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Lei Z, Wang L, Gao H, Guo S, Kang X, Yuan J, Lv Z, Jiang Y, Yi J, Chen Z, Wang G. Mechanisms underlying the compromised clinical efficacy of interferon in clearing HBV. Virol J 2024; 21:314. [PMID: 39633459 PMCID: PMC11619119 DOI: 10.1186/s12985-024-02589-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2024] [Accepted: 11/26/2024] [Indexed: 12/07/2024] Open
Abstract
Hepatitis B virus (HBV) is a hepatotropic DNA virus that can cause acute or chronic hepatitis, representing a significant global health concern. By 2019, approximately 296 million individuals were chronically infected with HBV, with 1.5 million new cases annually and 820,000 deaths due to HBV-related cirrhosis and liver cancer. Current treatments for chronic hepatitis B include nucleotide analogs (NAs) and interferons (IFNs), particularly IFN-α. NAs, such as entecavir and tenofovir, inhibit viral reverse transcription, while IFN-α exerts antiviral effects by directly suppressing viral replication, modulating viral genome epigenetics, degrading cccDNA, and activating immune responses. Despite its potential, IFN-α shows limited clinical efficacy, partly due to HBV's interference with the IFN signaling pathway. HBV encodes proteins like HBc, Pol, HBsAg, and HBx that disrupt IFN-α function. For example, HBV Pol inhibits STAT1 phosphorylation, HBsAg suppresses STAT3 phosphorylation, and HBx interferes with IFN-α efficacy through multiple mechanisms. Additionally, HBV downregulates key genes in the IFN signaling pathway, further diminishing IFN-α's antiviral effects. Understanding these interactions is crucial for improving IFN-α-based therapies. Future research may focus on overcoming HBV resistance by targeting viral proteins or optimizing IFN-α delivery. In summary, HBV's ability to resist IFN-α limits its therapeutic effectiveness, highlighting the need for new strategies to enhance treatment outcomes.
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Affiliation(s)
- Zhuoyan Lei
- Key Laboratory of Artificial Organs and Computational Medicine of Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, 8 Shuren St, Gongshu District, Hangzhou, 310015, Zhejiang Province, China
| | - Luye Wang
- Key Laboratory of Artificial Organs and Computational Medicine of Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, 8 Shuren St, Gongshu District, Hangzhou, 310015, Zhejiang Province, China
| | - Hanlin Gao
- Key Laboratory of Artificial Organs and Computational Medicine of Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, 8 Shuren St, Gongshu District, Hangzhou, 310015, Zhejiang Province, China
| | - Shubian Guo
- Key Laboratory of Artificial Organs and Computational Medicine of Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, 8 Shuren St, Gongshu District, Hangzhou, 310015, Zhejiang Province, China
| | - Xinjian Kang
- Key Laboratory of Artificial Organs and Computational Medicine of Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, 8 Shuren St, Gongshu District, Hangzhou, 310015, Zhejiang Province, China
| | - Jiajun Yuan
- Key Laboratory of Artificial Organs and Computational Medicine of Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, 8 Shuren St, Gongshu District, Hangzhou, 310015, Zhejiang Province, China
| | - Ziying Lv
- Key Laboratory of Artificial Organs and Computational Medicine of Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, 8 Shuren St, Gongshu District, Hangzhou, 310015, Zhejiang Province, China
| | - Yuxin Jiang
- Key Laboratory of Artificial Organs and Computational Medicine of Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, 8 Shuren St, Gongshu District, Hangzhou, 310015, Zhejiang Province, China
| | - Jinping Yi
- Department of Clinical Laboratory, the First Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Zhi Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, National Clinical Research Center for Infectious Diseases, Zhejiang University, Hangzhou, China
| | - Gang Wang
- Key Laboratory of Artificial Organs and Computational Medicine of Zhejiang Province, Shulan International Medical College, Zhejiang Shuren University, 8 Shuren St, Gongshu District, Hangzhou, 310015, Zhejiang Province, China.
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Luo M, Liang X, Zhou B, Hou J, Jiang DK. CXCR7 genetic variant predicts treatment response of pegylated-interferon α in HBeAg-positive chronic hepatitis B patients. Antiviral Res 2024; 231:106005. [PMID: 39265656 DOI: 10.1016/j.antiviral.2024.106005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2024] [Revised: 09/02/2024] [Accepted: 09/09/2024] [Indexed: 09/14/2024]
Abstract
OBJECTIVES CXC chemokine receptor 7 (CXCR7) plays pivotal roles in different virus infections. However, no research focused on the role of CXCR7 in hepatitis B virus (HBV)-infected patients. The primary aim of this study is to elucidate the role of CXCR7 in predicting the treatment response of chronic hepatitis B (CHB) patients undergoing pegylated interferon-alpha (PegIFNα) therapy. METHODS Two cohorts with a total of 945 Chinese CHB patients (Cohort 1, n = 238; Cohort 2, n = 707) were enrolled in this retrospective study, all the patients were positive for hepatitis B e antigen (HBeAg) and received PegIFNα treatment for 48 weeks and followed-up for 24 weeks post-treatment. Nineteen tag single-nucleotide polymorphisms (SNPs) were selected within and surrounding the CXCR7 gene region. The associations of CXCR7 SNPs and polygenic score (PGS) with PegIFNα treatment response were investigated in the two cohorts. RESULTS Among the 19 candidate SNPs of CXCR7, rs2952665 (A > G) was significantly associated with combined response (CR, defined as HBeAg seroconversion and HBV DNA level <3.3log10IU/mL, P = 0.002) and hepatitis B surface antigen (HBsAg) decline (P = 0.015) in the two cohorts at week 72. Furthermore, a PGS comprising CXCR7_rs2952665 and five additional SNPs, which were previously recognized as biomarkers of PegIFNα treatment response, demonstrated a robust correlation with both CR (P = 1.38 × 10-12) and HBsAg decline (P = 0.003) in all the patients. CONCLUSION This research illustrated that CXCR7_rs2952665 is a promising predictor of the PegIFNα therapy efficiency in Chinese HBeAg-positive CHB patients. A PGS consisting of CXCR7_rs2952665 and five previously reported SNPs predicts treatment response to PegIFNα better.
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Affiliation(s)
- Mengqi Luo
- State Key Laboratory of Organ Failure Research, MOE Key Laboratory of Infectious Diseases Research in South China, Guangdong Provincial Key Laboratory for Prevention and Control of Major Liver Diseases, Guangdong Provincial Clinical Research Center for Viral Hepatitis, Guangdong Institute of Liver Diseases, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China; The Key Laboratory of Molecular Pathology (Hepatic Diseases) of Guangxi, Department of Pathology, The Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi, China; Department of Gastroenterology and Hepatology, West China Hospital, Sichuan University, Chengdu, China
| | - Xinghe Liang
- State Key Laboratory of Organ Failure Research, MOE Key Laboratory of Infectious Diseases Research in South China, Guangdong Provincial Key Laboratory for Prevention and Control of Major Liver Diseases, Guangdong Provincial Clinical Research Center for Viral Hepatitis, Guangdong Institute of Liver Diseases, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Bin Zhou
- State Key Laboratory of Organ Failure Research, MOE Key Laboratory of Infectious Diseases Research in South China, Guangdong Provincial Key Laboratory for Prevention and Control of Major Liver Diseases, Guangdong Provincial Clinical Research Center for Viral Hepatitis, Guangdong Institute of Liver Diseases, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jinlin Hou
- State Key Laboratory of Organ Failure Research, MOE Key Laboratory of Infectious Diseases Research in South China, Guangdong Provincial Key Laboratory for Prevention and Control of Major Liver Diseases, Guangdong Provincial Clinical Research Center for Viral Hepatitis, Guangdong Institute of Liver Diseases, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China.
| | - De-Ke Jiang
- State Key Laboratory of Organ Failure Research, MOE Key Laboratory of Infectious Diseases Research in South China, Guangdong Provincial Key Laboratory for Prevention and Control of Major Liver Diseases, Guangdong Provincial Clinical Research Center for Viral Hepatitis, Guangdong Institute of Liver Diseases, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China; The Key Laboratory of Molecular Pathology (Hepatic Diseases) of Guangxi, Department of Pathology, The Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi, China.
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Luo M, Dong C, Liang X, Na R, Zhou B, Hou J, Jiang DK. A genetic variant of CXCR4 predicts pegylated interferon-alpha treatment response in HBeAg-positive chronic hepatitis B patients. J Clin Microbiol 2024; 62:e0139623. [PMID: 38259071 PMCID: PMC10865838 DOI: 10.1128/jcm.01396-23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2023] [Accepted: 12/11/2023] [Indexed: 01/24/2024] Open
Abstract
Chemokine receptor 4 (CXCR4) plays a vital role in immunoregulation during hepatitis B virus (HBV) infection. This study aimed to screen single-nucleotide polymorphisms (SNPs) of CXCR4 for predicting pegylated interferon-alpha (PegIFNα) therapy response in chronic hepatitis B (CHB) patients. This retrospective cohort study enrolled a total of 945 CHB patients in two cohorts (Cohort 1, n = 238; Cohort 2, n = 707), and all the patients were hepatitis B e antigen (HBeAg)-positive and treated with PegIFNα for 48 weeks and followed up for 24 weeks. Twenty-two tag SNPs were selected in CXCR4 and its flanking region. A polygenic score (PGS) was utilized to evaluate the cumulative effect of multiple SNPs. The relationships between CXCR4 SNPs and PGS and PegIFNα treatment response were explored in the two cohorts. Among the 22 candidate SNPs of CXCR4, rs28367495 (T > C) was significantly linked to PegIFNα treatment response in both cohorts. In patients with more number of rs28367495 C allele, a higher rate of combined response (CR, defined as HBeAg seroconversion and HBV DNA level < 3.3 log10 IU/mL; P = 1.51 × 10-4), a lower mean hepatitis B surface antigen (HBsAg) level (P = 4.76 × 10-4), and a higher mean HBsAg decline (P = 3.88 × 10-4) at Week 72 were achieved. Moreover, a PGS integrating CXCR4_rs28367495 and five previously reported SNPs was strongly correlated with CR (P = 1.26 × 10-13), HBsAg level (P = 4.90 × 10-4), and HBsAg decline (P = 0.005) in all the patients of the two cohorts. CXCR4_rs28367495 is a promising indicator for predicting the responsiveness to PegIFNα treatment for HBeAg-positive CHB patients. The new PGS may further improve the prediction performance.
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Affiliation(s)
- Mengqi Luo
- State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Institutes of Liver Diseases Research of Guangdong Province, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China
- The Key Laboratory of Molecular Pathology (Hepatic Diseases) of Guangxi, the Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, China
- Department of Pathology, the Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, China
| | - Chao Dong
- School of Basic Medicine, Inner Mongolia Medical University, Hohhot, China
| | - Xinghe Liang
- State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Institutes of Liver Diseases Research of Guangdong Province, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Rong Na
- Division of Urology, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China
- Department of Surgery, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China
| | - Bin Zhou
- State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Institutes of Liver Diseases Research of Guangdong Province, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jinlin Hou
- State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Institutes of Liver Diseases Research of Guangdong Province, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - De-Ke Jiang
- State Key Laboratory of Organ Failure Research, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Institutes of Liver Diseases Research of Guangdong Province, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China
- The Key Laboratory of Molecular Pathology (Hepatic Diseases) of Guangxi, the Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, China
- Department of Pathology, the Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, China
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Wang L, Lin N, Zhang Y, Guo S, Liu C, Lin C, Zeng Y, Wu W, Guo J, Zhu C, Zhan F, Ou Q, Xun Z. A novel TRIM22 gene polymorphism promotes the response to PegIFNα therapy through cytokine-cytokine receptor interaction signaling pathway in chronic hepatitis B. Microbiol Spectr 2023; 11:e0224723. [PMID: 37882560 PMCID: PMC10715138 DOI: 10.1128/spectrum.02247-23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2023] [Accepted: 09/08/2023] [Indexed: 10/27/2023] Open
Abstract
IMPORTANCE Pegylated interferon alfa (PegIFNα) has limited efficacy in the treatment of chronic hepatitis B (CHB). Although many biomarkers related to hepatitis B virus (HBV) have been proposed to stratify patients, the response rate to PegIFNα is still unsatisfactory. Herein, our data suggest that the single-nucleotide polymorphism (SNP) rs10838543 in TRIM22 potentiates a positive clinical response to PegIFNα treatment in patients with hepatitis B e antigen-positive CHB by increasing the levels of IFNL1, CCL3, and CCL5. These observations can help guide treatment decisions for patients with CHB to improve the response rate to PegIFNα.
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Affiliation(s)
- Long Wang
- Department of Laboratory Medicine, Fujian Key Laboratory of Laboratory Medicine, Gene Diagnosis Research Center, Fujian Clinical Research Center for Clinical Immunology Laboratory Test, The First Affiliated Hospital, Fujian Medical University , Fuzhou, Fujian, China
- The First Clinical College, Fujian Medical University , Fuzhou, Fujian, China
| | - Ni Lin
- The First Clinical College, Fujian Medical University , Fuzhou, Fujian, China
| | - Yanfang Zhang
- Department of Laboratory Medicine, Fujian Key Laboratory of Laboratory Medicine, Gene Diagnosis Research Center, Fujian Clinical Research Center for Clinical Immunology Laboratory Test, The First Affiliated Hospital, Fujian Medical University , Fuzhou, Fujian, China
- The First Clinical College, Fujian Medical University , Fuzhou, Fujian, China
| | - Shaoying Guo
- The First Clinical College, Fujian Medical University , Fuzhou, Fujian, China
| | - Can Liu
- Department of Laboratory Medicine, Fujian Key Laboratory of Laboratory Medicine, Gene Diagnosis Research Center, Fujian Clinical Research Center for Clinical Immunology Laboratory Test, The First Affiliated Hospital, Fujian Medical University , Fuzhou, Fujian, China
- The First Clinical College, Fujian Medical University , Fuzhou, Fujian, China
- Department of Laboratory Medicine, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University , Fuzhou, Fujian, China
| | - Caorui Lin
- Department of Laboratory Medicine, Fujian Key Laboratory of Laboratory Medicine, Gene Diagnosis Research Center, Fujian Clinical Research Center for Clinical Immunology Laboratory Test, The First Affiliated Hospital, Fujian Medical University , Fuzhou, Fujian, China
- Department of Laboratory Medicine, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University , Fuzhou, Fujian, China
| | - Yongbin Zeng
- Department of Laboratory Medicine, Fujian Key Laboratory of Laboratory Medicine, Gene Diagnosis Research Center, Fujian Clinical Research Center for Clinical Immunology Laboratory Test, The First Affiliated Hospital, Fujian Medical University , Fuzhou, Fujian, China
- Department of Laboratory Medicine, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University , Fuzhou, Fujian, China
| | - Wennan Wu
- Department of Laboratory Medicine, Fujian Key Laboratory of Laboratory Medicine, Gene Diagnosis Research Center, Fujian Clinical Research Center for Clinical Immunology Laboratory Test, The First Affiliated Hospital, Fujian Medical University , Fuzhou, Fujian, China
- Department of Laboratory Medicine, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University , Fuzhou, Fujian, China
| | - Jianhui Guo
- Department of Laboratory Medicine, Fujian Key Laboratory of Laboratory Medicine, Gene Diagnosis Research Center, Fujian Clinical Research Center for Clinical Immunology Laboratory Test, The First Affiliated Hospital, Fujian Medical University , Fuzhou, Fujian, China
- Department of Laboratory Medicine, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University , Fuzhou, Fujian, China
| | - Chenggong Zhu
- Department of Laboratory Medicine, Fujian Key Laboratory of Laboratory Medicine, Gene Diagnosis Research Center, Fujian Clinical Research Center for Clinical Immunology Laboratory Test, The First Affiliated Hospital, Fujian Medical University , Fuzhou, Fujian, China
- The First Clinical College, Fujian Medical University , Fuzhou, Fujian, China
| | - Fuguo Zhan
- Department of Laboratory Medicine, Fujian Key Laboratory of Laboratory Medicine, Gene Diagnosis Research Center, Fujian Clinical Research Center for Clinical Immunology Laboratory Test, The First Affiliated Hospital, Fujian Medical University , Fuzhou, Fujian, China
- Department of Laboratory Medicine, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University , Fuzhou, Fujian, China
| | - Qishui Ou
- Department of Laboratory Medicine, Fujian Key Laboratory of Laboratory Medicine, Gene Diagnosis Research Center, Fujian Clinical Research Center for Clinical Immunology Laboratory Test, The First Affiliated Hospital, Fujian Medical University , Fuzhou, Fujian, China
- The First Clinical College, Fujian Medical University , Fuzhou, Fujian, China
- Department of Laboratory Medicine, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University , Fuzhou, Fujian, China
| | - Zhen Xun
- Department of Laboratory Medicine, Fujian Key Laboratory of Laboratory Medicine, Gene Diagnosis Research Center, Fujian Clinical Research Center for Clinical Immunology Laboratory Test, The First Affiliated Hospital, Fujian Medical University , Fuzhou, Fujian, China
- The First Clinical College, Fujian Medical University , Fuzhou, Fujian, China
- Department of Laboratory Medicine, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University , Fuzhou, Fujian, China
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Hou J, Dong C, Chen J, Chen H, Na R, Zhou B, Hou J, Jiang DK. An intronic genetic variant of ZHX2 predicts response to pegylated interferon α therapy in HBeAg-positive chronic hepatitis B patients. Antiviral Res 2023; 220:105741. [PMID: 39492517 DOI: 10.1016/j.antiviral.2023.105741] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2023] [Revised: 10/21/2023] [Accepted: 10/27/2023] [Indexed: 11/05/2024]
Abstract
ZHX2 plays a crucial role in host immunity and modulates hepatitis B virus (HBV) replication. However, its correlation with immunomodulator-related treatment, i.g., pegylated interferon α(PegIFNα), for HBV remains uncertain. To explore the link between single nucleotide polymorphisms (SNPs) in ZHX2 and response to PegIFNα therapy for chronic hepatitis B (CHB) patients, we conducted a retrospective study in 945 hepatitis B e antigen (HBeAg)-positive CHB patients with at least 48 weeks of PegIFNα treatment and 24 weeks of follow-up from two phase-IV, multicenter trials (Cohort 1, n = 238; Cohort 2, n = 707). Thirty-eight tag SNPs were selected across the whole ZHX2 gene region. A polygenic score (PGS) was constructed by integrating multiple SNPs. The associations of ZHX2 SNPs and PGS with treatment response were assessed in both cohorts and their combination. Among the 38 tag SNPs, ZHX2_rs17289471 (T>C) was significantly associated with combined response (CR, i.e., HBeAg seroconversion and HBV DNA level <3.3log10IU/mL) at week 72 in both cohorts. The CR rate at week 72 increased steadily from rs17289471 TT to CT and CC genotype carriers in both Cohort 1 (P = 0.002) and Cohort 2 (P = 0.025) as well as Cohort 1 + 2 (P = 3.50 × 10-4). Moreover, a PGS integrating ZHX2_rs17289471 and five other previously identified SNPs was further significantly associated with CR rate at week 72 in Cohort 1 (P = 2.38 × 10-6), Cohort 2 (P = 1.04 × 10-7) and Cohort 1 + 2 (P = 9.37 × 10-13). Overall, ZHX2_rs17289471 and PGS have the potential to predict response to PegIFNα treatment of HBeAg-positive CHB patients.
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Affiliation(s)
- Jia Hou
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Guangdong Institute of Liver Diseases, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China; The Key Laboratory of Molecular Pathology (Hepatic Diseases) of Guangxi, Department of Pathology, The Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi, 533099, China
| | - Chao Dong
- School of Basic Medicine, Inner Mongolia Medical University, Hohhot, 010110, China
| | - Jiaxuan Chen
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Guangdong Institute of Liver Diseases, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Haitao Chen
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Guangdong Institute of Liver Diseases, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China; School of Public Health (Shenzhen), Sun Yat-sen University, Shenzhen, 528406, China
| | - Rong Na
- Division of Urology, Department of Surgery, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Bin Zhou
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Guangdong Institute of Liver Diseases, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China
| | - Jinlin Hou
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Guangdong Institute of Liver Diseases, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China.
| | - De-Ke Jiang
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Guangdong Institute of Liver Diseases, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China; The Key Laboratory of Molecular Pathology (Hepatic Diseases) of Guangxi, Department of Pathology, The Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi, 533099, China.
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Lou S, Wang J, Chen J, Xie H, Chen H, Zhou B, Zhang B, Hou J, Jiang DK. The Role of ALPK1 in Inhibiting Hepatitis B Virus Replication Facilitates the Identification of ALPK1 P660L Variant for Predicting Response to Pegylated Interferon α Therapy. J Infect Dis 2023; 228:694-703. [PMID: 36932045 DOI: 10.1093/infdis/jiad065] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Revised: 03/06/2023] [Accepted: 03/16/2023] [Indexed: 03/19/2023] Open
Abstract
BACKGROUND Alpha kinase 1 (ALPK1) agonist has recently been reported to demonstrate anti-hepatitis B virus (HBV) efficacy via activating NF-κB signaling, which is crucial for maximizing interferon (IFN) responses. Here, we investigated the impact of ALPK1 on HBV replication and explored ALPK1 variants for predicting the response to pegylated IFN-α (PegIFN-α) treatment. METHODS The potential anti-HBV effect of ALPK1 was evaluated in HBV-integrated and HBV-infected hepatoma cells. The potentially functional genetic variants of ALPK1 were screened out, and their correlations with PegIFN-α treatment response were assessed in 945 hepatitis B e antigen (HBeAg)-positive patients with chronic hepatitis B (CHB). RESULTS We revealed that ALPK1 inhibited HBV replication in hepatocytes via activating the JAK-STAT pathway. ALPK1 overexpression improved the anti-HBV effect of IFN-α in cell models. A missense variant, rs35389530 (P660L), of ALPK1 was strongly associated with combined response (CR; namely, HBeAg seroconversion and HBV DNA level <3.3log10 IU/mL) to PegIFN-α treatment in patients with CHB (P = 2.12 × 10-6). Moreover, a polygenic score integrating ALPK1_rs35389530 and 2 additional genetic variants was further significantly associated with CR (Ptrend = 9.28 × 10-7), hepatitis B surface antigen (HBsAg) level (Ptrend = .0002), and HBsAg loss (Ptrend = .025). CONCLUSIONS The anti-HBV effects of ALPK1 through activating JAK-STAT pathway provides a new perspective for CHB therapy. ALPK1_rs35389530 and polygenic score are potential biomarkers to predict PegIFN-α treatment response and may be used for optimizing CHB treatment.
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Affiliation(s)
- Shuang Lou
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Guangdong Institute of Liver Diseases, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China
- The Key Laboratory of Molecular Pathology (Hepatic Diseases) of Guangxi, Department of Pathology, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi, China
| | - Jialin Wang
- Food Safety and Health Research Center, School of Public Health, Southern Medical University, Guangzhou, China
| | - Jiaxuan Chen
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Guangdong Institute of Liver Diseases, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Haisheng Xie
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Guangdong Institute of Liver Diseases, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Haitao Chen
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Guangdong Institute of Liver Diseases, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China
- School of Public Health (Shenzhen), Sun Yat-sen University, Shenzhen, China
| | - Bin Zhou
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Guangdong Institute of Liver Diseases, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Bo Zhang
- Food Safety and Health Research Center, School of Public Health, Southern Medical University, Guangzhou, China
| | - Jinlin Hou
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Guangdong Institute of Liver Diseases, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - De-Ke Jiang
- State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Guangdong Institute of Liver Diseases, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China
- The Key Laboratory of Molecular Pathology (Hepatic Diseases) of Guangxi, Department of Pathology, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi, China
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Ayoub A, Anugwom CM, Prieto J, Balderramo D, Ferrer JD, Mattos AZ, Arrese M, Carrera E, Groothuismink ZMA, Oliveira J, Boonstra A, Debes JD. Assessment of STAT4 Variants and Risk of Hepatocellular Carcinoma in Latin Americans and Europeans. Cancers (Basel) 2023; 15:4530. [PMID: 37760499 PMCID: PMC10527221 DOI: 10.3390/cancers15184530] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2023] [Revised: 09/02/2023] [Accepted: 09/08/2023] [Indexed: 09/29/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the third leading cause of cancer death worldwide. The STAT4 rs7574865 genetic variant has been associated with an increased risk of developing HCC in Asian populations. However, this association has not been studied in Latin America and is poorly assessed in European populations. This case-control study investigated the association between STAT4 rs7574865 and HCC risk in these populations. We evaluated DNA samples from seven medical institutions across six Latin American countries and one Dutch institution in 1060 individuals (344 HCC and 716 controls). STAT4 rs7574865 SNP was genotyped using TaqMan-genotyping assay and analyzed using logistic regression. We found no significant association between the homozygous risk allele (G) of STAT4 and HCC development in either population, with odds ratios (OR) for GG versus TT of 0.85 (CI: 0.48-1.52, p = 0.58) and 0.81 (CI: 0.34-1.93, p = 0.67) for Latin Americans and Europeans respectively. No correlation was found between the risk allele and HCC based on underlying liver disease. However, we found that Latin Americans of European ancestry were more likely to carry the risk allele. Our results suggest that the STAT4 SNP rs7574865 does not influence the risk of developing HCC in Latin American or European populations, highlighting the importance of evaluating genetic risk factors in various ethnic groups and understanding the possible influence of ancestry on the genetic basis of disease.
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Affiliation(s)
- Alan Ayoub
- Faculty of Medicine, University of Zagreb, 10000 Zagreb, Croatia;
| | - Chimaobi M. Anugwom
- Department of Medicine, Division of Gastroenterology, Division of Infectious Disease, University of Minnesota, Minneapolis, MN 55455, USA;
- Health Partners Digestive Care, Saint Paul, MN 55130, USA
| | - Jhon Prieto
- Centro de Enfermedades Hepaticas y Digestives, Bogota 110121, Colombia;
| | - Domingo Balderramo
- Department of Gastroenterology, Hospital Privado Universitario de Córdoba, Instituto Universitario de Ciencias Biomédicas de Córdoba, Córdoba X5016, Argentina;
| | - Javier Diaz Ferrer
- Department of Gastroenterology, Universidad San Martin de Porres, Lima 15024, Peru;
| | - Angelo Z. Mattos
- Graduate Program in Medicine: Hepatology, Federal University of Health Sciences of Porto Alegre, Porto Alegre 90050-170, Brazil;
| | - Marco Arrese
- Department of Gastroenterology, Pontificia Universidad Católica de Chile, Santiago 3580000, Chile;
| | - Enrique Carrera
- Department of Gastroenterology, Universidad San Francisco de Quito, Quito 170901, Ecuador;
| | - Zwier M. A. Groothuismink
- Department of Gastroenterology and Hepatology, Erasmus Medical Center, 3015 CE Rotterdam, The Netherlands; (Z.M.A.G.); (J.O.); (A.B.)
| | - Jeffrey Oliveira
- Department of Gastroenterology and Hepatology, Erasmus Medical Center, 3015 CE Rotterdam, The Netherlands; (Z.M.A.G.); (J.O.); (A.B.)
| | - Andre Boonstra
- Department of Gastroenterology and Hepatology, Erasmus Medical Center, 3015 CE Rotterdam, The Netherlands; (Z.M.A.G.); (J.O.); (A.B.)
| | - Jose D. Debes
- Department of Medicine, Division of Gastroenterology, Division of Infectious Disease, University of Minnesota, Minneapolis, MN 55455, USA;
- Department of Gastroenterology and Hepatology, Erasmus Medical Center, 3015 CE Rotterdam, The Netherlands; (Z.M.A.G.); (J.O.); (A.B.)
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8
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Luo M, Zhang L, Yang C, Zhou B, Hou J, Jiang DK. CXCL13 variant predicts pegylated-interferon α treatment response in HBeAg-positive chronic hepatitis B patients. J Med Virol 2023; 95:e28963. [PMID: 37470204 DOI: 10.1002/jmv.28963] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2023] [Revised: 06/17/2023] [Accepted: 07/06/2023] [Indexed: 07/21/2023]
Abstract
As a key immune cytokine, C-X-C motif chemokine ligand 13 (CXCL13) has been reported to play critical roles in immune control of hepatitis B virus (HBV) infection. We aimed to screen single-nucleotide polymorphisms (SNPs) of CXCL13 for predicting response to pegylated interferon-alpha (PegIFNα) therapy of chronic hepatitis B (CHB) patients. Two independent cohorts with a total of 945 (Cohort 1, n = 238; Cohort 2, n = 707) hepatitis B e antigen (HBeAg)-positive CHB patients treated with PegIFNα were enrolled in this retrospective cohort study. Eight candidate SNPs were selected through gene-wide SNP mining within or flanking CXCL13. A polygenic score (PGS) was utilized to assess the cumulative effects of multiple SNPs. The associations of candidate SNPs and PGS with combined response (CR, defined as the combination of HBeAg seroconversion and HBV DNA level <3.3log10 IU/mL) and hepatitis B surface antigen (HBsAg) level were evaluated. Among the eight candidate SNPs, rs76084459 which is located at upstream of CXCL13 was significantly associated with both CR (p = 0.002) and HBsAg level (p = 0.015). A PGS integrating CXCL13_rs76084459 and five other SNPs, which were previously identified as predictors of PegIFNα treatment response, was further strongly correlated with CR (p = 1.759 × 10-10 ) and HBsAg level (p = 0.004). This study demonstrated that CXCL13_rs76084459 can predict response to PegIFNα treatment of HBeAg-positive CHB patients. A PGS composed of six SNPs including CXCL13_rs76084459 predicts PegIFNα treatment response better.
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Affiliation(s)
- Mengqi Luo
- State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Institutes of Liver Diseases Research of Guangdong Province, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China
- The Key Laboratory of Molecular Pathology (Hepatic Diseases) of Guangxi, The Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi, China
| | - Lingyan Zhang
- State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Institutes of Liver Diseases Research of Guangdong Province, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Chou Yang
- State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Institutes of Liver Diseases Research of Guangdong Province, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Bin Zhou
- State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Institutes of Liver Diseases Research of Guangdong Province, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jinlin Hou
- State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Institutes of Liver Diseases Research of Guangdong Province, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - De-Ke Jiang
- State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Institutes of Liver Diseases Research of Guangdong Province, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China
- The Key Laboratory of Molecular Pathology (Hepatic Diseases) of Guangxi, The Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi, China
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9
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Chen J, Lou S, Chen H, Zhou B, Sun J, Hou J, Jiang DK. CD55 Variant Associated with Pegylated-interferon α Therapy Response in HBeAg-positive Chronic Hepatitis B Patients. J Clin Transl Hepatol 2023; 11:295-303. [PMID: 36643051 PMCID: PMC9817056 DOI: 10.14218/jcth.2022.00057] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2022] [Revised: 04/20/2022] [Accepted: 05/04/2022] [Indexed: 01/18/2023] Open
Abstract
BACKGROUND AND AIMS Only a small percentage of chronic hepatitis B (CHB) patients effectively respond to treatment with pegylated-interferon alpha (PegIFNα) or nucleos(t)ide analogues (NUCs). We aimed to detect the correlations of complement regulators-associated single-nucleotide polymorphisms (SNPs) with treatment response of hepatitis B e antigen (HBeAg)-positive CHB patients. METHODS A total of 1,763 HBeAg-positive CHB patients were enrolled, 894 received PegIFNα for at least 48 weeks and were followed up for 24 weeks, and 869 received NUCs for 104 weeks. For each patient, nine SNPs in genes encoding for complement regulators were determined and genotyped. To assess the cumulative effect of numerous SNPs, a polygenic score (PGS) was utilized. The correlations of SNPs and PGS with the levels of combined response (CR) and hepatitis B s antigen (HBsAg) loss were also investigated. RESULTS In PegIFNα-treated patients, an intronic SNP of CD55, rs28371597, was strongly related to CR, and the CR rate in rs28371597_GG genotype carriers was only approximately half that of rs28371597_GT/TT genotype carriers (20.29% vs. 37.10%, p=2.00 × 10-3). A PGS incorporating CD55_rs28371597 and two additional SNPs, CFB_rs12614 and STAT4_rs7574865, which had been considered as predictors for PegIFNα treatment response before, was strongly correlated with the levels of CR (p-trend=7.94×10-6) and HBsAg loss (p-trend=9.40×10-3) in PegIFNα-treated patients. In NUCs-treated individuals, however, none of the nine SNPs were shown to be significantly linked to CHB treatment response. CONCLUSIONS CD55_rs28371597 is a promising biomarker for predicting CHB patients' responsiveness to PegIFNα therapy. The updated PGS may be used for optimizing CHB treatment.
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Affiliation(s)
- Jiaxuan Chen
- State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Guangdong Institute of Liver Diseases, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
- The Key Laboratory of Molecular Pathology (Hepatic Diseases) of Guangxi, Department of Pathology, the Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi, China
| | - Shuang Lou
- State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Guangdong Institute of Liver Diseases, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Haitao Chen
- State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Guangdong Institute of Liver Diseases, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
- School of Public Health (Shenzhen), Sun Yat-sen University, Shenzhen, Guangdong, China
| | - Bin Zhou
- State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Guangdong Institute of Liver Diseases, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Jian Sun
- State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Guangdong Institute of Liver Diseases, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Jinlin Hou
- State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Guangdong Institute of Liver Diseases, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - De-Ke Jiang
- State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Guangdong Institute of Liver Diseases, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
- The Key Laboratory of Molecular Pathology (Hepatic Diseases) of Guangxi, Department of Pathology, the Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi, China
- Correspondence to: De-Ke Jiang, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, China. ORCID: https://orcid.org/0000-0002-7888-2344. Tel/Fax: +86-20-62786533, E-mail:
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10
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Yin GQ, Chen KP, Gu XC. Heterogeneity of immune control in chronic hepatitis B virus infection: Clinical implications on immunity with interferon-α treatment and retreatment. World J Gastroenterol 2022; 28:5784-5800. [PMID: 36353205 PMCID: PMC9639659 DOI: 10.3748/wjg.v28.i40.5784] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Revised: 09/08/2022] [Accepted: 10/10/2022] [Indexed: 02/06/2023] Open
Abstract
Hepatitis B virus (HBV) infection is a global public health issue. Interferon-α (IFN-α) treatment has been used to treat hepatitis B for over 20 years, but fewer than 5% of Asians receiving IFN-α treatment achieve functional cure. Thus, IFN-α retreatment has been introduced to enhance antiviral function. In recent years, immune-related studies have found that the complex interactions between immune cells and cytokines could modulate immune response networks, in-cluding both innate and adaptive immunity, triggering immune responses that control HBV replication. However, heterogeneity of the immune system to control HBV infection, particularly HBV-specific CD8+ T cell heterogeneity, has consequ-ential effects on T cell-based immunotherapy for treating HBV infection. Altogether, the host’s genetic variants, negative-feedback regulators and HBV components affecting the immune system's ability to control HBV. In this study, we reviewed the literature on potential immune mechanisms affecting the immune control of HBV and the clinical effects of IFN-α treatment and retreatment.
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Affiliation(s)
- Guo-Qing Yin
- Center of Hepatology, Zhong-Da Hospital, Southeast University, Nanjing 210009, Jiangsu Province, China
| | - Ke-Ping Chen
- Center of Hepatology, Zhong-Da Hospital, Southeast University, Nanjing 210009, Jiangsu Province, China
| | - Xiao-Chun Gu
- Center of Hepatology, Zhong-Da Hospital, Southeast University, Nanjing 210009, Jiangsu Province, China
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11
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Luo M, Hou J, Mai H, Chen J, Chen H, Zhou B, Hou J, Jiang DK. TRIM26 inhibits hepatitis B virus replication by promoting HBx degradation and TRIM26 genetic polymorphism predicts PegIFNα treatment response of HBeAg-positive chronic hepatitis B Patients. Aliment Pharmacol Ther 2022; 56:878-889. [PMID: 35872575 DOI: 10.1111/apt.17124] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Revised: 01/11/2022] [Accepted: 06/23/2022] [Indexed: 12/13/2022]
Abstract
BACKGROUND Hepatitis B virus (HBV) infection is a serious global health burden. TRIM26 has been reported to affect hepatitis C virus replication. AIMS To manifest the role of TRIM26 on HBV replication and explore if there are single-nucleotide polymorphisms (SNPs) in TRIM26 associated with response to pegylated interferon-alpha (PegIFNα) treatment in patients with chronic hepatitis B (CHB). METHODS We investigated the effect and mechanism of TRIM26 on HBV replication in vitro. The association between SNPs in TRIM26 and PegIFNα treatment response was evaluated in two independent cohorts including 238 and 707 patients with HBeAg-positive CHB. RESULTS Knockdown of TRIM26 increased, while overexpression of TRIM26 inhibited, HBV replication. Co-immunoprecipitation assays and immunofluorescence showed that TRIM26 interacted and co-localised with HBx. Co-transfection of HBx-HIS and TRIM26-FLAG plasmids in Huh7 cells showed that TRIM26 inhibited the expression of HBx. Furthermore, TRIM26 inhibited HBV replication by mediating HBx ubiquitination degradation, and TRIM26 SPRY domain was responsible for the interaction and degradation of HBx. Besides, IFN increased TRIM26 expression. TRIM26 rs116806878 was associated with response to PegIFNα in two CHB cohorts. Moreover, a polygenic score integrating TRIM26 rs116806878, STAT4 rs7574865 and CFB rs12614 (previously reported to be associated with response to PegIFNα) was related to response to PegIFNα in CHB. CONCLUSIONS TRIM26 inhibits HBV replication; IFN promotes TRIM26 expression. TRIM26 exerts an inhibitory effect on HBx by promoting ubiquitin-mediated degradation of HBx. Furthermore, TRIM26 rs116806878 is a potential predictive biomarker of response to PegIFNα in patients with CHB.
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Affiliation(s)
- Mengqi Luo
- State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases and Hepatology Unit, Institutes of Liver Diseases Research of Guangdong Province, Nanfang Hospital, Southern Medical University, Guangzhou, China.,The Key Laboratory of Molecular Pathology (Hepatic Diseases) of Guangxi, Department of Pathology, The Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, China
| | - Jia Hou
- State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases and Hepatology Unit, Institutes of Liver Diseases Research of Guangdong Province, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Haoming Mai
- State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases and Hepatology Unit, Institutes of Liver Diseases Research of Guangdong Province, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jiaxuan Chen
- State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases and Hepatology Unit, Institutes of Liver Diseases Research of Guangdong Province, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Haitao Chen
- State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases and Hepatology Unit, Institutes of Liver Diseases Research of Guangdong Province, Nanfang Hospital, Southern Medical University, Guangzhou, China.,School of Public Health (Shenzhen), Sun Yat-sen University, Shenzhen, China
| | - Bin Zhou
- State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases and Hepatology Unit, Institutes of Liver Diseases Research of Guangdong Province, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jinlin Hou
- State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases and Hepatology Unit, Institutes of Liver Diseases Research of Guangdong Province, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - De-Ke Jiang
- State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases and Hepatology Unit, Institutes of Liver Diseases Research of Guangdong Province, Nanfang Hospital, Southern Medical University, Guangzhou, China.,The Key Laboratory of Molecular Pathology (Hepatic Diseases) of Guangxi, Department of Pathology, The Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, China
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12
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Qi X, Li F, Zhang Y, Zhu H, Yang F, Li X, Jiang X, Chen L, Huang Y, Zhang J. STAT4 genetic polymorphism significantly affected HBeAg seroconversion in HBeAg-positive chronic hepatitis B patients receiving Peginterferon-α therapy: A prospective cohort study in China Running title: STAT4 variation affecting response to PegIFN-α therapy. J Med Virol 2022; 94:4449-4458. [PMID: 35610746 DOI: 10.1002/jmv.27880] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2022] [Revised: 05/19/2022] [Accepted: 05/23/2022] [Indexed: 11/11/2022]
Abstract
AIM Variant in STAT4 was reported to correlate with response of IFN-α in a retrospective study in HBeAg-positive chronic hepatitis B (CHB) patients. Here we conducted a prospective study to analyze the effect of STAT4 genetic polymorphism on response of PegIFN-α-2a in HBeAg-positive patients. METHOD A prospective, multi-center, open-label, paralleled cohort study was performed. 150 treat-naïve and 156 nucleos(t)ide analogues (NAs)-experienced HBeAg-positive CHB patients were enrolled respectively. All patients received PegIFN-α-2a treatment for 48 weeks and 24-week follow-up post PegIFN-α-2a treatment. Before treatment, STAT4 genetic polymorphism were determined by PCR and DNA sequencing. Serological markers, serum HBV DNA level and adverse events were collected at each visit point. RESULT We observed a larger reduction of HBV DNA load and significant higher HBeAg seroconversion rate in GT/TT than in GG group at week 72 (P = 0.002 and P = 0.023) in treat-naïve patients. In NAs-experienced patients, the HBeAg seroconversion rate in GT/TT group was higher than in GG group at week 72 (P = 0.005). STAT4 rs7574865 gene polymorphism was the strongest independent predictor for HBeAg seroconversion in both two paralleled cohorts. Also, patients in GT/TT group had higher HBsAg loss rate than in GG group in the study. There was no significant difference in adverse events between GG and GT/TT groups. CONCLUSION This prospective cohort study confirmed that STAT4 rs7574865 polymorphism is associated with HBeAg seroconversion and HBsAg loss irrespective of naïve and NAs-experienced HBeAg-positive CHB patients treated with PegIFN-α-2a. This article is protected by copyright. All rights reserved.
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Affiliation(s)
- Xun Qi
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity， National Medical Center for Infectious Diseases, Huashan hospital, Fudan University, Shanghai, China, China.,Department of Hepatology, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - Fahong Li
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity， National Medical Center for Infectious Diseases, Huashan hospital, Fudan University, Shanghai, China, China
| | - Yao Zhang
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity， National Medical Center for Infectious Diseases, Huashan hospital, Fudan University, Shanghai, China, China
| | - Haoxiang Zhu
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity， National Medical Center for Infectious Diseases, Huashan hospital, Fudan University, Shanghai, China, China
| | - Feifei Yang
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity， National Medical Center for Infectious Diseases, Huashan hospital, Fudan University, Shanghai, China, China
| | - Xinyan Li
- Department of Hepatology, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - Xuhua Jiang
- Department of Hepatology, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - Liang Chen
- Department of Hepatology, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - Yuxian Huang
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity， National Medical Center for Infectious Diseases, Huashan hospital, Fudan University, Shanghai, China, China.,Department of Hepatology, Shanghai Public Health Clinical Center, Fudan University, Shanghai, China
| | - Jiming Zhang
- Department of Infectious Diseases, Shanghai Key Laboratory of Infectious Diseases and Biosafety Emergency Response, Shanghai Institute of Infectious Diseases and Biosecurity， National Medical Center for Infectious Diseases, Huashan hospital, Fudan University, Shanghai, China, China.,Key Laboratory of Medical Molecular Virology (MOE/MOH), Shanghai Medical College, Fudan University, Shanghai, China.,Department of Infectious Diseases, Jing'An Branch of Huashan Hospital, Fudan University, Shanghai, China
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13
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Colombatto P, Coco B, Bonino F, Brunetto MR. Management and Treatment of Patients with Chronic Hepatitis B: Towards Personalized Medicine. Viruses 2022; 14:701. [PMID: 35458431 PMCID: PMC9027850 DOI: 10.3390/v14040701] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2022] [Revised: 03/22/2022] [Accepted: 03/23/2022] [Indexed: 02/07/2023] Open
Abstract
The currently available antiviral treatments (Peg-Interferon-α and Nucleos(t)ide Analogues, NA) for chronic hepatitis B (CHB) achieve a functional cure (serum HBsAg and HDV-DNA clearance) of HBV infection in a limited number of patients. Nevertheless, the continuous pharmacological suppression of viral replication by NA halts liver disease progression lowering the risk of HCC development and improving the survival. In the near future, to fully exploit the potential of old and new drugs for HBV treatment a personalized approach to the patients will be required according to an accurate definition of their virologic, immunologic and clinical profile.
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Affiliation(s)
- Piero Colombatto
- Hepatology Unit and Laboratory of Molecular Genetics and Pathology of Hepatitis Viruses, Reference Center of the Tuscany Region for Chronic Liver Disease and Cancer, Department of Medical Specialties, University Hospital of Pisa, Via Paradisa 2, 56124 Pisa, Italy; (P.C.); (B.C.)
| | - Barbara Coco
- Hepatology Unit and Laboratory of Molecular Genetics and Pathology of Hepatitis Viruses, Reference Center of the Tuscany Region for Chronic Liver Disease and Cancer, Department of Medical Specialties, University Hospital of Pisa, Via Paradisa 2, 56124 Pisa, Italy; (P.C.); (B.C.)
| | - Ferruccio Bonino
- Institute of Biostructure and Bioimaging, National Research Council, Via De Amicis 95, 80145 Naples, Italy;
| | - Maurizia R. Brunetto
- Hepatology Unit and Laboratory of Molecular Genetics and Pathology of Hepatitis Viruses, Reference Center of the Tuscany Region for Chronic Liver Disease and Cancer, Department of Medical Specialties, University Hospital of Pisa, Via Paradisa 2, 56124 Pisa, Italy; (P.C.); (B.C.)
- Institute of Biostructure and Bioimaging, National Research Council, Via De Amicis 95, 80145 Naples, Italy;
- Internal Medicine, Department of Clinical and Experimental Medicine, University of Pisa, Via Savi 10, 56127 Pisa, Italy
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14
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Li J, Chen H, Chen J, Zhou B, Hou J, Jiang DK. A Missense Variant in Granulysin is Associated with the Efficacy of Pegylated-Interferon-Alpha Therapy in Chinese Patients with HBeAg-Positive Chronic Hepatitis B. Pharmgenomics Pers Med 2021; 14:1505-1515. [PMID: 34848996 PMCID: PMC8627316 DOI: 10.2147/pgpm.s337962] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2021] [Accepted: 11/03/2021] [Indexed: 11/23/2022] Open
Abstract
Purpose Granulysin (GNLY) is a cytotoxic granule that has been reported to have various antimicrobial activities. We evaluated the association between a missense variant in GNLY (rs11127) and treatment efficacy of pegylated interferon-alpha (PegIFNα) or nucleos(t)ide analogs (NUCs) in patients with chronic hepatitis B (CHB). Patients and Methods We included a total of 1823 patients with hepatitis B e antigen (HBeAg)-positive CHB (954 patients treated with PegIFNα and 869 patients treated with NUCs) in four Phase IV multicenter randomized controlled trials. The association of the GNLY rs11127 genotype with the combined response (CR), defined as HBeAg seroconversion and hepatitis B virus (HBV) DNA level <2000 IU/mL was evaluated. A polygenic score (PGS) was constructed to evaluate the cumulative effect of multiple single-nucleotide polymorphisms (SNPs), including rs11127 and several other SNPs, STAT4 rs7574865, CFB rs12614, and CD55 rs28371597, which were reported to be associated with CR. Results GNLY rs11127 was significantly associated with CR in patients treated with PegIFNα. The CR rate in patients with the rs11127 CC genotype was higher than that with the CT or TT genotype (40.98% vs 30.34% or 27.09%, P = 0.003). Furthermore, a PGS integrating GNLY rs11127 and three other SNPs was significantly associated with CR in PegIFNα-treated patients (P < 0.001). However, no significant correlation was found between GNLY rs11127 and CR in NUCs-treated patients. Conclusion GNLY rs11127 is an independent biomarker for predicting the response to PegIFNα therapy in HBeAg-positive CHB patients. Furthermore, the PGS, including GNLY rs11127, provides new insights for individualized treatment in clinical practice.
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Affiliation(s)
- Jing Li
- State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Guangdong Institute of Liver Diseases, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China
| | - Haitao Chen
- State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Guangdong Institute of Liver Diseases, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China.,School of Public Health (Shenzhen), Sun Yat-sen University, Shenzhen, People's Republic of China
| | - Jiaxuan Chen
- State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Guangdong Institute of Liver Diseases, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China
| | - Bin Zhou
- State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Guangdong Institute of Liver Diseases, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China
| | - Jinlin Hou
- State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Guangdong Institute of Liver Diseases, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China
| | - De-Ke Jiang
- State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Guangdong Institute of Liver Diseases, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, People's Republic of China
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15
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Ye J, Chen J. Interferon and Hepatitis B: Current and Future Perspectives. Front Immunol 2021; 12:733364. [PMID: 34557195 PMCID: PMC8452902 DOI: 10.3389/fimmu.2021.733364] [Citation(s) in RCA: 93] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Accepted: 08/17/2021] [Indexed: 12/12/2022] Open
Abstract
Chronic hepatitis B virus (HBV) infection remains a major health burden worldwide for which there is still no effective curative treatment. Interferon (IFN) consists of a group of cytokines with antiviral activity and immunoregulatory and antitumor effects, that play crucial roles in both innate and adaptive immune responses. IFN-α and its pegylated form have been used for over thirty years to treat chronic hepatitis B (CHB) with advantages of finite treatment duration and sustained virologic response, however, the efficacy is limited and side effects are common. Here, we summarize the status and unique advantages of IFN therapy against CHB, review the mechanisms of IFN-α action and factors affecting IFN response, and discuss the possible improvement of IFN-based therapy and the rationale of combinations with other antiviral agents in seeking an HBV cure.
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Affiliation(s)
- Jianyu Ye
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
| | - Jieliang Chen
- Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.,Research Unit of Cure of Chronic Hepatitis B Virus Infection, Chinese Academy of Medical Sciences, Shanghai, China
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16
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Wang L, Xu D, Cai L, Dai J, Li Y, Xu H. Expression and survival analysis of the STAT gene family in diffuse gliomas using integrated bioinformatics. Curr Res Transl Med 2021; 69:103274. [PMID: 33836320 DOI: 10.1016/j.retram.2020.103274] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Revised: 09/21/2020] [Accepted: 11/24/2020] [Indexed: 10/21/2022]
Abstract
Signal Transducer and Activator of Transcription (STAT) belongs to the acyltransferase family and participates in cell viability response to different cell stimuli and pathogens. By mediating the expression of a variety of genes, the STAT family plays a prominent part in mammal immunity, proliferation and differentiation. Dysregulations and mutations of STAT factors have been revealed in many kinds of cancers including diffuse gliomas; however, expression characteristic and prognostic value of STAT in diffuse gliomas remain to be elucidated. In this study, we analyzed the transcriptional and survival data of gliomas using ONCOMINE, cBioPortal, GEPIA, COXPRESDB and WEBGESTALTR databases. The results demonstrated that the transcriptional level of STAT1, STAT3 and STAT5A in gliomas was significantly higher than that in normal tissue. Furthermore, dysregulations of STAT1, STAT3, STAT4, STAT5B and STAT6 were referred to as the potential biomarkers to sub-group analysis of gliomas. Survival analysis by the Kaplan-Meier Plotter suggested that glioma patients with high expression of STAT1, STAT3 and STAT5B tended to have poor survival. These data revealed that the STAT family may be an essential aspect of glioma progression and prognosis.
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Affiliation(s)
- Liang Wang
- Department of Radiology, Zhongnan Hospital of Wuhan University, Wuhan University, China.
| | - Dan Xu
- Department of Radiology, Zhongnan Hospital of Wuhan University, Wuhan University, China
| | - Longbiao Cai
- Department of Radiology, Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology, China
| | - Jia Dai
- Tianmen Power Supply Company, State Grid Corporation of China, Hubei, China
| | - Yirong Li
- Department of Laboratory Medicine, Zhongnan Hospital, Wuhan University, Wuhan, 430071, China.
| | - Haibo Xu
- Department of Radiology, Zhongnan Hospital of Wuhan University, Wuhan University, China.
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17
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Li T, Yang X, Li W, Song J, Li Z, Zhu X, Wu X, Liu Y. ADAR1 Stimulation by IFN-α Downregulates the Expression of MAVS via RNA Editing to Regulate the Anti-HBV Response. Mol Ther 2020; 29:1335-1348. [PMID: 33279720 DOI: 10.1016/j.ymthe.2020.11.031] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2020] [Revised: 10/27/2020] [Accepted: 11/25/2020] [Indexed: 02/07/2023] Open
Abstract
The partial response of chronic hepatitis B virus (CHB) patients to interferon-α (IFN-α) therapy remains elusive, which requires a better understanding of the involved molecular mechanism. In our study, bioinformatics analysis was applied to relate IFN-α regulated candidate genes and RNA editing sites by RNA sequencing. Mitochondrial antiviral signaling protein (MAVS) antiviral effect was confirmed in HepG2.2.15 cells and in two mouse models. The associations between polymorphisms in MAVS gene and response to IFN-α therapy were confirmed in CHB patients. We found that IFN-α downregulates MAVS via RNA editing that was mediated by adenosine deaminase acting on RNA (ADAR1). ADAR1 inhibited MAVS expression via a human antigen R (HuR)-mediated post-transcriptional regulation. MAVS exerted an antiviral activity and reduced the level of hepatitis B virus (HBV) markers in vitro and in vivo. IFN-α antiviral effects were significantly enhanced by MAVS co-transfection. Hepatitis B core protein (HBc) interacted with SP1 to inhibit the promoter activity of MAVS that regulates its expression. CHB patients with a rs3746662A allele had higher MAVS expression and thus were more responsive to IFN-α treatment. In this work, we demonstrated that the decrease of MAVS expression is mediated by the IFN-α-ADAR1 axis. This study also highlighted the potential for the clinical application of MAVS in combination with IFN-α for the treatment of HBV infection.
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Affiliation(s)
- Tao Li
- State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing 100005, P.R. China
| | - Xiaoshuang Yang
- State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing 100005, P.R. China
| | - Wei Li
- Department of Interventional Radiology, the Affiliated Hospital of Qingdao University, Shandong 266003, P.R. China
| | - Jiaru Song
- State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing 100005, P.R. China
| | - Zhuo Li
- Department of Infectious Disease, Affiliated You'an Hospital, Capital University of Medical Science, Beijing 100069, P.R. China
| | - Xilin Zhu
- State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing 100005, P.R. China
| | - Xiaopan Wu
- State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing 100005, P.R. China.
| | - Ying Liu
- State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing 100005, P.R. China.
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18
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Jalil I, Arshad M, Khan S, Dasti JI. The STAT4 and not the IFNL3 variant is associated with hepatitis B virus clearance in a population from the Khyber Pakhtunkhwa region of Pakistan. Arab J Gastroenterol 2020; 21:91-94. [PMID: 32439233 DOI: 10.1016/j.ajg.2020.04.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2019] [Revised: 01/20/2020] [Accepted: 04/09/2020] [Indexed: 11/29/2022]
Abstract
BACKGROUND AND STUDY AIMS Host genetic modifiers of the risk and persistence of hepatitis B virus (HBV) infection in the Pakistani population have not been clearly elucidated. Recently, two genome-wide association studies described that STAT4 and IFNL3 variants are associated with different aspects of the course of HBV infection. However, the roles of these variants in the persistence of HBV infection have not been investigated in the HBV-infected population of Pakistan. Therefore, we examined the roles of the STAT4 and IFNL3 variants in a chronic HBV-infected population from the Khyber Pakhtunkhwa (KPK) region of Pakistan. PATIENTS AND METHODS STAT4 rs7574865 and IFNL3 rs12979860 genotyping were performed in 297 subjects (240 infected with HBV and 57 controls). Statistical analyses were performed using the chi-squared test, Student's t-test, Hardy-Weinberg equilibrium tests and logistic regression models. RESULTS Among the 297 subjects, compared with the IFNL3 rs12979860 genotype [odds ratio (OR) = 0.7, 95% confidence interval (CI) = 0.39-1.29, p = 0.2), the STAT4 rs7574865 genotype was independently associated with the risk of developing chronic HBV infection [OR = 1.9, 95% CI = 1.09-3.50, p = 0.02]. CONCLUSION The STAT4 rs7574865 and not the IFNL3 rs12979860 variant is associated with persistence of HBV infection in a Pakistani population from the KPK region.
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Affiliation(s)
- Ismail Jalil
- School of Biotechnology & Biomolecular Sciences, University of New South Wales, Sydney, NSW, Australia; Department of Microbiology, Qauid-i-Azam University, Islamabad, Pakistan.
| | - Muhammad Arshad
- Department of Microbiology, Qauid-i-Azam University, Islamabad, Pakistan
| | - Shahtaj Khan
- Department of Pathology, Hayatabad Medical Complex Peshawar, Pakistan
| | - Javid I Dasti
- Department of Microbiology, Qauid-i-Azam University, Islamabad, Pakistan
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19
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Yang C, Mai H, Peng J, Zhou B, Hou J, Jiang D. STAT4: an immunoregulator contributing to diverse human diseases. Int J Biol Sci 2020; 16:1575-1585. [PMID: 32226303 PMCID: PMC7097918 DOI: 10.7150/ijbs.41852] [Citation(s) in RCA: 65] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2019] [Accepted: 02/13/2020] [Indexed: 12/12/2022] Open
Abstract
Signal transducer and activator of transcription 4 (STAT4) is a member of the STAT family and localizes to the cytoplasm. STAT4 is phosphorylated after a variety of cytokines bind to the membrane, and then dimerized STAT4 translocates to the nucleus to regulate gene expression. We reviewed the essential role played by STAT4 in a wide variety of cells and the pathogenesis of diverse human diseases, especially many kinds of autoimmune and inflammatory diseases, via activation by different cytokines through the Janus kinase (JAK)-STAT signaling pathway.
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Affiliation(s)
- Chou Yang
- State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, GuangZhou, China
| | - Haoming Mai
- State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, GuangZhou, China
| | - Jinxin Peng
- State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, GuangZhou, China
| | - Bin Zhou
- State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, GuangZhou, China
| | - Jinlin Hou
- State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, GuangZhou, China
| | - Deke Jiang
- State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, GuangZhou, China
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20
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Ou Q, Guo J, Zeng Y, Chen H. Insights for clinical diagnostic indicators of virus and host in chronic hepatitis B infection. J Viral Hepat 2020; 27:224-232. [PMID: 31954089 DOI: 10.1111/jvh.13260] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2019] [Revised: 10/19/2019] [Accepted: 12/17/2019] [Indexed: 02/06/2023]
Abstract
Covalently closed circular DNA (cccDNA), which is stably present in the nucleus of hepatocytes, is an important indicator for evaluating antiviral efficacy. Since cccDNA quantification requires an invasive procedure, serum biological markers that can effectively reflect the transcriptional activity of intrahepatic virus and the efficacy of treatment are required. Here, from the aspects of virus and host, we outline the focus of clinical research of HBV in recent years, including HBV RNA, empty virus, hepatitis B core-related antigen and changes in the immune response. We briefly discuss their significance in predicting disease activity and monitoring treatment response in chronic hepatitis B. On this basis, some issues worthy of attention in laboratory diagnosis are proposed.
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Affiliation(s)
- Qishui Ou
- Department of Laboratory Medicine, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China.,The Genetic Diagnostic Laboratory, Fujian Medical University, Fuzhou, China.,First Clinical College, Fujian Medical University, Fuzhou, China
| | - Jianhui Guo
- Department of Laboratory Medicine, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China.,The Genetic Diagnostic Laboratory, Fujian Medical University, Fuzhou, China.,First Clinical College, Fujian Medical University, Fuzhou, China
| | - Yongbin Zeng
- Department of Laboratory Medicine, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China.,The Genetic Diagnostic Laboratory, Fujian Medical University, Fuzhou, China.,First Clinical College, Fujian Medical University, Fuzhou, China
| | - Huijuan Chen
- Department of Laboratory Medicine, The First Affiliated Hospital of Fujian Medical University, Fuzhou, China.,The Genetic Diagnostic Laboratory, Fujian Medical University, Fuzhou, China.,First Clinical College, Fujian Medical University, Fuzhou, China
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21
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Chen H, Sun J, Zhou B, Peng J, Xie Q, Liang X, Fan R, Conran C, Xu J, Ji Y, Zhang X, Sun L, Jia J, Wang G, Hou J, Jiang DK. A missense variant in complement factor B (CFB) is a potential predictor of 24-week off-treatment response to PegIFNα therapy in Chinese HBeAg-positive chronic hepatitis B patients. Aliment Pharmacol Ther 2020; 51:469-478. [PMID: 31943297 DOI: 10.1111/apt.15624] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2019] [Revised: 09/26/2019] [Accepted: 12/08/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND To date, 14 single-nucleotide polymorphisms (SNPs) have been identified as susceptibility loci for chronic hepatitis B (CHB). AIM To investigate if these SNPs are associated with treatment response of hepatitis B e antigen (HBeAg)-positive CHB patients. METHODS We performed a retrospective analysis of 1623 Han Chinese HBeAg-positive CHB patients (782 patients treated with pegylated interferon alpha [PegIFNα] for 48 weeks plus 24 weeks follow-up, and 841 patients treated with nucleos(t)ide analogues [NUCs] for 104 weeks) included in four phase-IV multicentre randomised controlled trials. All 14 SNPs were genotyped for each CHB patient. A polygenic score (PGS) was used to evaluate the cumulative effect of multiple SNPs. The associations of SNPs or PGS with combined response (CR) and hepatitis B s antigen (HBsAg) loss were assessed. RESULTS We found that rs12614, a missense variant of complement factor B (CFB), was significantly associated with CR in PegIFNα-treated patients, and the CR rate in patients with the rs12614 TT/CT genotype was less than one-third of that in patients with the CC genotype (7.4% vs 22.6%, P = 0.009). Moreover, a PGS integrating CFB rs12614 and STAT4 rs7574865 (previously reported to be associated with response to PegIFNα) was significantly associated with both CR (P-trend = 4.000 × 10-4 ) and HBsAg loss (P-trend = 0.010) in PegIFNα-treated patients. However, none of the SNPs were associated with treatment response in NUCs-treated patients. CONCLUSIONS CFB rs12614 is an independent predictor of response to PegIFNα therapy in Chinese HBeAg-positive CHB patients. A PGS integrating CFB rs12614 with STAT4 rs7574865 can effectively discriminate responders to PegIFNα from nonresponders.
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22
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Chen H, Sun J, Zhou B, Xie Q, Liang X, Fan R, Conran C, Xu J, Ji Y, Zhang X, Sun L, Jia J, Wang G, Hou J, Jiang DK. Variants in STAT4 Associated With Cure of Chronic HBV Infection in HBeAg-positive Patients Treated With Pegylated Interferon-alpha. Clin Gastroenterol Hepatol 2020; 18:196-204.e8. [PMID: 31042581 DOI: 10.1016/j.cgh.2019.04.044] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2019] [Revised: 04/16/2019] [Accepted: 04/19/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Variants in STAT4 (rs7574865) have been associated with seroconversion to hepatitis B e antigen (HBeAg) and reduction in levels of hepatitis B virus (HBV) DNA in patients with chronic infection treated with interferon alpha (IFNA). We evaluated the associations among rs7574865, loss of HB surface antigen (HBsAg, a marker of functional cure of HBV infection), and response to treatment with pegylated IFNA (PegIFN) or nucleos(t)ide analogues (NUCs) in HBeAg-positive patients with chronic HBV infection. METHODS We performed a retrospective analysis of 1823 HBeAg-positive patients with chronic HBV infection (954 patients treated with PegIFN and 869 patients treated with NUCs) included in 4 phase-4 multicenter randomized controlled trials. The Cochran-Armitage trend test was used to evaluate the association of rs7574865 genotype with combined response (CR, defined as HBeAg seroconversion and HBV DNA level <2000 IU/mL) and loss of HBsAg at week 72, for patients given PegIFN, or week 104, for patients given NUCs. RESULTS We found a significant association between rs7574865 genotype and CR (P = .004) and loss of HBsAg (P = .037) in patients treated with PegIFN. In patients with HBV genotype B infection, 43.6% of those with rs7574865 TT achieved a CR, compared to patients with rs7574865 GG (20.5%), and 7.7% had loss of HBsAg, compared to 1.9% of patients with rs7574865 GG. However, in patients treated with NUCs, we found no association of rs7574865 genotype with CR (P = .811) or loss of HBsAg (P=.439). CONCLUSIONS In a retrospective analysis of data from 4 clinical trials, we found rs7574865 in STAT4 to be associated with functional cure of chronic HBV infection by PegIFN treatment, but not NUCs treatment, in HBeAg-positive patients with HBV genotype B infection.
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Affiliation(s)
- Haitao Chen
- State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Institutes of Liver Diseases Research of Guangdong Province, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, GuangZhou, China
| | - Jian Sun
- State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Institutes of Liver Diseases Research of Guangdong Province, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, GuangZhou, China
| | - Bin Zhou
- State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Institutes of Liver Diseases Research of Guangdong Province, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, GuangZhou, China
| | - Qing Xie
- Department of Infectious Diseases, Rui Jin Hospital Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xier Liang
- State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Institutes of Liver Diseases Research of Guangdong Province, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, GuangZhou, China
| | - Rong Fan
- State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Institutes of Liver Diseases Research of Guangdong Province, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, GuangZhou, China
| | - Carly Conran
- University of Illinois College of Medicine, Chicago, Illinois
| | - Jianfeng Xu
- Program for Personalized Cancer Care, NorthShore University HealthSystem, Evanston, Illinois
| | - Yuan Ji
- Department of Public Health Sciences, University of Chicago, Chicago, Illinois
| | - Xinxin Zhang
- Department of Infectious Disease, Institute of Infectious and Respiratory Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Li Sun
- Xiamen Amoytop Biotech Co Ltd, Xiamen, China
| | - Jidong Jia
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Guiqiang Wang
- Department of Infectious Diseases, Center for Liver Diseases, Peking University First Hospital, Beijing, China; Peking University International Hospital, Beijing, China; The Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou, China.
| | - Jinlin Hou
- State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Institutes of Liver Diseases Research of Guangdong Province, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, GuangZhou, China.
| | - De-Ke Jiang
- State Key Laboratory of Organ Failure Research, Guangdong Key Laboratory of Viral Hepatitis Research, Institutes of Liver Diseases Research of Guangdong Province, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, GuangZhou, China.
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23
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Thanapirom K, Suksawatamnuay S, Sukeepaisarnjaroen W, Treeprasertsuk S, Tanwandee T, Charatcharoenwitthaya P, Thongsawat S, Leerapun A, Piratvisuth T, Boonsirichan R, Bunchorntavakul C, Pattanasirigool C, Pornthisarn B, Tuntipanichteerakul S, Sripariwuth E, Jeamsripong W, Sanpajit T, Poovorawan Y, Komolmit P. Association of the S267F variant on NTCP gene and treatment response to pegylated interferon in patients with chronic hepatitis B: a multicentre study. Antivir Ther 2019. [PMID: 28635613 DOI: 10.3851/imp3179] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
BACKGROUND Sodium taurocholate co-transporting polypeptide (NTCP) is a cell receptor for HBV. The S267F variant on the NTCP gene is inversely associated with the chronicity of HBV infection, progression to cirrhosis and hepatocellular carcinoma in East Asian populations. The aim of this study was to determine whether the S267F variant was associated with response to pegylated interferon (PEG-IFN) in patients with chronic HBV infection. METHODS A total of 257 patients with chronic HBV, treated with PEG-IFN for 48 weeks, were identified from 13 tertiary hospitals included in the hepatitis B database of the Thai Association for the Study of the Liver (THASL). RESULTS Of these, 202 patients were infected with HBV genotype C (84.9%); 146 patients were hepatitis B e antigen (HBeAg)-positive (56.8%). Genotypic frequencies of the S267F polymorphism were 85.2%, 14.8% and 0% for the GG, GA and AA genotypes, respectively. S267F GA was associated with sustained alanine aminotransferase (ALT) normalization (OR = 3.25, 95% CI 1.23, 8.61; P=0.02) in HBeAg-positive patients. Patients with S267F variant tended to have more virological response, sustained response with hepatitis B surface antigen (HBsAg) loss at 24 weeks following PEG-IFN treatment. There was no association between the S267F variant and improved patient outcomes in HBeAg-negative patients. CONCLUSIONS The S267F variant on the NTCP gene is independently associated with sustained normalization of ALT following treatment with PEG-IFN in patients with HBV infection who are HBeAg-positive. The findings of this study provide additional support for the clinical significance of the S267F variant of NTCP beyond HBV entry.
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Affiliation(s)
- Kessarin Thanapirom
- Division of Gastroenterology, Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand.,Center of Excellence in Liver Diseases, King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand
| | - Sirinporn Suksawatamnuay
- Division of Gastroenterology, Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand.,Center of Excellence in Liver Diseases, King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand
| | | | - Sombat Treeprasertsuk
- Division of Gastroenterology, Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand.,Center of Excellence in Liver Diseases, King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand
| | - Tawesak Tanwandee
- Division of Gastroenterology, Department of Medicine, Siriraj Hospital, Bangkok, Thailand
| | | | - Satawat Thongsawat
- Department of Internal Medicine, Chiang Mai University, Chiang Mai, Thailand
| | - Apinya Leerapun
- Department of Internal Medicine, Chiang Mai University, Chiang Mai, Thailand
| | | | | | | | | | | | | | | | | | | | - Yong Poovorawan
- Center of Excellence in Clinical Virology, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Piyawat Komolmit
- Division of Gastroenterology, Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand.,Center of Excellence in Liver Diseases, King Chulalongkorn Memorial Hospital, Thai Red Cross Society, Bangkok, Thailand
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24
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Zhang Z, Wang C, Liu Z, Zou G, Li J, Lu M. Host Genetic Determinants of Hepatitis B Virus Infection. Front Genet 2019; 10:696. [PMID: 31475028 PMCID: PMC6702792 DOI: 10.3389/fgene.2019.00696] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2018] [Accepted: 07/03/2019] [Indexed: 12/14/2022] Open
Abstract
Chronic hepatitis B virus (HBV) infection is still a major health problem worldwide. Recently, a great number of genetic studies based on single nucleotide polymorphisms (SNPs) and genome-wide association studies have been performed to search for host determinants of the development of chronic HBV infection, clinical outcomes, therapeutic efficacy, and responses to hepatitis B vaccines, with a focus on human leukocyte antigens (HLA), cytokine genes, and toll-like receptors. In addition to SNPs, gene insertions/deletions and copy number variants are associated with infection. However, conflicting results have been obtained. In the present review, we summarize the current state of research on host genetic factors and chronic HBV infection, its clinical type, therapies, and hepatitis B vaccine responses and classify published results according to their reliability. The potential roles of host genetic determinants of chronic HBV infection identified in these studies and their clinical significance are discussed. In particular, HLAs were relevant for HBV infection and pathogenesis. Finally, we highlight the need for additional studies with large sample sizes, well-matched study designs, appropriate statistical methods, and validation in multiple populations to improve the treatment of HBV infection.
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Affiliation(s)
- Zhenhua Zhang
- Department of Infectious Diseases, the Second Affiliated Hospital of Anhui Medical University, Hefei, China
- College of Pharmacy, Anhui Medical University, Hefei, China
| | - Changtai Wang
- Department of Infectious Diseases, the Affiliated Anqing Hospital of Anhui Medical University, Anqing, China
| | - Zhongping Liu
- Department of Infectious Diseases, the Second Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Guizhou Zou
- Department of Infectious Diseases, the Second Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Jun Li
- College of Pharmacy, Anhui Medical University, Hefei, China
| | - Mengji Lu
- Institute of Virology, University Hospital of Duisburg-Essen, Essen, Germany
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El Sharkawy R, Thabet K, Lampertico P, Petta S, Mangia A, Berg T, Metwally M, Bayoumi A, Boonstra A, Brouwer WP, Smedile A, Abate ML, Loglio A, Douglas MW, Khan A, Santoro R, Fischer J, Leeming DJ, Liddle C, George J, Eslam M. A STAT4 variant increases liver fibrosis risk in Caucasian patients with chronic hepatitis B. Aliment Pharmacol Ther 2018; 48:564-573. [PMID: 29963713 DOI: 10.1111/apt.14866] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2018] [Revised: 02/11/2018] [Accepted: 06/10/2018] [Indexed: 12/11/2022]
Abstract
BACKGROUND Host genetic modifiers of the natural history of chronic hepatitis B (CHB) remain poorly understood. Recently, a genome-wide association study (GWAS)-identified polymorphism in the STAT4 gene that contributes to the risk for hepatocellular carcinoma (HCC) was shown to be associated with the full spectrum of hepatitis B virus (HBV) outcomes in Asian patients. However, the functional mechanisms for this effect are unknown and the role of the variant in modulating HBV disease in Caucasians has not been investigated. AIMS To determine whether STAT4 genetic variation is associated with liver injury in Caucasian patients with CHB and to investigate potential mechanisms mediating this effect. METHODS STAT4 rs7574865 was genotyped in 1085 subjects (830 with CHB and 255 healthy controls). STAT4 expression in liver, PBMCs and NK cells, STAT4 phosphorylation and secretion of interferon-gamma (IFN-γ) according to STAT4 genetic variation was examined. RESULTS STAT4 rs7574865 genotype was independently associated with hepatic inflammation (OR: 1.42, 95% CI: 1.07-2.06, P = 0.02) and advanced fibrosis (OR: 1.83, 95% CI: 1.19-2.83, P = 0.006). The minor allele frequency of rs7574865 was significantly lower than that in healthy controls. rs7574865 GG risk carriers expressed lower levels of STAT4 in liver, PBMCs and in NK cells, while NK cells from patients with the risk genotype had impaired STAT4 phosphorylation following stimulation with IL-12/IL-18 and a reduction in secretion of IFN-γ. CONCLUSION Genetic susceptibility to HBV persistence, hepatic inflammation and fibrosis in Caucasians associates with STAT4 rs7574865 variant. Downstream effects on NK cell function through STAT4 phosphorylation-dependent IFN-γ production likely contribute to these effects.
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Affiliation(s)
| | - K Thabet
- Sydney, NSW, Australia.,Minia, Egypt
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Nan Y, Wu C, Zhang YJ. Interplay between Janus Kinase/Signal Transducer and Activator of Transcription Signaling Activated by Type I Interferons and Viral Antagonism. Front Immunol 2017; 8:1758. [PMID: 29312301 PMCID: PMC5732261 DOI: 10.3389/fimmu.2017.01758] [Citation(s) in RCA: 103] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2017] [Accepted: 11/27/2017] [Indexed: 12/13/2022] Open
Abstract
Interferons (IFNs), which were discovered a half century ago, are a group of secreted proteins that play key roles in innate immunity against viral infection. The major signaling pathway activated by IFNs is the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway, which leads to the expression of IFN-stimulated genes (ISGs), including many antiviral effectors. Viruses have evolved various strategies with which to antagonize the JAK/STAT pathway to influence viral virulence and pathogenesis. In recent years, notable progress has been made to better understand the JAK/STAT pathway activated by IFNs and antagonized by viruses. In this review, recent progress in research of the JAK/STAT pathway activated by type I IFNs, non-canonical STAT activation, viral antagonism of the JAK/STAT pathway, removing of the JAK/STAT antagonist from viral genome for attenuation, and the potential pathogenesis roles of tyrosine phosphorylation-independent non-canonical STATs activation during virus infection are discussed in detail. We expect that this review will provide new insight into the understanding the complexity of the interplay between JAK/STAT signaling and viral antagonism.
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Affiliation(s)
- Yuchen Nan
- Department of Preventive Veterinary Medicine, College of Veterinary Medicine, Northwest A&F University, Yangling, China.,Molecular Virology Laboratory, VA-MD Regional College of Veterinary Medicine, Maryland Pathogen Research Institute, University of Maryland, College Park, MD, United States
| | - Chunyan Wu
- Department of Preventive Veterinary Medicine, College of Veterinary Medicine, Northwest A&F University, Yangling, China
| | - Yan-Jin Zhang
- Molecular Virology Laboratory, VA-MD Regional College of Veterinary Medicine, Maryland Pathogen Research Institute, University of Maryland, College Park, MD, United States
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Ju H, Liu H, Tian ZB, Jiang YP, Zhang CP, Liu XS. Association of polymorphisms in key Th-17 immune response genes with HBeAg-positive chronic hepatitis B susceptibility and response to PEG-IFNa-2α. Virology 2017; 509:35-41. [DOI: 10.1016/j.virol.2017.05.011] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2017] [Revised: 05/16/2017] [Accepted: 05/17/2017] [Indexed: 02/06/2023]
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Abstract
The human gut is in constant complex interaction with the external environment. Although much is understood about the composition and function of the microbiota, much remains to be learnt about the mechanisms by which these organisms interact with the immune system in health and disease. Type 1 interferon (T1IFN), a ubiquitous and pleiotropic family of cytokines, is a critical mediator of the response to viral, bacterial, and other antigens sampled in the intestine. Although inflammation is enhanced in mouse model of colitis when T1IFN signaling is lost, the action of T1IFN is context specific and can be pro- or anti-inflammatory. In humans, T1IFN has been used to treat inflammatory diseases, including multiple sclerosis and inflammatory bowel disease but intestinal inflammation can also develop after the administration of T1IFN. Recent findings indicate that "tonic" or "endogenous" T1IFN, induced by signals from the commensal microbiota, modulates the local signaling environment to prime the intestinal mucosal immune system to determine later responses to pathogens and commensal organisms. This review will summarize the complex immunological effects of T1IFN and recent the role of T1IFN as a mediator between the microbiota and the mucosal immune system, highlighting human data wherever possible. It will discuss what we can learn from clinical experiences with T1IFN and how the T1IFN pathway may be manipulated in the future to maintain mucosal homeostasis.
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29
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Zhang XX, Li MR, Xi HL, Cao Y, Zhang RW, Zhang Y, Xu XY. Dynamic Characteristics of Serum Hepatitis B Surface Antigen in Chinese Chronic Hepatitis B Patients Receiving 7 Years of Entecavir Therapy. Chin Med J (Engl) 2017; 129:929-35. [PMID: 27064037 PMCID: PMC4831527 DOI: 10.4103/0366-6999.179802] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Background: The ultimate goal of hepatitis B treatment is hepatitis B surface antigen (HBsAg) seroclearance. Several factors have been suggested to be associated with the rate of HBsAg reduction in antiviral-naive or lamivudine therapy cohorts. However, there are few studies evaluating the factors during long-term entecavir (ETV) therapy. In the present study, we aimed to evaluate the factors to predict the outcome of ETV therapy for 7 years. Methods: A total of 47 chronic hepatitis B (CHB) patients treated with ETV monotherapy were included in this study. Liver biochemistry, hepatitis B virus (HBV) serological markers, serum HBV DNA, and HBsAg titers were tested at baseline, 3 months, 6 months, and yearly from 1 to 7. The associations between factors and HBsAg reduction were assessed using multivariate tests with repeated measure analysis of variance. Results: At baseline, serum HBsAg levels showed a positive correlation with baseline HBV DNA levels (r = 0.625, P < 0.001). The mean HBsAg titers after ETV treatment were significantly lower than the baseline titers (P ranges from 0.025 to 0.000,000,6). The HBsAg reduction rate during the 1st year was greater compared to after 1 year of treatment (P < 0.05). Multivariate test showed that hepatitis B e antigen (HBeAg) seroclearance and/or HBsAg reduction ≥0.5 log10 IU/ml at 6 months had a high negative predictive value (96.77%) for HBsAg seroclearance (P = 0.002, P = 0.012, respectively). Conclusions: The HBsAg reduction rate during the 1st year was greater than that after 1 year of treatment. Further, HBeAg status and HBsAg levels at month 6 are the optimal factors for the early prediction of HBsAg seroclearance after long-term ETV therapy in CHB patients.
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Affiliation(s)
| | | | | | | | | | | | - Xiao-Yuan Xu
- Department of Infectious Disease, Peking University First Hospital, Beijing 100034, China
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Yuan T, Jiang Y, Li M, Li W. Chronic hepatitis B surface antigen seroclearance-related immune factors. Hepatol Res 2017; 47:49-59. [PMID: 27084584 DOI: 10.1111/hepr.12726] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2016] [Revised: 04/01/2016] [Accepted: 04/12/2016] [Indexed: 12/23/2022]
Abstract
The ultimate aims of the treatment of hepatitis B virus infection are the loss of hepatitis B surface antigen (HBsAg) and hepatitis B surface antibody seroconversion. Unfortunately, these goals are rarely reached. Many factors are associated with HBsAg seroconversion, including genetic, immune, and viral factors. However, the mechanism of HBsAg seroclearance, and particularly the immune mechanism, is still difficult to elucidate. The immune factor interferon-α is currently the main antiviral therapy for chronic hepatitis B virus infection. However, a sustained shift from response of HBsAg to hepatitis B surface antibody seroconversion is rarely obtained. Recent studies have revealed that several of the newly identified immune factors are closely related to the removal of HBsAg. In this article, we review recent studies on these immune factors, their influence on hepatitis B progression, and HBsAg seroconversion.
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Affiliation(s)
- Ting Yuan
- Liver Diseases Research Center, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Yongfang Jiang
- Liver Diseases Research Center, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Mei Li
- Liver Diseases Research Center, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Wei Li
- Liver Diseases Research Center, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China
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Asimakopoulos A, Mangia A, Dore GJ, Lloyd AR, George J, Eslam M. Polymorphisms in STAT4 are not associated with treatment response and spontaneous clearance of hepatitis C virus in europeans. Hepatology 2016; 64:2264-2265. [PMID: 27121959 DOI: 10.1002/hep.28626] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2016] [Revised: 03/21/2016] [Accepted: 04/19/2016] [Indexed: 12/07/2022]
Affiliation(s)
- Anastasia Asimakopoulos
- Storr Liver Centre, Westmead Millennium Institute and Westmead Hospital, University of Sydney, Sydney, Australia
| | - Alessandra Mangia
- Division of Hepatology, Ospedale Casa Sollievo della Sofferenza IRCCS, San Giovanni Rotondo, Italy
| | - Gregory J Dore
- School of Medical Sciences, University of New South Wales, Sydney, Australia
| | - Andrew R Lloyd
- Kirby Institute, The University of New South Wales, Sydney, NSW, Australia
| | - Jacob George
- Storr Liver Centre, Westmead Millennium Institute and Westmead Hospital, University of Sydney, Sydney, Australia
| | - Mohammed Eslam
- Storr Liver Centre, Westmead Millennium Institute and Westmead Hospital, University of Sydney, Sydney, Australia
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Xie DY, Wang SM, Yang JM, Wang LH, Chen HY, Huai C, Shang J, Mao Q, Lei CL, Luo GH, Qian J, Lu DR. IFIT1 polymorphisms predict interferon-α treatment efficiency for hepatitis B virus infection. World J Gastroenterol 2016; 22:9813-9821. [PMID: 27956805 PMCID: PMC5124986 DOI: 10.3748/wjg.v22.i44.9813] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2016] [Revised: 08/19/2016] [Accepted: 09/08/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the association between interferon-induced protein with tetratricopeptide repeats 1 (IFIT1) polymorphisms and interferon-α (IFNα) treatment efficiency among Chinese hepatitis B virus (HBV) infection patients.
METHODS Two hundred and twenty five newly diagnosed chronic hepatitis B (CHB) patients were enrolled in the study. All of these patients received IFNα treatment for a course of 48 wk, and were followed up for 24 wk after the treatment was end. Clinical information about virological response, hepatitis B e antigen (HBeAg) seroconversion rate and combined response at the end of the treatment, as well as the sustained response by the time of following up 24 wk after the treatment, was collected. Four tag-single nucleotide polymorphisms (SNPs) of IFIT1 were selected and assessed for their association with these clinical outcomes.
RESULTS At the end of the treatment, HBeAg seroconversion was observed in 27.1% patients. Thirty-six point nine percent patients achieved virological response, and 15.6% patients exhibited combined response. Sustained response was obtained in 26.2% patients. The main HBV genotype of the study was genotype B. Patients who infected with HBV genotype B or C showed better treatment efficiency, no matter which clinical outcome was considered. Among the four SNPs assessed, rs303218 (A > G) was found to be significantly associated with the end point virological response when assuming additive model [OR = 0.64 (95%CI: 0.42-0.96), P = 0.032]. Patients who carried rs303218 GG genotype had a rather higher rate of achieving virological response (response rate: 52%, OR = 0.40, 95%CI: 0.18-0.91; P = 0.028) when compared to those had AA genotype (response rate: 27%). The most significant interaction was observed in patients who had relative lower baseline aspartate transaminase. No association between SNPs and HBeAg seroconversion, combined response or sustained response was observed.
CONCLUSION IFIT1 involves in the regulation of IFNα treatment for CHB and its polymorphism rs303218 can predict the end point virological response. The finding requires further validation.
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