from chronic hepatitis B (CHB) and identify the characteristics of proteins involved. Methodology/Principal Findings We affinity-purified sample serum with weak cation-exchange (WCX) magnetic beads and matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF MS) analysis to search for potential markers. The 4210 Da protein, which differed substantially between HCC and CHB isolates, was later identified to be eukaryotic peptide chain release factor GTP-binding subunit eRF3b. Further research showed that eRF3b/GSPT2 was positively expressed in liver tissues. GSPT2 mRNA was, however differentially expressed in blood. Compared with normal controls, the relative expression of GSPT2/18s rRNA was higher in CHB patients than in patients with either LC or HCC (P = 0.035 for CHB vs. LC; P = 0.020 for CHB vs. HCC). The data of further research showed that eRF3b/GSPT2 promoted the entrance of the HepG2 cells into the S-phase and that one of the substrates of the mTOR kinase, 4E-BP1, was hyperphosphorylated in eRF3b-overexpressing HepG2 cells. Conclusions Overall, the differentially expressed protein eRF3b, which was discovered as a biomarker for HCC, could change the cell cycle and influence the phosphorylation status of 4E-BP1 on Ser65 in HepG2.

Decreased frequency of circulating Th9 cells in patients with chronic hepatitis B infection

Chronic hepatitis B (CHB) is one of the major infectious diseases in which CD4+ T helper (Th) cells play a crucial role. Th9 cells are a distinct subset of CD4+ Th cells with important physiological functions.

Effects of small interfering RNA-mediated downregulation of the Krüppel-like factor 4 gene on collagen metabolism in human hepatic stellate cells

The nuclear transcription factor Krüppel-like factor 4 (KLF4) has an important role in cellular biological processes. However, the influence of KLF4 on collagen metabolism remains to be elucidated. In the present study, the effects and underlying mechanism of action of KLF4 on collagen metabolism was investigated in human hepatic stellate cells (HSC), by downregulating KLF4 expression using small interfering RNA (siRNA). The effects of KLF4 silencing by three predesigned siRNAs (siRNA1‑3) were evaluated using both reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) and western blotting in the human LX2 HSC line. The mRNA expression levels of KLF4 were decreased by ~34, 40, and 69% in the siRNA1, siRNA2, and siRNA3 groups, respectively, as compared with the control group. These results were concordant with the protein expression levels of KLF4, as determined by western blot analysis. In the siRNA3 group, the quantity of type Ⅰ and type III collagen, and the expression levels of collagen metabolism proteins including matrix metalloproteinase‑1 (MMP‑1) and tissue inhibitors of metalloproteinases‑1 (TIMP‑1), were determined using both RT‑qPCR and western blotting. Both the mRNA and protein expression levels of type I and type III collagen were significantly decreased in the siRNA3 group, as compared with the control group. The mRNA and protein expression levels of TIMP‑1 were also significantly reduced in the siRNA3‑treated cells, whereas the mRNA and protein expression levels of MMP‑1 were significantly upregulated. Furthermore, KLF4 gene silencing significantly decreased the expression levels of numerous cytokines, including transforming grow factor‑β1, tumor necrosis factor‑α, and interleukin‑1β. The results of the present study provide evidence of siRNA‑mediated silencing of KLF4 expression, which may promote extracellular matrix (ECM) degradation, and inhibition of ECM synthesis. Therefore, KLF4 may be a promising target for the development of novel antifibrotic therapies.