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Heiat M, Javanbakht M, Jafari D, Poudineh M, Heydari F, Sharafi H, Alavian SM. Correlation of IL-10 and IL18 with the development of liver cirrhosis associated with hepatitis B virus infection: A systematic review. Cytokine 2025; 186:156818. [PMID: 39671883 DOI: 10.1016/j.cyto.2024.156818] [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: 07/01/2024] [Revised: 10/02/2024] [Accepted: 11/16/2024] [Indexed: 12/15/2024]
Abstract
BACKGROUND Patients who have been infected with the Hepatitis B virus (HBV) are susceptible to developing liver cirrhosis (LC) and hepatocellular carcinoma (HCC). The objective of this systematic review was to comprehensively scrutinize the existing evidence concerning the association between host genetic polymorphisms and HBV-associated LC. METHODS We searched databases of PubMed, Scopus, and Web of Science for relevant articles published from building databases to 25 October 2023. RESULT We detected 104 relevant articles, relating to 84 individuals genes. Nine genes had the strong evidence of correlation, including IL-10, IL-18, IL-1B, TGF- β, TLR3, STAT4, IL-1RN, Tim3, and IFN receptors. A positive correlation was found for 33 genes but this data had not yet been replicated, 11 genes had limited or mixed evidence of a correlation, and 34 genes indicated no correlation. IL-10 and IL-18 had the most evidence of correlation. There was a notable amount of diversity in both the design and method of studies and data quality. CONCLUSION IL-10 and IL-18 had the most evidence of correlation. There was a notable amount of diversity in both the design and method of studies and data quality. It is of necessary to take into account the fundamental mechanism behind these associations and discern those that are confounded by the coexistence of other LC/HCC risk factors and response to therapy. These results are expected to guide future studies on the genetic susceptibility of HBV-related LC/HCC.
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Affiliation(s)
- Mohammad Heiat
- Baqiyatallah Research Center for Gastroenterology and Liver Diseases (BRCGL), Clinical Sciences Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran.
| | - Mohammad Javanbakht
- Nephrology and Urology Research Center, Clinical Science Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Davood Jafari
- Department of Immunology, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Mohadeseh Poudineh
- Student Research Committee, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Fatemeh Heydari
- Student Research Committee, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | | | - Seyed Moayed Alavian
- Baqiyatallah Research Center for Gastroenterology and Liver Diseases (BRCGL), Clinical Sciences Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
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Nguyen TT, Ho TC, Bui HTT, Tran VK, Nguyen TT. Multi-clustering study on the association between human leukocyte antigen -DP-DQ and hepatitis B virus-related hepatocellular carcinoma and cirrhosis in Viet Nam. World J Gastroenterol 2024; 30:4880-4903. [PMID: 39679310 PMCID: PMC11612715 DOI: 10.3748/wjg.v30.i46.4880] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Revised: 09/04/2024] [Accepted: 10/16/2024] [Indexed: 11/21/2024] Open
Abstract
BACKGROUND Human leukocyte antigen (HLA) class II molecules are cell surface receptor proteins found on antigen-presenting cells. Polymorphisms and mutations in the HLA gene can affect the immune system and the progression of hepatitis B. AIM To study the relation between rs2856718 of HLA-DQ, rs3077, and rs9277535 of HLA-DP, hepatitis B virus (HBV)-related cirrhosis, and hepatocellular carcinoma (HCC). METHODS In this case-control study, the genotypes of these single nucleotide polymorphisms (SNPs) were screened in 315 healthy controls, 471 chronic hepatitis B patients, 250 patients with HBV-related liver cirrhosis, and 251 patients with HCC using TaqMan real-time PCR. We conducted Hardy-Weinberg equilibrium and linkage disequilibrium tests on the genotype distributions of rs2856718, rs3077, and rs9277535 before hierarchical clustering analysis to build the complex interaction between the markers in each patient group. RESULTS The physical distance separating these SNPs was 29816 kB with the disequilibrium (D') values ranging from 0.07 to 0.34. The close linkage between rs3077 and rs9277535 was attributed to a distance of 21 kB. The D' value decreased from moderate in the healthy control group (D' = 0.50, P < 0.05) to weak in the hepatic disease group (D' < 0.3, P < 0.05). In a combination of the three variants rs2856718, rs3077, and rs9277535, the A allele decreased hepatic disease risk [A-A-A haplotype, risk ratio (RR) = 0.44 (0.14; 1.37), P < 0.05]. The G allele had the opposite effect [G-A/G-G haplotype, RR = 1.12 (1.02; 1.23), P < 0.05]. In liver cancer cases, the A-A-A/G haplotype increased the risk of HCC by 1.58 (P < 0.05). CONCLUSION Rs9277535 affects liver fibrosis progression due to HBV infection, while rs3077 is associated with a risk of HBV-related HCC. The link between rs2856718, rs3077, and rs9277535 and disease risk was determined using a multi-clustering analysis.
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Affiliation(s)
- Thuy Thu Nguyen
- Center for Gene and Protein Research, Hanoi Medical University, Hanoi 116177, Viet Nam
| | - Tu Cam Ho
- Center for Gene and Protein Research, Hanoi Medical University, Hanoi 116177, Viet Nam
- Institute of Virology, TUM School of Medicine, Technical University of Munich, Munich 81675, Germany
| | - Huong Thi Thu Bui
- Department of Biochemistry, Thai Nguyen University of Medicine and Pharmacy, Thai Nguyen 251540, Viet Nam
| | - Van-Khanh Tran
- Center for Gene and Protein Research, Hanoi Medical University, Hanoi 116177, Viet Nam
| | - Tue Trong Nguyen
- Medical Technology Department, Hanoi Medical University, Hanoi 116177, Viet Nam
- Clinical Laboratory, Hanoi Medical University Hospital, Hanoi 116177, Viet Nam
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Zhao Y, Chen K, Yang H, Zhang F, Ding L, Liu Y, Zhang L, Zhang Y, Wang H, Deng Y. HLA-DR genetic polymorphisms and hepatitis B virus mutations affect the risk of hepatocellular carcinoma in Han Chinese population. Virol J 2023; 20:283. [PMID: 38037048 PMCID: PMC10691135 DOI: 10.1186/s12985-023-02253-2] [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: 10/06/2023] [Accepted: 11/26/2023] [Indexed: 12/02/2023] Open
Abstract
BACKGROUND Human leucocyte antigen (HLA)-DR plays a crucial role in the immune response against hepatitis B virus (HBV). We aimed to investigate the associations of HLA-DR single nucleotide polymorphisms (SNPs) with the generation of hepatocellular carcinoma (HCC)-related HBV mutations. The effects of HLA-DR SNPs and their interactions with HBV mutations on HCC risks were also determined. METHODS Five HLA-DR SNPs (rs3135363, rs9268644, rs35445101, rs24755213, and rs984778) were genotyped in 792 healthy controls, 586 chronic hepatitis B (CHB) patients, 536 liver cirrhosis (LC) patients, and 1500 HCC patients using quantitative PCR. Sanger sequencing was used to identify the HBV mutations. Logistic regression model was performed to evaluate the association of HLA-DR SNPs with HCC risk and the frequencies of HCC-related HBV mutations. RESULTS The variant genotypes at rs3135363, rs9268644, rs35445101, rs24755213, and rs984778 were associated with decreased HCC risks. In genotype C HBV-infected subjects, variant genotypes of these SNPs were associated with decreased frequencies of HCC-related HBV mutations such as C1653T, T1674C/G, G1719T, T1753A/C, A1762T/G1764A, A1846T, G1896A, G1899A, and preS deletion. AG genotype at rs3135363, CA genotype at rs9268644, and AG genotype at rs24755213 reduced the generation of T1753A/C and G1896A in genotype B HBV-infected subjects, respectively. In addition, the interactions of rs3135363, rs9268644, rs24755213 with C1653T, T1753A/C, A1846T, and G1896A decreased the risks of HCC. CONCLUSIONS HLA-DR genetic polymorphisms might predispose the host to immunoselection of HCC-related HBV mutations and affect the HCC risks possibly through interacting with HBV mutations.
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Affiliation(s)
- Yubao Zhao
- Department of Infectious Diseases, Second Affiliated Hospital of Shandong First Medical University, 706 Taishan Street, Tai'an, Shandong Province, China
| | - Kun Chen
- School of Public Health, Shandong First Medical University & Shandong Academy of Medical Sciences, 6699 Qingdao Road, Jinan, Shandong Province, China
| | - Hui Yang
- School of Public Health, Shandong First Medical University & Shandong Academy of Medical Sciences, 6699 Qingdao Road, Jinan, Shandong Province, China
| | - Feng Zhang
- Department of Gastrointestinal Surgery, Tai'an Central Hospital, 29 Longtan Road, Tai'an, Shandong Province, China
| | - Lu Ding
- Department of Public Health, Jinan Central Hospital, 105 Jiefang Road, Jinan, Shandong Province, China
| | - Yan Liu
- School of Public Health, Shandong First Medical University & Shandong Academy of Medical Sciences, 6699 Qingdao Road, Jinan, Shandong Province, China
| | - Le Zhang
- School of Public Health, Shandong First Medical University & Shandong Academy of Medical Sciences, 6699 Qingdao Road, Jinan, Shandong Province, China
| | - Yuchen Zhang
- School of Public Health, Shandong First Medical University & Shandong Academy of Medical Sciences, 6699 Qingdao Road, Jinan, Shandong Province, China
| | - Huiliang Wang
- Department of Infectious Diseases, Second Affiliated Hospital of Shandong First Medical University, 706 Taishan Street, Tai'an, Shandong Province, China
| | - Yang Deng
- School of Public Health, Shandong First Medical University & Shandong Academy of Medical Sciences, 6699 Qingdao Road, Jinan, Shandong Province, China.
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Mohammadi H, Alavian SM, Sharafi H. Association of single nucleotide polymorphisms in immune-related genes with spontaneous HBsAg seroconversion: A systematic review and meta-analysis. Int Immunopharmacol 2022; 110:108982. [PMID: 35752129 DOI: 10.1016/j.intimp.2022.108982] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2022] [Revised: 05/28/2022] [Accepted: 06/15/2022] [Indexed: 11/19/2022]
Abstract
BACKGROUND Studies have reported that the immune system modulation genes are involved in the seroconversion during hepatitis B virus (HBV) infection. Here, a systematic review with meta-analysis is implemented on the association of polymorphisms in immune-related genes with the spontaneous hepatitis B surface antigen (HBsAg) seroconversion. METHODS A systematic literature search was conducted in the main electronic databases of Scopus, PubMed, and Web of Science before May 2022. Pooled odds ratio (OR) and their corresponding 95% confidence interval (CI) were used to evaluate the strength of the association between genetic polymorphisms and the chance of spontaneous HBsAg seroconversion. RESULTS A total of 40 studies finally included for meta-analysis of 2 HLA-DP SNPs, 2 HLA-DQ SNPs, 3 IFNL3/4 SNPs, 2 IL10 SNPs, and 5 TNF SNPs. Based on the overall pooled analysis, HLA-DP rs3077 A (OR = 1.47, 95%CI: 1.32-1.65), HLA-DP rs9277535 A (OR = 1.48, 95%CI: 1.32-1.66), HLA-DQ rs2856718 G (OR = 1.37, 95%CI: 1.18-1.59), HLA-DQ rs7453920 A (OR = 1.41, 95%CI: 1.04-1.93), IFNL3/4 rs12980275 G (OR = 1.26, 95%CI: 1.01-1.58), TNFA rs1799964 T (OR = 1.17, 95%CI: 1.02-1.35), and TNFA rs1800630 C (OR = 1.26, 95%CI: 1.03-1.55) increased significantly the chance of spontaneous HBsAg seroconversion. CONCLUSION This meta-analysis showed that the HLA-DP gene rs3077 and rs9277535 SNPs, HLA-DQ gene rs2856718 and rs7453920 SNPs, IFNL3/4 gene rs12980275 SNP, TNFA gene rs1799964 and rs1800630 SNPs are involved in the spontaneous HBsAg seroconversion.
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Affiliation(s)
- Hamed Mohammadi
- Non-Communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj, Iran; Department of Immunology, School of Medicine, Alborz University of Medical Sciences, Karaj, Iran
| | - Seyed Moayed Alavian
- Middle East Liver Diseases (MELD) Center, Tehran, Iran; Baqiyatallah Research Center for Gastroenterology and Liver Diseases (BRCGL), Baqiyatallah University of Medical Sciences, Tehran, Iran
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Liu W, Deng Y, Li Z, Chen Y, Zhu X, Tan X, Cao G. Cancer Evo-Dev: A Theory of Inflammation-Induced Oncogenesis. Front Immunol 2021; 12:768098. [PMID: 34880864 PMCID: PMC8645856 DOI: 10.3389/fimmu.2021.768098] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Accepted: 11/04/2021] [Indexed: 12/13/2022] Open
Abstract
Chronic inflammation is a prerequisite for the development of cancers. Here, we present the framework of a novel theory termed as Cancer Evolution-Development (Cancer Evo-Dev) based on the current understanding of inflammation-related carcinogenesis, especially hepatocarcinogenesis induced by chronic infection with hepatitis B virus. The interaction between genetic predispositions and environmental exposures, such as viral infection, maintains chronic non-resolving inflammation. Pollution, metabolic syndrome, physical inactivity, ageing, and adverse psychosocial exposure also increase the risk of cancer via inducing chronic low-grade smoldering inflammation. Under the microenvironment of non-resolving inflammation, pro-inflammatory factors facilitate the generation of somatic mutations and viral mutations by inducing the imbalance between the mutagenic forces such as cytidine deaminases and mutation-correcting forces including uracil-DNA glycosylase. Most cells with somatic mutations and mutated viruses are eliminated in survival competition. Only a small percentage of mutated cells survive, adapt to the hostile environment, retro-differentiate, and function as cancer-initiating cells via altering signaling pathways. These cancer-initiating cells acquire stem-ness, reprogram metabolic patterns, and affect the microenvironment. The carcinogenic process follows the law of "mutation-selection-adaptation". Chronic physical activity reduces the levels of inflammation via upregulating the activity and numbers of NK cells and lymphocytes and lengthening leukocyte telomere; downregulating proinflammatory cytokines including interleukin-6 and senescent lymphocytes especially in aged population. Anti-inflammation medication reduces the occurrence and recurrence of cancers. Targeting cancer stemness signaling pathways might lead to cancer eradication. Cancer Evo-Dev not only helps understand the mechanisms by which inflammation promotes the development of cancers, but also lays the foundation for effective prophylaxis and targeted therapy of various cancers.
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Affiliation(s)
- Wenbin Liu
- Department of Epidemiology, Second Military Medical University, Shanghai, China
| | - Yang Deng
- School of Public Health, Shandong First Medical University & Shandong Academy of Medical Sciences, Tai’an, China
| | - Zishuai Li
- Department of Epidemiology, Second Military Medical University, Shanghai, China
| | - Yifan Chen
- Department of Epidemiology, Second Military Medical University, Shanghai, China
| | - Xiaoqiong Zhu
- Department of Nutrition, School of Public Health, Anhui Medical University, Hefei, China
| | - Xiaojie Tan
- Department of Epidemiology, Second Military Medical University, Shanghai, China
| | - Guangwen Cao
- Department of Epidemiology, Second Military Medical University, Shanghai, China
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Mai H, Chen J, Chen H, Liu Z, Huang G, Wang J, Xiao Q, Ren W, Zhou B, Hou J, Jiang D. Fine Mapping of the MHC Region Identifies Novel Variants Associated with HBV-Related Hepatocellular Carcinoma in Han Chinese. J Hepatocell Carcinoma 2021; 8:951-961. [PMID: 34430511 PMCID: PMC8378933 DOI: 10.2147/jhc.s321919] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Accepted: 07/29/2021] [Indexed: 12/24/2022] Open
Abstract
Introduction Genome-wide association studies identified susceptibility loci in the major histocompatibility complex region for hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). However, the causal variants underlying HBV-related HCC pathogenesis remain elusive. Methods With a total of 1,161 HBV-related HCC cases and 1,353 chronic HBV carriers without HCC, we imputed human leukocyte antigen (HLA) variants based on a Chinese HLA reference panel and evaluated the associations of these variants with the risk of HBV-related HCC. Conditional analyses were used to identify independent signals associated with the risk of HBV-related HCC (P false-discovery rate (FDR) <0.20). A total of 14,930 variants within the MHC region were genotyped or imputed. Results We identified two variants, rs114401688 (P = 1.05 × 10−6, PFDR = 2.43 × 10−3) and rs115126566 (P = 9.04 × 10−5, PFDR = 1.77 × 10−1), that are independently associated with the risk of HBV-related HCC. Single nucleotide polymorphism (SNP) rs114401688 is in linkage disequilibrium with a previously reported SNP rs9275319. In the current study, we found that its association with HCC could be explained by HLA-DQB1*04 and HLA-DRB1*04. SNP rs115126566 is a novel risk variant and may function by regulating transcriptions of HLA-DPA1/DPB1 through enhancer-mediated mechanisms. HLA zygosity analysis showed that homozygosity at HLA-DQB1 gene is suggestively associated with a higher risk of HCC (P = 0.10) and the risk was more pronounced in the older age group (age ≥50, P = 0.03). Discussion Our findings further the understanding of the genetic basis for HBV-related HCC predisposition in chronic HBV carriers.
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Affiliation(s)
- Haoming Mai
- 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, 510515, 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, 510515, 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, 510515, People's Republic of China.,School of Public Health (Shenzhen), Sun Yat-sen University, Shenzhen, 518107, People's Republic of China
| | - Zhiwei Liu
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA
| | - Guanlin Huang
- 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, 510515, People's Republic of China
| | - Jialin Wang
- 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, 510515, People's Republic of China
| | - Qianyi Xiao
- School of Public Health, Fudan University, Shanghai, 200032, People's Republic of China
| | - Weihua Ren
- Central Laboratory, First Affiliated Hospital, Henan University of Science and Technology, Luoyang, Henan Province, 471009, 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, 510515, 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, 510515, People's Republic of China
| | - Deke 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, 510515, People's Republic of China
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Mohamed AA, Abdel-Rahman AAH, Saad S, Mousa S, Tantawi O, Zahran FE, Shafik NF, Elshimy RA, Alkhalegy AAH, Kandil A, Ahmed R, Khalil M, Soliman MY, Abo-Amer YEE, Abd-Elsalam S. HLA-DQ Gene Polymorphisms Associated with Hepatitis B Virus in Patients with Hepatocellular Carcinoma Progression. CURRENT CANCER THERAPY REVIEWS 2021; 17:75-81. [DOI: 10.2174/1573394716666200712151208] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2020] [Revised: 05/07/2020] [Accepted: 05/13/2020] [Indexed: 11/22/2022]
Abstract
Background:
The development and progression of hepatitis B (HBV)-related disease
can lead to liver cirrhosis and hepatocellular carcinoma (LC and HCC, respectively). Human leukocyte
antigen (HLA) DQ polymorphism has been reported in other recent studies to deal with the association
between HBV and liver disease. Our study on the Egyptian population was introduced to
assess the strong association between HLA-DQ polymorphism and HBV infection in addition to
the progression of HCC.
Aim:
The aim of this work was to estimate HLA-DQ gene polymorphisms in HBV and HCC.
Methods:
HLA-DQ genotype polymorphism was assayed by using the ABI Taq Man allelic discrimination
assay in different groups in this study. According to the relevant HLA Class II single
nucleotide polymorphism (SNP) literature, one single nucleotide polymorphism (SNPs) was selected
as the candidate site; it was an HLA-DQ, which showed minor allele frequencies AA, GA, and
GG.
Results:
Haplotype analysis was performed on all the subjects in the study; AA haplotype was the
most frequent haplotype in HCC cases (18%) in comparison with HBV and healthy individuals
(3%). The haplotype GA was more frequent in the HCC group and slightly more frequent in LC
when compared to HBV only cases and also when compared to the control group. In contrast, the
GG haplotype was recorded less frequently in HCC individuals, but the HBV and LC groups
showed more frequency of this haplotype compared with the HCC group. There was a correlation
between AFP serum levels and the frequency of GA and AA polymorphism in HCC cases.
Conclusion:
We found that AA and GA haplotype was significantly most frequent in HCC. Our
findings suggest that HLA-DQ AA and GG polymorphism might serve as a novel potential predictive
marker for HCC and may function in tumorigenesis of HBV.
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Affiliation(s)
- Amal A. Mohamed
- Biochemsitry Department, National Hepatology & Tropical Medicine Research Institute, Cairo, Egypt
| | | | - Somia Saad
- Chemsitry Department, Faculty of Science, Menoufia University, Al Minufya, Egypt
| | - Shrook Mousa
- Internal Medicine Department, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Omnia Tantawi
- Internal Medicine Department, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Fawkia E. Zahran
- Internal Medicine Department, Faculty of Medicine, Al Azhar University, Cairo, Egypt
| | - Nevine F. Shafik
- Chemical Pathology, National Cancer Institute NCI, Cairo University, Cairo, Egypt
| | - Reham A.A. Elshimy
- Chemical Pathology, National Cancer Institute NCI, Cairo University, Cairo, Egypt
| | | | - Alaa Kandil
- Hepatology, Gastroenterology and Infectious Diseases Department, Faculty of Medicine, Benha University, Benha, Egypt
| | - Rehab Ahmed
- Department of Hepatology, National Hepatology and Tropical Medicine Research Institute (NHTMRI), Cairo, Egypt
| | - Mahmoud Khalil
- Infectious Diseases Department, National Hepatology and Tropical Medicine Research Institute (NHTMRI), Cairo, Egypt
| | - Moataz Y. Soliman
- Hepatology, Gastroenterology and Infectious Diseases Department, Mahala Hepatology Teaching Hospital, Gharbia, Egypt
| | - Yousry E.-E. Abo-Amer
- Hepatology, Gastroenterology and Infectious Diseases Department, Mahala Hepatology Teaching Hospital, Gharbia, Egypt
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Zeng Z, Liu H, Xu H, Lu H, Yu Y, Xu X, Yu M, Zhang T, Tian X, Xi H, Guan L, Zhang J, O'Brien SJ. Genome-wide association study identifies new loci associated with risk of HBV infection and disease progression. BMC Med Genomics 2021; 14:84. [PMID: 33736632 PMCID: PMC7977299 DOI: 10.1186/s12920-021-00907-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2021] [Accepted: 02/17/2021] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Recent studies have identified susceptibility genes of HBV clearance, chronic hepatitis B, liver cirrhosis, hepatocellular carcinoma, and showed the host genetic factors play an important role in these HBV-related outcomes. METHODS Collected samples from different outcomes of HBV infection and performed genotyping by Affymetrix 500 k SNP Array. GCTA tool, PLINK, and Bonferroni method were applied for analysis of genotyping and disease progression. ANOVA was used to evaluate the significance of the association between biomarkers and genotypes in healthy controls. PoMo, FST, Vcftools and Rehh package were used for building the racial tree and population analysis. FST statistics accesses 0.15 was used as a threshold to detect the signature of selection. RESULTS There are 1031 participants passed quality control from 1104 participants, including 275 HBV clearance, 92 asymptomatic persistence infection (ASPI), 93 chronic hepatitis B (CHB), 188 HBV-related decompensated cirrhosis (DC), 214 HBV-related hepatocellular carcinoma (HCC) and 169 healthy controls (HC). In the case-control study, one novel locus significantly associated with CHB (SNP: rs1264473, Gene: GRHL2, P = 1.57 × 10-6) and HCC (SNP: rs2833856, Gene: EVA1C, P = 1.62 × 10-6; SNP: rs4661093, Gene: ETV3, P = 2.26 × 10-6). In the trend study across progressive stages post HBV infection, one novel locus (SNP: rs1537862, Gene: LACE1, P = 1.85 × 10-6), and three MHC loci (HLA-DRB1, HLA-DPB1, HLA-DPA2) showed significant increased progressive risk from ASPI to CHB. Underlying the evolutionary study of HBV-related genes in public database, the derived allele of two HBV clearance related loci, rs3077 and rs9277542, are under strong selection in European population. CONCLUSIONS In this study, we identified several novel candidate genes associated with individual HBV infectious outcomes, progressive stages, and liver enzymes. Two SNPs that show selective significance (HLA-DPA1, HLA-DPB1) in non-East Asian (European, American, South Asian) versus East Asian, indicating that host genetic factors contribute to the ethnic disparities of susceptibility of HBV infection. Taken together, these findings provided a new insight into the role of host genetic factors in HBV related outcomes and progression.
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Affiliation(s)
- Zheng Zeng
- Department of Infectious Diseases, Peking University First Hospital, Beijing, 100034, China.
| | | | | | - Haiying Lu
- Department of Infectious Diseases, Peking University First Hospital, Beijing, 100034, China
| | - Yanyan Yu
- Department of Infectious Diseases, Peking University First Hospital, Beijing, 100034, China
| | - Xiaoyuan Xu
- Department of Infectious Diseases, Peking University First Hospital, Beijing, 100034, China
| | - Min Yu
- Department of Infectious Diseases, Peking University First Hospital, Beijing, 100034, China
| | - Tao Zhang
- BGI-Shenzhen, Shenzhen, 518083, China
| | - Xiulan Tian
- Department of Infectious Diseases, Peking University First Hospital, Beijing, 100034, China
| | - Hongli Xi
- Department of Infectious Diseases, Peking University First Hospital, Beijing, 100034, China
| | | | | | - Stephen J O'Brien
- Laboratory of Genomic Diversity, Center for Computer Technologies, ITMO University, St. Petersburg, Russia, 197101.
- Guy Harvey Oceanographic Center, Halmos College of Natural Sciences and Oceanography, Nova Southeastern University, Ft Lauderdale, FL, 33004, USA.
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Wang C, Zhang X, Ling Q, Zheng S, Xu X. A model integrating donor gene polymorphisms predicts fibrosis after liver transplantation. Aging (Albany NY) 2020; 13:1264-1275. [PMID: 33291080 PMCID: PMC7835018 DOI: 10.18632/aging.202302] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Accepted: 09/21/2020] [Indexed: 01/10/2023]
Abstract
Post-transplant liver fibrosis (PTLF) is a common and severe complication in liver recipients. In this study, we assessed the impact of donor liver genetics on the development of PTLF. A total of 232 patients undergoing liver transplantation were included. Twenty-two single nucleotide polymorphisms (SNPs) associated with liver fibrosis were analyzed. Univariate analysis revealed seven donor SNPs to be associated with PTLF. In a multivariate analysis, independent risk factors of PTLF were genetic variation of donor GRP78 rs430397 (OR = 8.99, p = 0.003), GSTP1 rs1695 (OR = 0.13, p = 0.021), miRNA-196a rs12304647 (OR = 16.01, p =0.001), and TNF-α rs1800630 (OR = 79.78, p = 0.001); blood tacrolimus levels at maintenance > 7 ng/ml (OR =7.48, p <0.001); and post-transplant diabetes mellitus (OR = 7.50, p = 0.001). A predictive model that included donor SNPs showed better prognostic ability for PTLF than a model with only clinical parameters (AUROC: 0.863 vs 0.707, P < 0.001). Given that donor gene SNPs are associated with an increased risk of PTLF, this model integrated with donor gene polymorphisms may help clinicians predict PTLF.
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Affiliation(s)
- Chao Wang
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
- NHC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou 310003, China
| | - Xueyou Zhang
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Qi Ling
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Shusen Zheng
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Xiao Xu
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
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10
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Deng Y, Li P, Liu W, Pu R, Yang F, Song J, Yin J, Han X, Li C, Zhao J, Wang H, Cao G. The genetic polymorphism down-regulating HLA-DRB1 enhancer activity facilitates HBV persistence, evolution and hepatocarcinogenesis in the Chinese Han population. J Viral Hepat 2020; 27:1150-1161. [PMID: 32568442 DOI: 10.1111/jvh.13353] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2020] [Revised: 05/08/2020] [Accepted: 05/25/2020] [Indexed: 02/06/2023]
Abstract
Genetic predisposition of human leucocyte antigen (HLA)-DR has been linked to nonresponse to hepatitis B virus (HBV) vaccination. We sought to reveal their effects on chronic infection and evolution of HBV and development of hepatocellular carcinoma (HCC). Genetic polymorphisms at HLA-DR enhancer regions were genotyped in 4588 participants using quantitative PCR. HBV mutations were determined by sequencing. A dual-luciferase assay was applied to detect the enhancer activity. Associations between HLA-DR polymorphisms and postoperative prognosis were investigated in another cohort of 397 HBV-infected HCC patients. Variant alleles (rs3135395-T, rs3135338-C and rs477515-T) were significantly associated with a decreased risk of HBV persistence in Chinese patients. rs3135395-T, rs3135338-C, rs477515-T and rs2395178-G also significantly decreased HCC risk. rs3135395-T, rs477515-T and rs2395178-G were inversely associated with the generation of A1762T/G1764A, T1753V and C1653T, the HCC-risk HBV mutations. Multiplicative interactions of the variant genotypes with the HCC-risk HBV mutations were significantly associated with a decreased risk of HCC. In multivariate Cox analysis, rs477515-T independently predicted a favourable prognosis, with a hazard ratio of 0.48 (P = .002). The activity of the HLA-DRB1 enhancer with rs477515-T was significantly higher than that with rs477515-C. The activity of the HLA-DRB1 enhancer with rs477515-T and that with rs477515-C was significantly up-regulated by interferon-γ and interleukin-4, respectively. Interleukin-6 significantly inhibited the HLA-DRB1 enhancer activity, and this effect was more evident in those carrying rs477515-T. Polymorphisms predisposing to down-regulation of HLA-DR facilitate the Th1-to-Th2 transition and promote HCC development, possibly via selecting the HCC-risk HBV mutations. This can be transformed into specific prophylaxis of HCC.
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Affiliation(s)
- Yang Deng
- Department of Epidemiology, Naval Medical University, Shanghai, China
| | - Peng Li
- Department of Epidemiology, Naval Medical University, Shanghai, China
| | - Wenbin Liu
- Department of Epidemiology, Naval Medical University, Shanghai, China
| | - Rui Pu
- Department of Epidemiology, Naval Medical University, Shanghai, China
| | - Fan Yang
- Department of Epidemiology, Naval Medical University, Shanghai, China
| | - Jiahui Song
- Department of Epidemiology, Naval Medical University, Shanghai, China
| | - Jianhua Yin
- Department of Epidemiology, Naval Medical University, Shanghai, China
| | - Xue Han
- Division of Chronic Diseases, Center for Disease Control and Prevention of Yangpu District, Shanghai, China
| | - Chengzhong Li
- Department of Infectious Diseases, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Jun Zhao
- Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Hongyang Wang
- Key Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer, Ministry of Education, Shanghai, China.,Shanghai Key Laboratory of Hepatobiliary Tumor Biology, Shanghai, China
| | - Guangwen Cao
- Department of Epidemiology, Naval Medical University, Shanghai, China.,Key Laboratory of Signaling Regulation and Targeting Therapy of Liver Cancer, Ministry of Education, Shanghai, China.,Shanghai Key Laboratory of Hepatobiliary Tumor Biology, Shanghai, China
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11
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Irham LM, Wong HSC, Perwitasari DA, Chou WH, Yang HI, Chang WC. Single-nucleotide polymorphism of rs7944135 (macrophage-expressed gene 1) is associated with hepatitis B surface antigen seroclearance in chronic hepatitis B infection: A cohort study. Medicine (Baltimore) 2019; 98:e17936. [PMID: 31860948 PMCID: PMC6940119 DOI: 10.1097/md.0000000000017936] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
Clearance of the hepatitis B surface antigen (HBsAg) is the ultimate aim of treatment for patients with chronic hepatitis B (CHB) infection. Genetic, factor age, and gender were reported to be involved in the clearance of HBsAg. However, the rate of HBsAg seroclearance in CHB patients is still low globally and few of the single-nucleotide polymorphism (SNP) had been identified to associated with HBsAg seroclearance in CHB patients.Recently, 3 associated SNPs (rs7944135, rs171941, and rs6462008) were reported in the clearance of HBsAg in the Korean population. However, these SNPs have not been investigated in the CHB Taiwanese population. In present study, these 3 SNPs were genotyped in 2565 Taiwanese CHB patients including 493 CHB patients with HBsAg seroclearance and 2072 without HBsAg seroclearance.We observed that SNP rs7944135 was solely associated with HBsAg seroclearance. Subjects with the AA genotype at rs7944135 of macrophage-expressed gene 1 had a higher susceptibility to HBsAg clearance, compared to those with the AG or GG genotype under the genotypic model (odds ratio [OR] = 1.76. 95% confidence interval [CI] = 1.14-2.72, P = .045). Furthermore, we found a 1.74-fold increased risk of acquiring HBsAg seroclearance associated with the AA genotype compared to AG + GG of rs7944135 under the recessive model (OR = 1.74. 95% CI = 1.13-2.66, P = .014). According to the cumulative fraction curve with the log-rank test revealed that patients with the AA genotype of rs7944135 showed higher susceptibility to occur HBsAg seroclearance (P = .039) and HBV DNA undetectable (P = .0074) compared to those with the AG or GG genotype.This study examined the associations of 3 SNPs (rs7944135, rs171941, and rs6462008) with HBsAg seroclearance, and we identified that rs7944135 is solely associated with HBsAg seroclearance in Taiwanese CHB patients.
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Affiliation(s)
- Lalu Muhammad Irham
- Department of Clinical Pharmacy, School of Pharmacy, College of Pharmacy
- Master Program for Clinical Pharmacogenomics and Pharmacoproteomics, School of Pharmacy, Taipei Medical University, Taipei, Taiwan
- Faculty of Pharmacy, University of Ahmad Dahlan, Yogyakarta, Indonesia
| | - Henry Sung-Ching Wong
- Department of Clinical Pharmacy, School of Pharmacy, College of Pharmacy
- Master Program for Clinical Pharmacogenomics and Pharmacoproteomics, School of Pharmacy, Taipei Medical University, Taipei, Taiwan
| | | | - Wan-Hsuan Chou
- Department of Clinical Pharmacy, School of Pharmacy, College of Pharmacy
- Master Program for Clinical Pharmacogenomics and Pharmacoproteomics, School of Pharmacy, Taipei Medical University, Taipei, Taiwan
| | - Hwai-I Yang
- Genomics Research Center, Academia Sinica
- Institute of Clinical Medicine, National Yang-Ming University
| | - Wei-Chiao Chang
- Department of Clinical Pharmacy, School of Pharmacy, College of Pharmacy
- Master Program for Clinical Pharmacogenomics and Pharmacoproteomics, School of Pharmacy, Taipei Medical University, Taipei, Taiwan
- Genomics Research Center, Academia Sinica
- Integrative Research Center for Critical Care, Wan fang Hospital, Taipei Medical University, Taipei
- Department of Medical Research, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan
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12
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Yang F, Ma L, Yang Y, Liu W, Zhao J, Chen X, Wang M, Zhang H, Cheng S, Shen F, Wang H, Zhou W, Cao G. Contribution of Hepatitis B Virus Infection to the Aggressiveness of Primary Liver Cancer: A Clinical Epidemiological Study in Eastern China. Front Oncol 2019; 9:370. [PMID: 31179237 PMCID: PMC6537574 DOI: 10.3389/fonc.2019.00370] [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: 03/22/2019] [Accepted: 04/23/2019] [Indexed: 12/25/2022] Open
Abstract
Background and aims: The contribution of hepatitis B virus (HBV) infection to the aggressiveness of primary liver cancer (PLC) remains controversial. We aimed to characterize this in eastern China. Methods: We enrolled 8,515 PLC patients whose specimens were reserved at the BioBank of the hepatobiliary hospital (Shanghai, China) during 2007-2016. Of those, 3,124 who received primary radical resection were involved in survival analysis. A nomogram was constructed to predict the survivals using preoperative parameters. Results: Hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (ICC), and combined hepatocellular cholangiocarcinoma (CHC) accounted for 94.6, 3.7, and 1.7%, respectively. The rates of HBV infection were 87.5, 49.2, and 80.6%, respectively. HBV infection was significantly associated with 10-year earlier onset, more cirrhosis, higher α-fetoprotein, higher carbohydrate antigen 19-9 (CA19-9), more microvascular invasion (MVI), lower neutrophil-to-lymphocyte ratio (NLR), and lower platelet-to-lymphocyte ratio (PLR) in HCC. HBV infection was also associated with 7-year earlier onset, more cirrhosis, higher α-fetoprotein, more MVI, and lower PLR in ICC. In the multivariate Cox analysis, high circulating HBV DNA, α-fetoprotein, CA19-9, NLR, tumor size, number, encapsulation, Barcelona Clinic Liver Cancer (BCLC) stage, and MVI predicted an unfavorable prognosis in HCC; only CA19-9 and BCLC stage, rather than HBV-related parameters, had prognostic values in ICC. A nomogram constructed with preoperative HBV-related parameters including HBV load, ultrasonic cirrhosis, and α-fetoprotein perform better than the current staging systems in predicting postoperative survival in HCC. Conclusion: HBV promotes the aggressiveness of HCC in Chinese population. The contributions of HBV to ICC and other etiological factors to HCC might be indirect via arousing non-resolving inflammation.
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Affiliation(s)
- Fan Yang
- Department of Epidemiology, Second Military Medical University, Shanghai, China
| | - Longteng Ma
- Department of Epidemiology, Second Military Medical University, Shanghai, China
| | - Yuan Yang
- Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Wenbin Liu
- Department of Epidemiology, Second Military Medical University, Shanghai, China
| | - Jun Zhao
- Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Xi Chen
- Department of Epidemiology, Second Military Medical University, Shanghai, China
| | - Mengchao Wang
- Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Hongwei Zhang
- Department of Epidemiology, Second Military Medical University, Shanghai, China
| | - Shuqun Cheng
- Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Feng Shen
- Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Hongyang Wang
- Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Weiping Zhou
- Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Guangwen Cao
- Department of Epidemiology, Second Military Medical University, Shanghai, China
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13
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Akcay IM, Katrinli S, Ozdil K, Doganay GD, Doganay L. Host genetic factors affecting hepatitis B infection outcomes: Insights from genome-wide association studies. World J Gastroenterol 2018; 24:3347-3360. [PMID: 30122875 PMCID: PMC6092584 DOI: 10.3748/wjg.v24.i30.3347] [Citation(s) in RCA: 46] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2018] [Revised: 05/29/2018] [Accepted: 06/25/2018] [Indexed: 02/06/2023] Open
Abstract
The clinical outcome of hepatitis B virus (HBV) infection depends on the success or failure of the immune responses to HBV, and varies widely among individuals, ranging from asymptomatic self-limited infection, inactive carrier state, chronic hepatitis, cirrhosis, hepatocellular carcinoma, to liver failure, depending on the success or failure of immune response to HBV. Genome-wide association studies (GWAS) identified key genetic factors influencing the pathogenesis of HBV-related traits. In this review, we discuss GWAS for persistence of HBV infection, antibody response to hepatitis B vaccine, and HBV-related advanced liver diseases. HBV persistence is associated with multiple genes with diverse roles in immune mechanisms. The strongest associations are found within the classical human leukocyte antigen (HLA) genes, highlighting the central role of antigen presentation in the immune response to HBV. Associated variants affect both epitope binding specificities and expression levels of HLA molecules. Several other susceptibility genes regulate the magnitude of adaptive immune responses, determining immunity vs tolerance. HBV persistence and nonresponse to vaccine share the same risk variants, implying overlapping genetic bases. On the other hand, the risk variants for HBV-related advanced liver diseases are largely different, suggesting different host-virus dynamics in acute vs chronic HBV infections. The findings of these GWAS are likely to pave the way for developing more effective preventive and therapeutic interventions by personalizing the management of HBV infection.
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Affiliation(s)
- Izzet Mehmet Akcay
- Department of Molecular Biology and Genetics, Istanbul Technical University, Istanbul 34469, Turkey
| | - Seyma Katrinli
- Department of Molecular Biology and Genetics, Istanbul Technical University, Istanbul 34469, Turkey
| | - Kamil Ozdil
- Department of Gastroenterology and Hepatology, Umraniye Teaching and Research Hospital, Istanbul 34764, Turkey
| | - Gizem Dinler Doganay
- Department of Molecular Biology and Genetics, Istanbul Technical University, Istanbul 34469, Turkey
| | - Levent Doganay
- Department of Gastroenterology and Hepatology, Umraniye Teaching and Research Hospital, Istanbul 34764, Turkey
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14
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Quantitative assessment of HLA-DQ gene polymorphisms with the development of hepatitis B virus infection, clearance, liver cirrhosis, and hepatocellular carcinoma. Oncotarget 2017; 9:96-109. [PMID: 29416599 PMCID: PMC5787527 DOI: 10.18632/oncotarget.22941] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2017] [Accepted: 11/03/2017] [Indexed: 12/14/2022] Open
Abstract
Hepatitis B is one of the most common infectious diseases, which leads to public health problems in the world, especially in Asian counties. In recent years, extensive human genetic association studies have been carried out to identify susceptible genes and genetic polymorphisms to understand the genetic contributions to the disease progression of HBV infection. HLA-DQ gene variations have been reported to be associated with HBV infection/clearance, disease progression and the development of hepatitis B-related complications, including liver cirrhosis (LC) and hepatocellular carcinoma (HCC). However, the results are either inconclusive or controversial. Therefore, to derive a more precise estimation of the association, a meta-analysis was performed. Our data revealed that the HLA-DQ alleles rs2856718-G, rs7453920-A and rs9275319-G were significantly associated with decreased risk of HBV infection and HBV natural clearance. Logistic regression analyses showed that HLA-DQ alleles rs9275572-A significantly increased HBV infection clearance, and decreased HBV natural clearance. However, rs2856718-G and rs9275572-A were not associated with development of cirrhosis. The HLA-DQ polymorphisms (rs2856718 and rs9275572) were associated with a decreased HBV-related HCC risk in all genetic models, but rs9272105-A increased the risk of HBV-related HCC. In addition, no significant association was observed between HLA-DQ rs9275319-G polymorphism and HBV-related HCC. These stratified analyses were limited due to relatively modest size of correlational studies. In future, further investigation on a large population and different ethnicities are warranted. Our findings contribute to the personalized care and prognosis in hepatitis B.
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15
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Ochi Y, Hashimoto S, Kawabe N, Murao M, Nakano T, Kan T, Nakaoka K, Ohki M, Kurashita T, Takamura T, Nomura S, Nishikawa T, Fukui A, Osakabe K, Ichino N, Yoshioka K. HLA-DQ gene polymorphisms are associated with hepatocellular carcinoma and hepatitis B surface antigen in chronic hepatitis B virus infection. Hepatol Res 2017; 47:755-766. [PMID: 27580643 DOI: 10.1111/hepr.12812] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2016] [Revised: 08/14/2016] [Accepted: 08/29/2016] [Indexed: 01/31/2023]
Abstract
AIM Genome-wide association studies have revealed that single nucleotide polymorphism (SNP) of human leukocyte antigen (HLA)-DQ is associated with the clearance of hepatitis B surface antigen (HBsAg) in acute hepatitis B virus (HBV) infection. We examined the effects of SNPs on the development of hepatocellular carcinoma (HCC) and markers of HBV in chronic HBV infection. METHODS The SNPs of HLA-DQ (rs2856718 and rs7453920) were determined in 299 patients with chronic HBV infection. RESULTS In 224 hepatitis B e antigen (HBeAg)-negative patients, those with rs2856718 genotype AG + GG had significantly lower hepatitis B core-related antigen levels (P = 0.0184), less frequent treatment with nucleotide/nucleoside analogs (NAs) (P = 0.0433), and less frequent HCC development (P = 0.0256) than those with genotype AA. Multivariate analysis selected age (P = 0.0460), platelet count (P = 0.0481), γ-glutamyl transpeptidase (P = 0.0030), and nucleotide/nucleoside analog treatment (P = 0.0003) as factors independently associated with HCC development. HBeAg-negative patients with rs7453920 genotype GG had significantly lower HBsAg levels (P < 0.0001), a higher prevalence of HBV genotype C (P = 0.0063), and a lower prevalence of the wild-type basal core promoter region (P = 0.0045) than those with genotype AA + AG. Multivariate analysis selected age (P < 0.0001), platelet count (P = 0.0021), HBV DNA levels (P = 0.0314), wild type of precore region (P = 0.0015), and rs7453920 (P < 0.0001) as factors independently associated with HBsAg levels. CONCLUSION This study revealed an association between rs2856718 and HCC development and an association between rs7453920 and HBsAg levels.
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Affiliation(s)
- Yuka Ochi
- Department of Liver, Biliary Tract and Pancreas Diseases, Fujita Health University, Toyoake, Japan
| | - Senju Hashimoto
- Department of Liver, Biliary Tract and Pancreas Diseases, Fujita Health University, Toyoake, Japan
| | - Naoto Kawabe
- Department of Liver, Biliary Tract and Pancreas Diseases, Fujita Health University, Toyoake, Japan
| | - Michihito Murao
- Department of Liver, Biliary Tract and Pancreas Diseases, Fujita Health University, Toyoake, Japan
| | - Takuji Nakano
- Department of Liver, Biliary Tract and Pancreas Diseases, Fujita Health University, Toyoake, Japan
| | - Toshiki Kan
- Department of Liver, Biliary Tract and Pancreas Diseases, Fujita Health University, Toyoake, Japan
| | - Kazunori Nakaoka
- Department of Liver, Biliary Tract and Pancreas Diseases, Fujita Health University, Toyoake, Japan
| | - Masashi Ohki
- Department of Liver, Biliary Tract and Pancreas Diseases, Fujita Health University, Toyoake, Japan
| | - Takamitsu Kurashita
- Department of Liver, Biliary Tract and Pancreas Diseases, Fujita Health University, Toyoake, Japan
| | - Tomoki Takamura
- Department of Liver, Biliary Tract and Pancreas Diseases, Fujita Health University, Toyoake, Japan
| | - Sayuri Nomura
- Department of Liver, Biliary Tract and Pancreas Diseases, Fujita Health University, Toyoake, Japan
| | - Toru Nishikawa
- Department of Liver, Biliary Tract and Pancreas Diseases, Fujita Health University, Toyoake, Japan
| | - Aiko Fukui
- Department of Clinical Pharmacy Practice and Health Care Management, Faculty of Pharmacy, Meijo University, Nagoya, Japan
| | - Keisuke Osakabe
- Faculty of Medical Technology, School of Health Sciences, Fujita Health University, Toyoake, Japan
| | - Naohiro Ichino
- Faculty of Medical Technology, School of Health Sciences, Fujita Health University, Toyoake, Japan
| | - Kentaro Yoshioka
- Department of Liver, Biliary Tract and Pancreas Diseases, Fujita Health University, Toyoake, Japan
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16
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Relationship between HLA-DQ Gene Polymorphism and Hepatitis B Virus Infection. BIOMED RESEARCH INTERNATIONAL 2017; 2017:9679843. [PMID: 28512640 PMCID: PMC5420426 DOI: 10.1155/2017/9679843] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/29/2016] [Revised: 03/21/2017] [Accepted: 04/02/2017] [Indexed: 12/24/2022]
Abstract
Hepatitis B virus (HBV) infection is the predominant risk factor for chronic hepatitis B (CHB). The association between HBV infection and human leukocyte antigen- (HLA-) DQ polymorphism (rs2856718 and rs7453920) has been demonstrated in other studies; however, the results were controversial or inconclusive. Therefore, to derive a more precise estimation of the association, a meta-analysis was performed. Crude odds ratios (ORs) and their 95% confidence intervals (CIs) were used to assess the strength of association between HLA-DQ polymorphism (rs2856718 and rs7453920) and HBV infection risk. A total of 11 articles were used to evaluate the effect of the two polymorphisms on risk of HBV infection. The pooled data showed that HLA-DQ rs2856718-G polymorphism showed protection against HBV infection, and rs2856718-A was a risk factor for chronic HBV infection. The pooled risk estimates indicated that HLA-DQ rs7453920-A polymorphism was associated with decreased risk of HBV infection, and rs7453920-G serves as a risk factor in HBV infection. However, these stratified analyses were lacking credibility due to the limitation of correlational study numbers; further investigation on a large population and different ethnicities is warranted.
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17
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Zhu H, Wu J, Shen X. Genome-wide association study: new genetic insights into HBV/HCV-related hepatocellular carcinoma genomes. Scand J Gastroenterol 2017; 52:209-215. [PMID: 27797287 DOI: 10.1080/00365521.2016.1245778] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Hepatocellular carcinoma (HCC) is the third common cause of cancer-related death with highest prevalence in developing countries, such as Southeast China and Saharan African. The major pathogenic factors can be categorized into environmental effects and genetic variations, and it is mostly caused by hepatitis B or C virus (HBV and HCV). The geographic prevalence of chronic hepatitis B and C (CHB and CHC) varies, with HBV heavily-infected in developing countries and HCV prevalent in developed countries. The infection of either hepatitis virus B or C causes damage to the liver cells through cellular immune attack by the mechanism of inflammation. However, how liver cell injury progresses to HCC development is still poorly understood. Along with the maturation of genome-wide association study (GWAS) technology, the specific genetic mutations responsible for the progression from CHB or CHC to HCC have been identified. Moreover, the findings of similar studies for these variants are different from each other due to diverse populations. More functional experiments are warranted to confirm the precise roles of these genetic mutations in the correlations between HBV/HCV and HCC for the future clinical application.
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Affiliation(s)
- Hairong Zhu
- a Department of Gastroenterology , Fudan University Affiliated Zhongshan Hospital , Shanghai , China
| | - Jian Wu
- b Shanghai Institute of Liver Disease, Fudan University Affiliated Zhongshan Hospital , Shanghai , China.,c Department of Medical Microbiology, Key Laboratory of Molecular Virology , Fudan University Shanghai Medical College , Shanghai , China
| | - Xizhong Shen
- a Department of Gastroenterology , Fudan University Affiliated Zhongshan Hospital , Shanghai , China.,b Shanghai Institute of Liver Disease, Fudan University Affiliated Zhongshan Hospital , Shanghai , China
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18
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Xiang X, Guo Y, Yang L, Ge Q, Mijit S, Xu F. Association of human leukocyte antigen DP/DQ gene polymorphisms with chronic hepatitis B in Chinese Han and Uygur populations. INFECTION GENETICS AND EVOLUTION 2016; 43:407-11. [PMID: 27291710 DOI: 10.1016/j.meegid.2016.06.022] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 01/22/2016] [Revised: 05/31/2016] [Accepted: 06/07/2016] [Indexed: 12/17/2022]
Abstract
Several genome-wide association studies (GWAS) have shown that human leukocyte antigen (HLA) DP/DQ gene polymorphisms are associated with susceptibility to chronic hepatitis B virus (HBV) infection. We clarified the roles of the HLA-DP/DQ gene in HBV infection in different nationalities. Three single nucleotide polymorphisms (SNPs) in HLA-DP (rs9277471, rs9277535 and rs9277542) and the SNP rs9272346 in HLA-DQ were studied. In total, 779 patients were recruited to this study, including 400 Chinese Han and 399 Uygurs. The rs9277535 variant genotypes were directly associated with HBV persistence compared to healthy controls in an additive model of the Chinese Han population (odds ratio [OR]=1.88, 95% confidence interval [CI]=1.03-3.41, P=0.040), and in a recessive model of the Chinese female population (OR=2.02, 95% CI=1.26-3.24, P=0.003). In addition, rs9277471 and rs9277542 variant genotypes significantly decreased the risk of HBV infection compared to healthy controls in an additive model of the Chinese Han population (OR=0.53, 95% CI=0.29-0.98, P=0.042; OR=0.53, 95% CI=0.29-0.97, P=0.039) and in a dominant model of the Chinese female population (OR=0.50, 95% CI=0.31-0.80, P=0.004; OR=0.49, 95% CI=0.31-0.79, P=0.003). The GG genotype of rs9277346 was associated with HBV infection in the Chinese Han population (additive model: OR=0.38, 95%CI=017-0.82, P=0.014; recessive model: OR=0.41, 95% CI=0.19-0.86, P=0.019) and in males (additive model: OR=0.31, 95% CI=0.14-0.65, P=0.002; dominant model: OR=0.65, 95% CI=0.43-0.97, P=0.034; recessive model: OR=0.36, 95% CI=0.18-0.73, P=0.005). In addition, allele G of rs9277346 was marginally related to a reduction in risk for HBV infection in the Uygur population. Our study suggests that HLA-DP/DQ polymorphisms can affect susceptibility and resistance to HBV infection in Chinese populations, and are possibly linked to race and sex.
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Affiliation(s)
- Xin Xiang
- Centre of Clinical Laboratory, the Traditional Chinese Medicine Hospital of Xinjiang Uygur Autonomous Region, Urumqi, China
| | - Yuxuan Guo
- Centre of Clinical Laboratory, the Traditional Chinese Medicine Hospital of Xinjiang Uygur Autonomous Region, Urumqi, China
| | - Li Yang
- Centre of Clinical Laboratory, the Traditional Chinese Medicine Hospital of Xinjiang Uygur Autonomous Region, Urumqi, China
| | - Qinghui Ge
- Centre of Clinical Laboratory, the Traditional Chinese Medicine Hospital of Xinjiang Uygur Autonomous Region, Urumqi, China; College of Traditional Chinese Medicine, Xinjiang Medical University, Urumqi, China
| | - Sadatgul Mijit
- Centre of Clinical Laboratory, the Traditional Chinese Medicine Hospital of Xinjiang Uygur Autonomous Region, Urumqi, China; College of Traditional Chinese Medicine, Xinjiang Medical University, Urumqi, China
| | - Feili Xu
- Centre of Clinical Laboratory, the Traditional Chinese Medicine Hospital of Xinjiang Uygur Autonomous Region, Urumqi, China.
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19
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Wang L, Zou ZQ, Wang K. Clinical Relevance of HLA Gene Variants in HBV Infection. J Immunol Res 2016; 2016:9069375. [PMID: 27243039 PMCID: PMC4875979 DOI: 10.1155/2016/9069375] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2016] [Accepted: 04/14/2016] [Indexed: 01/01/2023] Open
Abstract
Host gene variants may influence the natural history of hepatitis B virus (HBV) infection. The human leukocyte antigen (HLA) system, the major histocompatibility complex (MHC) in humans, is one of the most important host factors that are correlated with the clinical course of HBV infection. Genome-wide association studies (GWASs) have shown that single nucleotide polymorphisms (SNPs) near certain HLA gene loci are strongly associated with not only persistent HBV infection but also spontaneous HBV clearance and seroconversion, disease progression, and the development of liver cirrhosis and HBV-related hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB). These variations also influence the efficacy of interferon (IFN) and nucleot(s)ide analogue (NA) treatment and response to HBV vaccines. Meanwhile, discrepant conclusions were reached with different patient cohorts. It is therefore essential to identify the associations of specific HLA allele variants with disease progression and viral clearance in chronic HBV infection among different ethnic populations. A better understanding of HLA polymorphism relevance in HBV infection outcome would enable us to elucidate the roles of HLA SNPs in the pathogenesis and clearance of HBV in different areas and ethnic groups, to improve strategies for the prevention and treatment of chronic HBV infection.
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Affiliation(s)
- Li Wang
- Infectious Disease Hospital of Yantai, 62 Huanshan Road, Zhifu District, Yantai, Shandong 264001, China
| | - Zhi-Qiang Zou
- Infectious Disease Hospital of Yantai, 62 Huanshan Road, Zhifu District, Yantai, Shandong 264001, China
| | - Kai Wang
- Hepatology Department, Qilu Hospital of Shandong University, 44 Wenhua West Road, Lixia District, Jinan, Shandong 250012, China
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20
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Liu WB, Wu JF, Du Y, Cao GW. Cancer Evolution-Development: experience of hepatitis B virus-induced hepatocarcinogenesis. ACTA ACUST UNITED AC 2016; 23:e49-56. [PMID: 26966413 DOI: 10.3747/co.23.2836] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Here, we present the basic concept and theoretical framework of a scientific hypothesis called Cancer Evolution-Development ("Cancer Evo-Dev"), based on our recent studies of the molecular mechanisms by which chronic infection with the hepatitis B virus induces hepatocarcinogenesis, together with related advances in that field. Several aspects central to our hypothesis are presented: ■ Immune imbalance-caused by the interaction of genetic predispositions and environmental exposures such as viral infection-is responsible for the maintenance of chronic non-resolving inflammation. Non-resolving inflammation promotes the occurrence and progression of cancers, characterized by an evolutionary process of "mutation-selection-adaptation" for both viruses and host cells.■ Under a microenvironment of non-resolving inflammation, proinflammatory factors promote mutations in viral or host genomes by transactivation of the expression of cytidine deaminases and their analogues. Most cells with genomic mutations and mutated viruses are eliminated in the competition for survival in the inflammatory microenvironment. Only a small percentage of the mutated cells that alter their survival signal pathways and exhibit the characteristics of "stem-ness" can survive and function as cancer-initiating cells.■ Cancers generally develop with properties of "backward evolution" and "retro-differentiation," indicating the indispensability of stem-like signal pathways in the evolution and development of cancers. The hypothesis of Cancer Evo-Dev not only lays the theoretical foundation for understanding the mechanisms by which inflammation promotes the development of cancers, but also plays an important role in specific prophylaxis, prediction, early diagnosis, and targeted treatment of cancers.
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Affiliation(s)
- W B Liu
- Department of Epidemiology, Second Military Medical University, Shanghai, P.R.C
| | - J F Wu
- Department of Epidemiology, Second Military Medical University, Shanghai, P.R.C
| | - Y Du
- Department of Epidemiology, Second Military Medical University, Shanghai, P.R.C
| | - G W Cao
- Department of Epidemiology, Second Military Medical University, Shanghai, P.R.C
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21
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Wen J, Song C, Jiang D, Jin T, Dai J, Zhu L, An J, Liu Y, Ma S, Qin N, Liang C, Chen J, Jiang Y, Yang L, Liu J, Liu L, Geng T, Chen C, Jiang J, Chen J, Zhu F, Zhu Y, Yu L, Shen H, Zhai X, Xu J, Hu Z. Hepatitis B virus genotype, mutations, human leukocyte antigen polymorphisms and their interactions in hepatocellular carcinoma: a multi-centre case-control study. Sci Rep 2015; 5:16489. [PMID: 26568165 PMCID: PMC4644975 DOI: 10.1038/srep16489] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2015] [Accepted: 10/14/2015] [Indexed: 12/25/2022] Open
Abstract
Three genome-wide association studies (GWAS) have been conducted on the genetic susceptibility of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), two of which consistently identified tagging single nucleotide polymorphisms (SNPs) around HLA-DQ/DR. In contrast, large multi-centre association studies between HBV genotype, mutations and the risk of HCC are relatively rare, and their interactions with host variants are even less. We performed a multi-centre study of 1,507 HBV-related HCC cases and 1,560 HBV persistent carriers as controls to evaluate the effects of HBV genotype, mutations, GWAS-identified HLA-DQ/DR SNPs (rs9272105 and rs9275319) and their interactions on HCC risk. We found HBV genotype C was more frequent in HBV-related HCC. And 11 HBV hotspot mutations were independently and significantly associated with HCC risk. We also detected significant interactions of rs9272105 with both the HBV genotype and mutations. Through stepwise regression analysis, HBV genotype, the 11 mutations, HLA-DQ/DR SNPs, and the interaction of rs9272105 with mutation A1752G were all entered into the HCC prediction model, and the area under the curve for the panel including the HLA-DQ/DR SNPs, HBV genotype and mutations was 0.840. The HBV genotype, the mutations and the HLA-DQ/DR SNPs may serve as biomarkers for the surveillance of HBV persistent carriers.
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Affiliation(s)
- Juan Wen
- Department of Epidemiology and Biostatistics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Jiangsu Collaborative Innovation Center For Cancer Personalized Medicine, Cancer Center, School of Public Health, Nanjing Medical University, Nanjing, China
- Nanjing Maternity and Child Health Care Institute, Nanjing Maternity and Child Health Care Hospital Affiliated with Nanjing Medical University, Nanjing, China
| | - Ci Song
- Department of Epidemiology and Biostatistics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Jiangsu Collaborative Innovation Center For Cancer Personalized Medicine, Cancer Center, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Deke Jiang
- State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China
- Ministry of Education Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai, China
- Fudan Center for genetic Epidemiology and Center for Genetic Translational Medicine and Prevention, Fudan University, Shanghai, China
| | - Tianbo Jin
- School of Life Sciences, Northwest University, Xi’an, China
- National Engineering Research Center for Miniaturized Detection Systems, Xi’an, China
| | - Juncheng Dai
- Department of Epidemiology and Biostatistics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Jiangsu Collaborative Innovation Center For Cancer Personalized Medicine, Cancer Center, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Liguo Zhu
- Department of Epidemiology and Biostatistics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Jiangsu Collaborative Innovation Center For Cancer Personalized Medicine, Cancer Center, School of Public Health, Nanjing Medical University, Nanjing, China
- Jiangsu Province Center for Disease Prevention and Control, Nanjing, China
| | - Jiaze An
- Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi’an, China
| | - Yao Liu
- Department of Epidemiology and Biostatistics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Jiangsu Collaborative Innovation Center For Cancer Personalized Medicine, Cancer Center, School of Public Health, Nanjing Medical University, Nanjing, China
- Pathology Center and Department of Pathology, Soochow University, Suzhou, China
| | - Shijie Ma
- Department of Gastroenterology, Huai’an First People’s Hospital of Nanjing Medical University, Huai’an, China
| | - Na Qin
- Department of Epidemiology and Biostatistics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Jiangsu Collaborative Innovation Center For Cancer Personalized Medicine, Cancer Center, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Cheng Liang
- Department of Epidemiology and Biostatistics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Jiangsu Collaborative Innovation Center For Cancer Personalized Medicine, Cancer Center, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Jiaping Chen
- Department of Epidemiology and Biostatistics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Jiangsu Collaborative Innovation Center For Cancer Personalized Medicine, Cancer Center, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Yue Jiang
- Department of Epidemiology and Biostatistics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Jiangsu Collaborative Innovation Center For Cancer Personalized Medicine, Cancer Center, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Linlin Yang
- Department of Hepatobiliary Surgery, Nantong Tumor Hospital, Nantong, China
| | - Jibin Liu
- Department of Hepatobiliary Surgery, Nantong Tumor Hospital, Nantong, China
| | - Li Liu
- Digestive Endoscopy Center, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Tingting Geng
- National Engineering Research Center for Miniaturized Detection Systems, Xi’an, China
| | - Chao Chen
- School of Life Sciences, Northwest University, Xi’an, China
- National Engineering Research Center for Miniaturized Detection Systems, Xi’an, China
| | - Jie Jiang
- Jiangsu Province Center for Disease Prevention and Control, Nanjing, China
| | - Jianguo Chen
- Department of Epidemiology, Qidong Liver Cancer Institute, Qidong, China
- Tumor Institute, Nantong Tumor Hospital, Nantong, China
| | - Fengcai Zhu
- Jiangsu Province Center for Disease Prevention and Control, Nanjing, China
| | - Yefei Zhu
- Jiangsu Province Center for Disease Prevention and Control, Nanjing, China
| | - Long Yu
- State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China
| | - Hongbing Shen
- Department of Epidemiology and Biostatistics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Jiangsu Collaborative Innovation Center For Cancer Personalized Medicine, Cancer Center, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Xiangjun Zhai
- Jiangsu Province Center for Disease Prevention and Control, Nanjing, China
| | - Jianfeng Xu
- State Key Laboratory of Genetic Engineering, Collaborative Innovation Center for Genetics and Development, School of Life Sciences, Fudan University, Shanghai, China
- Ministry of Education Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai, China
- Fudan Center for genetic Epidemiology and Center for Genetic Translational Medicine and Prevention, Fudan University, Shanghai, China
- Center for Cancer Genomics, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA
| | - Zhibin Hu
- Department of Epidemiology and Biostatistics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Jiangsu Collaborative Innovation Center For Cancer Personalized Medicine, Cancer Center, School of Public Health, Nanjing Medical University, Nanjing, China
- Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Nanjing Medical University Affiliated Cancer Hospital, Cancer Institute of Jiangsu Province, Nanjing, China
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22
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Du Y, Zhang YW, Pu R, Han X, Hu JP, Zhang HW, Wang HY, Cao GW. Phosphatase and tensin homologue genetic polymorphisms and their interactions with viral mutations on the risk of hepatocellular carcinoma. Chin Med J (Engl) 2015; 128:1005-13. [PMID: 25881591 PMCID: PMC4832937 DOI: 10.4103/0366-6999.155057] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Background: Chronic hepatitis B virus (HBV) infection is the major cause of hepatocellular carcinoma (HCC). Some HBV mutants and dysregulation of phosphatase and tensin homolog (PTEN) may promote the development of HCC synergistically. We aimed to test the effects of PTEN genetic polymorphisms and their interactions with important HBV mutations on the development of HCC in HBV-infected subjects. Methods: Quantitative polymerase chain reaction was applied to genotype PTEN polymorphisms (rs1234220, rs2299939, rs1234213) in 1012 healthy controls, 302 natural clearance subjects, and 2011 chronic HBV-infected subjects including 1021 HCC patients. HBV mutations were determined by sequencing. The associations of PTEN polymorphisms and their interactions with HBV mutations with HCC risk were assessed using multivariate logistic regression analysis. Results: Rs1234220 C allele was significantly associated with HCC risk compared to healthy controls (adjusted odds ratio [AOR] = 1.35, 95% confidence interval [CI] = 1.07–1.69) and HCC-free HBV-infected subjects (AOR = 1.27, 95% CI = 1.01–1.57). rs1234220 C allele was significantly associated with increased frequencies of HCC-risk A1652G, C1673T, and C1730G mutations in genotype B HBV-infected subjects. Rs2299939 GT genotype was inversely associated with HCC risk in HBV-infected patients (AOR = 0.75, 95% CI = 0.62–0.92). The interaction of rs2299939 variant genotypes (GT+TT) with A3054T mutation significantly increased HCC risk (AOR = 2.41, 95% CI = 1.08–5.35); whereas its interaction with C3116T mutation significantly reduced HCC risk (AOR = 0.34, 95% CI = 0.18–0.66). These significant effects were only evident in males after stratification. Conclusions: PTEN polymorphisms and their interactions with HBV mutations may contribute to hepatocarcinogenesis in males. The host-virus interactions are important in identifying HBV-infected subjects who are more likely to develop HCC.
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Affiliation(s)
| | | | | | | | | | | | | | - Guang-Wen Cao
- Department of Epidemiology, Second Military Medical University, Shanghai 200433, China
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23
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Li Z, Hou X, Cao G. Is mother-to-infant transmission the most important factor for persistent HBV infection? Emerg Microbes Infect 2015; 4:e30. [PMID: 26060603 PMCID: PMC4451268 DOI: 10.1038/emi.2015.30] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2015] [Revised: 03/24/2015] [Accepted: 04/06/2015] [Indexed: 02/06/2023]
Abstract
Of the infants born to hepatitis B surface antigen (HBsAg)-positive mothers globally, 42.1% who did not receive hepatitis B virus (HBV) passive-active immunoprophylaxis and 2.9% of infants who received the immunoprophylaxis acquired HBV infection perinatally. Moreover, perinatal infection occurred in 84.2% (18.8%-100%) and 8.7% (0.0-21.0%) of infants born to hepatitis B e-antigen (HBeAg)-positive mothers who did not and did receive immunoprophylaxis, respectively; by contrast, the infection rates were 6.7% (0.0-15.4%) and 0.4% (0.0-2.5%) for infants born to HBeAg-negative-carrier mothers, respectively. The chronicity rates of HBV infection acquired perinatally were 28.2% (17.4%-33.9%) in infants born to HBeAg-negative mothers and 64.5% (53.5%-100%) in infants born to HBeAg-positive mothers. HBV mother-to-child transmission was more frequent in East Asia relative to other areas. In addition to differences in the endemic HBV genotype, the interchange of allelic dominance in genetic polymorphisms in HLA class II and NF-κB between the Chinese and European populations may explain why chronic HBV infection frequently affects the Chinese. The risk of progressing into chronic infection was inversely related to the age of children at the time of horizontal transmission. To further diminish HBV chronic infection, it is necessary to enforce antiviral treatment after the 28th week of gestation for HBeAg-positive mothers and to improve the health habits of carrier mothers and household sanitary conditions.
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Affiliation(s)
- Zixiong Li
- Department of Epidemiology, Second Military Medical University , Shanghai 200433, China
| | - Xiaomei Hou
- Department of Epidemiology, Second Military Medical University , Shanghai 200433, China
| | - Guangwen Cao
- Department of Epidemiology, Second Military Medical University , Shanghai 200433, China
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