Association of LIN28B polymorphisms with chronic hepatitis B virus infection.

BACKGROUND: LIN28B is involved in multiple cellular developmental processes, tissue inflammatory response and tumourigenesis. The association of LIN28B polymorphisms with hepatitis B virus (HBV) infection remains unknown. METHODS: This study investigated the association of LIN28B rs314277, rs314280, rs369065 and rs7759938 polymorphisms in patients with chronic HBV infection, a major cause of liver disease including hepatocellular carcinoma (HCC). A total of 781 individuals including 515 cases of chronic HBV infection (91 asymptomatic carrier status, 128 chronic hepatitis, 127 cirrhosis and 169 HCC), 97 HBV infection resolvers and 169 healthy controls were investigated. RESULTS: LIN28 rs314280 genotypes GA + AA were higher in resolver and controls than patients (P = 0.011). Patients had significantly lower rs314280 allele A than resolvers (P = 0.031, OR 0.689, 95%CI 0.491-0.969) or controls (P = 0.034, OR 0.741, 95%CI 0.561-0.978). In dominant model, patients had significantly lower rs314280 genotypes AA+GA than controls (P = 0.008, OR 0.623, 95%CI 0.439-0.884). LIN28 rs7759938 genotypes TC + CC were higher in resolvers and controls than patients (P = 0.015). Patients had significantly lower rs7759938 allele C than resolvers (P = 0.048, OR 0.708, 95%CI 0.503-0.999). In dominant model, patients had significantly lower rs7759938 genotypes TC + CC than controls (P = 0.010, OR 0.632, 95%CI 0.445-0.897). Chronic hepatitis patients had lower frequency of rs369065 genotype TC than asymptomatic carriers, cirrhosis and HCC (P = 0.019). CONCLUSIONS: These results suggest that LIN28 rs314280 and rs7759938 may be related to the susceptibility of chronic HBV infection. Further studies are warranted to examine the association of LIN28B polymorphisms with HBV-related diseases, especially HCC.

Association of polymorphism rs1053005 in STAT3 with chronic hepatitis B virus infection in Han Chinese population.

BACKGROUND: Signal transducer and activator of transcription 3 (STAT3) is involved in hepatitis B virus (HBV) infection and HBV-related hepatocellular carcinoma (HCC). The association between polymorphism rs1053005 and haplotypes formed by rs1053004 and rs1053005 in the 3'UTR of STAT3 and chronic HBV infection has yet to be investigated. METHODS: This study included 567 patients with chronic HBV infection (239 chronic hepatitis, 141 liver cirrhosis and 187 HCC), 98 HBV infection resolvers, and 169 healthy controls. STAT3 rs1053004 and rs1053005 polymorphisms were genotyped by TaqMan SNP Genotyping Assays. RESULTS: The rs1053004 genotype CC [P value by Bonferroni correction (P c ) = 0.002] and allele C (P c = 0.019) were more frequent in patients with chronic HBV infection than in healthy controls. The rs1053005 genotype GG was also more frequent in patients with chronic HBV infection than in healthy controls (P c = 0.046). The rs1053004-rs1053005 haplotype T-G was less frequent in patients with chronic HBV infection than in healthy controls (Pc < 0.001). Haplotype C-A was more frequent in patients with liver cirrhosis than in patients with HCC (P c = 0.042). The rs1053004 genotype TC, rs1053005 genotype AG and rs1053004-rs1053005 haplotype T-A were associated with higher HBV DNA levels. CONCLUSIONS: STAT3 rs1053004 and rs1053005 polymorphisms and haplotypes formed by rs1053004 and rs1053005 are associated with chronic HBV infection and the haplotypes appear to be also associated with the development of liver disease. Studies in large sample sizes of patients and control populations are required to verify and extend these findings.

Association of the tandem polymorphisms (rs148314165, rs200820567) in TNFAIP3 with chronic hepatitis B virus infection in Chinese Han population.

BACKGROUND: Chronic hepatitis B virus (HBV) infection remains an important public health issue. A20, a ubiquitin-editing protein encoded by tumor necrosis factor alpha-inducible protein 3 (TNFAIP3) gene, is complicated in HBV infection and liver injury. The tandem polymorphisms (rs148314165, rs200820567), deletion T followed by a T to A transversion and collectively referred to as TT > A in TNFAIP3, may attenuate A20 expression. METHODS: The rs148314165 and rs200820567 polymorphisms were examined using PCR amplification followed by direct sequencing in 419 patients with chronic HBV infection, 77 HBV infection resolvers and 175 healthy controls of Chinese Han ethnicity. RESULTS: The genotypes and alleles of rs148314165 and rs200820567 polymorphisms determined and the haplotypes constructed were consistently identical, confirming the reliable determination of the TT > A variant. The genotypes of rs148314165 and rs200820567 in HBV patients, HBV infection resolvers and healthy controls are in Hardy-Weinberg equilibrium (P > 0. 05). The patients with chronic HBV infection had higher frequency of TT > A variant than healthy controls (6.6% vs. 3.4%; OR, 1.979; 95% CI, 1.046-3.742; P = 0.033). The frequency of TT > A variant between patients with chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma had no significant differences. CONCLUSIONS: The TT > A variant of TNFAIP3 may be associated with the susceptibility of chronic HBV infection but not the clinical diseases. Studies in large sample size of HBV patient and control populations are required to further clarify the role of this important variant in chronic HBV infection and the disease progression related to the infection.

Elevated serum soluble CD14 levels in chronic HBV infection are significantly associated with HBV-related hepatocellular carcinoma.

Hepatitis B virus (HBV) infection is a major cause of chronic liver diseases including hepatocellular carcinoma (HCC). CD14 and its soluble form sCD14 play important roles in immunity and are involved in the translocation of bacteria and their products which is related to the pathogenesis in chronic HBV infection. This study investigated serum sCD14 levels in HBV chronically infected patients with various clinical diseases. Serum sCD14 levels in HBV patients were significantly elevated compared with those of healthy controls. HCC patients had significantly highest levels of serum sCD14 across all the HBV-related diseases. Serum sCD14 levels significantly discriminated HCC from other HBV-related non-HCC diseases. The area under the receiver operating characteristic curve (AUC) of sCD14 levels for HCC was significantly higher in comparison with other HBV-related non-HCC diseases. The AUC of sCD14 for HCC (0.868, 95 % CI 0.791-0.946, P < 0.001) was higher than that of alpha-fetoprotein (0.660, 95 % CI 0.508-0.811, P = 0.039). Serum level of sCD14 was associated with the overall survival (OS) of HCC patients, with sCD14 levels >20 ng/mL being significantly related to poorer OS (P = 0.017). Multivariate regression showed that serum sCD14 level was an independent factor associated with the OS rates of HBV-related HCC patients (HR 2.544, 95 % CI 1.169-5.538, P = 0.019). HCC resection resulted in a significant decrease of sCD14 levels (P < 0.001). These findings suggest the potential role of sCD14 in the pathogenesis of chronic HBV infection, especially the development of HCC, and the potential usefulness of sCD14 as a biomarker for discriminating clinical diseases and predicting survival of HCC patients in chronic HBV infection.

Highly elevated soluble Tim-3 levels correlate with increased hepatocellular carcinoma risk and poor survival of hepatocellular carcinoma patients in chronic hepatitis B virus infection.

BACKGROUND AND OBJECTIVE: Upregulated T-cell immunoglobulin and mucin domain containing molecule-3 (Tim-3) in hepatitis B virus (HBV)-specific CD8+ T-cells contributes to CD8+ T-cell exhaustion during chronic HBV infection. The membrane-bound Tim-3 can be cleaved from the cell surface by sheddase, yielding soluble Tim-3 (sTim-3). This study investigated serum sTim-3 levels in patients with chronic HBV infection of various liver diseases. METHODS: Serum sTim-3 levels were quantitatively determined in 288 patients with chronic HBV infection of various liver diseases. The sTim-3 levels were analyzed in relation to liver diseases including HBV-related hepatocellular carcinoma (HCC) and overall survival of HCC patients. RESULTS: Serum sTim-3 levels in the patients with chronic HBV infection were significantly elevated compared with healthy controls (P<0.001) and the levels from asymptomatic HBV carrier status, chronic hepatitis, liver cirrhosis to HCC were progressively increased. Serum sTim-3 levels were closely associated with the severity of liver function abnormalities. Importantly, serum sTim-3 levels were independently associated with HCC risk (OR, 4.310; 95% CI, 2.141-8.676, P<0.001) in comparison to non-HCC diseases in chronic HBV infection and significantly associated with the overall survival of HCC patients, with a level >3000 pg/mL being related to shorter overall survival than a level ≤3000 pg/mL (P=0.019). CONCLUSION: Serum sTim-3 is involved in disease progression and HCC development in chronic HBV infection and its quantitative determination may be potentially used as a marker for monitoring the disease progression and predicting the HCC prognosis in chronic HBV infection.

High Serum Procalcitonin Concentrations in Patients With Hemorrhagic Fever With Renal Syndrome Caused by Hantaan Virus.

Objective: This study analyzed the significance of procalcitonin (PCT) in patients with hemorrhagic fever with renal syndrome (HFRS) caused by Hantaan virus. Methods: The demographics and clinical and laboratory data including PCT at hospital admission in 146 adults with HFRS were retrospectively analyzed. Results: PCT level was significantly higher in severe patients (n = 72) than in mild patients (n = 74, p < 0.001) and independently associated with disease severity (OR 2.544, 95% CI 1.330-4.868, p = 0.005). PCT had an area under the receiver operating characteristic curve (AUC) value of 0.738 (95% CI 0.657-0.820, p < 0.001) for predicting severity. PCT level was significantly increased in patients with bacterial infection (n = 87) compared with those without (n = 59, p = 0.037) and associated with bacterial infection (OR 1.685, 95% CI 1.026-2.768, p = 0.039). The AUC value of PCT for predicting bacterial infection was 0.618 (95% CI 0.524-0.711, p = 0.016). PCT level was significantly elevated in non-survivors (n = 13) compared with survivors (n = 133, p < 0.001) and independently associated with mortality (OR 1.075, 95% CI 1.003-1.152, p = 0.041). The AUC value of PCT for predicting mortality was 0.819 (95% CI 0.724-0.914, p < 0.001). Conclusion: PCT concentrations at admission would be predictive of disease severity, secondary bacterial infection and mortality in patients with HFRS caused by Hantaan virus.

Platelet Distribution Width at First Day of Hospital Admission in Patients with Hemorrhagic Fever with Renal Syndrome Caused by Hantaan Virus May Predict Disease Severity and Critical Patients' Survival.

Thrombocytopenia is one of the main characteristics of hemorrhagic fever with renal syndrome (HFRS). This study aimed to evaluate the associations of platelet distribution width (PDW) with the disease severity and critical patients' survival of HFRS. The demographics, clinical data, and white blood cell and platelet parameters including PDW in 260 patients hospitalized for HFRS were analyzed. The results showed that PDW on the first day (PDW1) was positively associated with the disease severity (p = 0.005). Multiple regression analysis showed that in addition to age (odds ratio [OR], 1.091; 95% confidence interval [CI], 1.015-1.172) and occurrence of sepsis (OR, 22.283; 95% CI, 2.985-166.325), PDW1 (OR, 0.782; 95% CI, 0.617-0.992) was a risk factor of the mortality, having an area under the receiver operating characteristic curve of 0.709 (95% CI, 0.572-0.846, p = 0.013) for predicting mortality, with a sensitivity of 70% and a specificity of 67% at a cutoff of 16.5 fL, in patients with critical HFRS. These results suggest the potential of PDW at the first day of hospitalization as a valuable parameter for evaluating the severity of HFRS and a moderate parameter for predicting the prognosis of critical HFRS patients. A prospective study in large patient population is needed to validate these findings.

Association of red blood cell distribution width with severity of hepatitis B virus-related liver diseases.

BACKGROUND: Red blood cell distribution width (RDW) has been indicated to be an inflammatory indicator in a variety of diseases. However, no consistent conclusions regarding it's relevance to hepatitis B virus (HBV) -related liver diseases have been made. This meta-analysis was conducted to assess the significance of RDW in HBV-related liver diseases. METHODS: A comprehensive literature review was conducted using PubMed, Embase, and China National Knowledge Infrastructure (CNKI) through August 20, 2017 to identify studies that reported the association between RDW and HBV-related liver diseases. The standard mean difference (SMD) and corresponding 95% confidence interval (CI) were used to assess the associations. RESULTS: Twenty-four studies met the eligibility criteria were included in the meta-analysis. These studies included 3272 HBV-infected patients and 2209 healthy controls. Chronic hepatitis B (CHB) patients had significantly increased RDW levels compared with healthy controls (SMD =1.399, 95% CI 0.971-1.827, p < 0.001]. Moreover, acute on chronic liver failure (ACLF) patients (SMD = 1.309, 95% CI 0.775-1.843, p < 0.001) and cirrhotic patients (SMD = 0.948, 95% CI 0.715-1.180, p < 0.001) had significantly elevated RDW levels compared with CHB patients. However, no statistical significance was obtained in RDW levels between cirrhosis and ACLF (SMD = 0.167, 95% CI -0.382 -0.716, p = 0.051). CONCLUSION: RDW values were elevated in HBV-related liver diseases and correlated with the disease severity, suggesting that RDW levels may differentiate CHB from healthy controls and ACLF and cirrhosis from CHB but they appear to have no distinguishing characteristic between ACLF and cirrhosis.

Circulating soluble programmed death-1 levels may differentiate immune-tolerant phase from other phases and hepatocellular carcinoma from other clinical diseases in chronic hepatitis B virus infection.

Programmed death-1 (PD-1) is involved in the immune dysfunction of hepatitis B virus (HBV) infection and hepatocellular carcinoma (HCC). This study analyzed the association of circulating soluble PD-1 (sPD-1) levels with the phases and clinical diseases in chronic HBV infection. Serum sPD-1 levels were determined by enzyme linked immunosorbent assay in patients with different phases and liver diseases of chronic HBV infection. The sPD-1 levels in patients with chronic HBV infection were significantly elevated compared with HBV infection resolvers or healthy controls. According to phases, sPD-1 level in immune-tolerant phase (IT) was significantly lower than in other phases. Multivariate analysis showed that sPD-1 was an independent factor associated with IT. Area under the receiver operating characteristic (ROC) curves (AUC) showed that sPD-1 was significantly discriminative of IT from other phases with a cut-off of 1.535 ng/mL (AUC, 0.984; P<0.001). According to clinical diseases, sPD-1 level in HBV-related HCC was significantly higher than in other clinical diseases. Multivariate analysis showed that sPD-1 was an independent factor associated with HCC. The sPD-1 was significantly discriminative of HCC from other clinical diseases with a cut-off of 6.058 ng/mL (AUC, 0.962; P<0.001). The sPD-1 levels were significantly associated with HCC patients' overall survival. HCC resection resulted in remarkable reduction in sPD-1 levels. These results demonstrate the involvement of sPD-1 in the disease course of chronic HBV infection and indicate the potential to apply sPD-1 as a biomarker for differentiating IT from other phases and HCC from other disease conditions in chronic HBV infection.

Association of LTBR polymorphisms with chronic hepatitis B virus infection and hepatitis B virus-related hepatocellular carcinoma.

Lymphotoxin-ß receptor (LTßR) signaling is involved in hepatitis B virus (HBV) infection, hepatitis and liver carcinogenesis. However, the potential association between LTBR polymorphisms and HBV infection remains unclear. This study investigated the associations between LTBR polymorphisms and chronic HBV infection and HBV-related hepatocellular carcinoma (HCC). The study included 409 patients with chronic HBV infection, 73 HBV infection resolvers, and 197 healthy controls. Two polymorphisms rs12354 and rs3759333 were selected and genotyped by polymerase chain reaction-ligase detection reaction method. The frequencies of rs12354 genotype GT and allele T in HBV infection resolvers were significantly higher than those in patients with chronic HBV infection and healthy controls (genotype GT: 38.4% vs. 22.2% and 38.4% vs. 20.8%, P=0.004 and P=0.004, respectively; allele T: 20.5% vs. 13.1% and 20.5% vs. 12.9%, P=0.017 and P=0.028, respectively). The frequencies of rs3759333 genotypes and alleles between HBV patients, HBV infection resolvers and healthy controls had no statistical difference. The genotype and allele frequencies of rs12354 and rs3759333 had no statistical differences between chronic hepatitis B and HBV-related HCC patients. The serum LTßR levels and the overall survival rate between HBV-related HCC patients carrying different rs12354 and rs3759333 genotypes had no statistical differences. These results suggest that the LTBR rs12354 polymorphism might be associated with the spontaneous resolution of HBV infection. Additional studies with large sample size are needed to confirm and extend these findings.

Association of genetic variation in B-cell activating factor with chronic hepatitis B virus infection.

The outcome of hepatitis B virus (HBV) infection is considered to be related to the host immunogenetic susceptibility. B cell activating factor (BAFF) is involved in both B cell and T cell mediated immunity and its circulating levels were shown to be significantly elevated in HBV-related liver diseases. This study examined BAFF rs9514828 and rs12583006 polymorphisms in 386 patients with various liver diseases related to chronic HBV infection, 69 HBV infection resolvers, and 191 healthy controls. Both rs9514828 and rs12583006 polymorphisms and serum BAFF levels were determined in 232 patients with chronic HBV infection, and 61 healthy controls. The results showed that patients with chronic hepatitis had higher frequencies of rs9514828 genotype TT (19.75% vs. 11.86%, OR=2.397, 95% CI=1.121-5.125, P=0.023), genotypes CT+TT (74.69% vs. 63.55%, OR=1.478, 95% CI=1.050-2.080, P=0.045), and allele T (47.22% vs. 37.72%, OR=1.478, 95% CI=1.050-2.080, P=0.025) compared with patients with cirrhosis. Patients with chronic HBV infection and HBV infection resolvers had higher frequency of rs9514828 and rs12583006 haplotype TA compared with healthy controls (21.6% vs. 15.0%, OR=1.672, 95% CI=1.138-2.456, P=0.009 and 27.3% vs. 15.0%, OR=2.258, 95%CI=1.272-4.007, P=0.005, respectively). The rs9514828 and rs12583006 genotypes had no significant association with serum BAFF levels. These results suggest that the rs9514828 allele T may predispose to the liver inflammation in chronic HBV infection, and the rs9514828 and rs12583006 polymorphisms may combinatorially confer susceptibility to chronic HBV infection and resolution of the infection, possibly not through direct effect on serum BAFF levels.

How admissions to various medical specialty divisions determines the outcome of patients with hepatocellular carcinoma: results from a retrospective study in a large hospital of northwest China.

BACKGROUND AND OBJECTIVE: The treatment of hepatocellular carcinoma (HCC) involves multidisciplinary clinical divisions and patients may be admitted to clinical divisions of different disciplinary nature. Few studies have assessed the potential effect of hospital admissions into different divisions on patient treatment options and survival. This study aimed to analyze this potential effect. METHODS: We analyzed data of HCC patients between 2002 and 2011 in a large hospital of northwest China and compared the treatment options and patient outcomes following initial admission into two major clinical disciplinary divisions: internal medicine and surgical. Barcelona Clinic Liver Cancer criteria were used for staging. RESULTS: The study included 2,045 patients. Analysis showed that more patients initially admitted to surgical divisions received curative treatments (resection, transplantation, and local ablation) than those admitted to internal medicine divisions; while more patients initially hospitalized to internal medicine divisions chose supportive care than those admitted to surgical divisions. Stages 0, A, and B patients initially admitted to surgical divisions had higher survival rates compared with those initially admitted to internal medicine divisions (P=0.036, 0.057 and 0.001, respectively). Survival rates of patients who were in stages C and D showed no differences. The survival differences between patients initially admitted to internal medicine and surgical divisions vanished after adjusting for treatment distribution. CONCLUSION: This study showed that the initial hospitalization divisions may affect the outcome of HCC patients because of different treatment options, suggesting that enforcing multidisciplinary collaboration to optimize the treatment of HCC patients at various stages may improve patient survival.

STAT3 regulates glycolysis via targeting hexokinase 2 in hepatocellular carcinoma cells.

Signal transducer and activator of transcription 3 (STAT3) and hexokinase 2 (HK2) are involved in hepatocellular carcinoma (HCC). Deregulation of cellular energetics involving an increase in glycolysis is a characteristic of HCC. This study examined whether STAT3 regulates HCC glycolysis through the HK2 pathway in HCC cells. Human HCC cell lines HepG2 and Hep3B cells were transfected with pcDNA3.1(+)-EGFP-STAT3, STAT3 siRNA and HK2 siRNA, respectively, or treated with rapamycin, an inhibitor of mammalian target of rapamycin (mTOR), and the effects on STAT3 and HK2 expression and cell glycolysis were determined. STAT3 and HK2 expressions were evaluated by real-time polymerase chain reaction and Western blotting. The level of glycolysis metabolism was assessed by the determination of glucose consumption and lactate production.The results showed that transfection of HepG2 and Hep3B cells with pcDNA3.1(+)-EGFP-STAT3 significantly increased STAT3 mRNA and protein expression, glucose consumption and lactate production, and HK2 mRNA and protein expression. However, transfection of HepG2 and Hep3B cells with STAT3 siRNA significantly decreased glucose consumption and lactate production and HK2 mRNA and protein expression. Transfection of HepG2 and Hep3B cells with HK2 siRNA significantly decreased glucose consumption and lactate production. Treatment of HepG2 and Hep3B cells with rapamycin significantly reduced HK2 mRNA and protein expression and glucose consumption and lactate production. These results suggest that mTOR-STAT3-HK2 pathway is involved in the glycolysis of HCC cells and STAT3 may regulate HCC glycolysis through HK2 pathway, providing potential multiple therapeutic targets through intervention of glycolysis for the treatment of HCC.

Therapeutic effect of renin angiotensin system inhibitors on liver fibrosis.

BACKGROUND AND OBJECTIVE: Currently, there is no effective therapy available for liver fibrosis. This study aims to evaluate the efficacy of renin angiotensin system inhibitors on liver fibrosis. METHOD: Full-text randomized controlled trials in patients with liver fibrosis were identified and included in the meta-analysis. The primary outcome measure was the histological fibrosis score of the liver. Secondary outcome measures included fibrosis area of the liver, serological levels of fibrosis markers, adverse events, and withdrawals. RESULTS: From 6973 non-duplicated entries by systematic search, four randomized controlled trials with 210 patients were identified. The renin angiotensin system inhibitors therapy resulted in a marginally significant reduction in liver fibrosis score (MD = -0.30; 95% CI: -0.62-0.02, p = 0.05) and a significant reduction in liver fibrosis area (MD = -2.36%; 95% CI: -4.22%--0.50%, p = 0.01) as compared with control. The therapy was well tolerated and there was no significant difference in withdrawals between treatment and control groups (RD = 0.00; 95% CI: -0.06-0.06, p = 0.97). CONCLUSIONS: Renin angiotensin system inhibitor therapy results in a reduction in liver fibrosis score and liver fibrosis area in patients with hepatic fibrosis with good safety profile. However, randomized controlled trials of high-quality will clarify the effectiveness of renin angiotensin system inhibitors on liver fibrosis.

Immune checkpoint proteins PD-1 and TIM-3 are both highly expressed in liver tissues and correlate with their gene polymorphisms in patients with HBV-related hepatocellular carcinoma.

Immune checkpoint proteins programmed death-1 (PD-1) and T-cell immunoglobulin domain and mucin domain containing molecule-3 (TIM-3) expression and their gene polymorphisms have separately been shown to be associated with hepatitis B virus (HBV) infection and hepatocellular carcinoma (HCC). This study simultaneously examined PD-1 and TIM-3 expression in liver tissues and PD1 and TIM3 polymorphisms and analyzed their correlations in 171 patients with HBV-related HCC and 34 patients with HBV-related cirrhosis.PD-1 and TIM-3 expression in liver tissues were examined by immunohistochemistry and the genotypes of PD1 rs10204525 and TIM3 rs10053538 polymorphisms were determined using genomic DNA extracted from peripheral blood as template.Both PD-1 and TIM-3 expressions in liver infiltrating lymphocytes of HCC tumor tissues were significantly higher than those in tumor adjacent tissues or cirrhotic tissues. The elevated PD-1 and TIM-3 expressions were significantly associated with higher tumor grades. The levels between PD-1 and TIM-3 expression in tumor tissues and tumor adjacent tissues had a significant positive intercorrelation. The expressions of PD-1 and TIM-3 in tumor tissues, tumor adjacent tissues, and cirrhotic tissues were significantly associated with PD1 and TIM3 polymorphisms, with genotype AA of PD1 rs10204525 and genotypes GT+TT of TIM3 rs10053538 being associated with significantly increased PD-1 and TIM-3 expression, respectively.These findings support the potential to improve the efficiency of immune checkpoint-targeted therapy and reduce resistance to the therapy by blocking both PD-1 and TIM-3 and suggest the potential to apply the genotype determination of PD1 rs10204525 and TIM3 rs10053538 as biomarkers of immune checkpoint-directed therapies.

Genetic polymorphisms of immune checkpoint proteins PD-1 and TIM-3 are associated with survival of patients with hepatitis B virus-related hepatocellular carcinoma.

Programmed cell death protein 1 (PD-1) and T-cell immunoglobulin domain and mucin domain containing molecule 3 (TIM-3) are involved in hepatitis B virus (HBV) infection and hepatocellular carcinoma (HCC). This study examined the associations of PD1 and TIM3 polymorphisms with the overall survival (OS) of a prospective cohort of 258 HBV-related HCC patients. Results showed that PD1 +8669 G allele-containing genotypes or TIM3 -1516 genotype GG were significantly associated with longer OS (P < 0.001 and P = 0.001, respectively). In multivariate analysis, PD1 +8669 G allele-containing genotypes and TIM3 -1516 genotype GG were independently associated with longer OS (hazard ratio (HR), 1.835; 95% confidence interval (CI), 1.342-2.509; P < 0.001 and HR, 2.070; 95%CI, 1.428-3.002; P < 0.001, respectively). PD1 +8669 G allele-containing genotypes were significantly associated with longer OS in patients receiving surgical (resection or radiofrequency) treatment, transcatheter arterial chemoembolization (TACE) or supportive and symptomatic treatment. TIM3 -1516 genotype GG was significantly associated with longer OS in TACE patients. In multivariate analysis, PD1 +8669 G allele-containing genotypes were independently associated with longer OS in each treatment population. TIM3 -1516 genotype GG was independently associated with longer OS in patients receiving surgical treatment or TACE. These findings suggest that PD1 +8669 A/G and TIM3 -1516 G/T polymorphisms may affect the prognosis of HBV-related HCC and may be new predictors of prognosis for HCC patients.