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Moudi B, Heidari Z, Mahmoudzadeh-Sagheb H. Impact of host gene polymorphisms on susceptibility to chronic hepatitis B virus infection. INFECTION GENETICS AND EVOLUTION 2016; 44:94-105. [DOI: 10.1016/j.meegid.2016.06.043] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/06/2016] [Revised: 06/21/2016] [Accepted: 06/22/2016] [Indexed: 12/15/2022]
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Rathakrishnan A, Klekamp B, Wang SM, Komarasamy TV, Natkunam SK, Sathar J, Azizan A, Sanchez-Anguiano A, Manikam R, Sekaran SD. Clinical and immunological markers of dengue progression in a study cohort from a hyperendemic area in Malaysia. PLoS One 2014; 9:e92021. [PMID: 24647042 PMCID: PMC3960168 DOI: 10.1371/journal.pone.0092021] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2014] [Accepted: 02/14/2014] [Indexed: 11/21/2022] Open
Abstract
Background With its elusive pathogenesis, dengue imposes serious healthcare, economic and social burden on endemic countries. This study describes the clinical and immunological parameters of a dengue cohort in a Malaysian city, the first according to the WHO 2009 dengue classification. Methodology and Findings This longitudinal descriptive study was conducted in two Malaysian hospitals where patients aged 14 and above with clinical symptoms suggestive of dengue were recruited with informed consent. Among the 504 participants, 9.3% were classified as non-dengue, 12.7% without warning signs, 77.0% with warning signs and 1.0% with severe dengue based on clinical diagnosis. Of these, 37% were misdiagnosed as non-dengue, highlighting the importance of both clinical diagnosis and laboratory findings. Thrombocytopenia, prolonged clotting time, liver enzymes, ALT and AST served as good markers for dengue progression but could not distinguish between patients with and without warning signs. HLA-A*24 and -B*57 were positively associated with Chinese and Indians patients with warning signs, respectively, whereas A*03 may be protective in the Malays. HLA-A*33 was also positively associated in patients with warning signs when compared to those without. Dengue NS1, NS2A, NS4A and NS4B were found to be important T cell epitopes; however with no apparent difference between with and without warning signs patients. Distinction between the 2 groups of patients was also not observed in any of the cytokines analyzed; nevertheless, 12 were significantly differentially expressed at the different phases of illness. Conclusion The new dengue classification system has allowed more specific detection of dengue patients, however, none of the clinical parameters allowed distinction of patients with and without warning signs. While the HLA-A*33 may be predictive marker for development of warning signs; larger studies will be needed to support this findings.
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Affiliation(s)
- Anusyah Rathakrishnan
- Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Benjamin Klekamp
- Department of Global Health, College of Public Health, University of South Florida, Tampa, Florida, United States of America
| | - Seok Mui Wang
- Institute of Medical Molecular Biotechnology, Faculty of Medicine, University Technology Mara, Selangor, Malaysia
| | - Thamil Vaani Komarasamy
- Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | | | - Jameela Sathar
- Clinical Hematology Laboratory, Department of Hematology, Hospital Ampang, Ampang, Selangor, Malaysia
| | - Azliyati Azizan
- Department of Global Health, College of Public Health, University of South Florida, Tampa, Florida, United States of America
| | - Aurora Sanchez-Anguiano
- Department of Global Health, College of Public Health, University of South Florida, Tampa, Florida, United States of America
| | - Rishya Manikam
- Department of Trauma and Emergency Medicine, University Malaya Medical Centre, Kuala Lumpur, Malaysia
| | - Shamala Devi Sekaran
- Department of Medical Microbiology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
- * E-mail:
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Chaaithanya IK, Muruganandam N, Anwesh M, Rajesh R, Ghosal SR, Kartick C, Prasad KN, Muthumani K, Vijayachari P. HLA class II allele polymorphism in an outbreak of chikungunya fever in Middle Andaman, India. Immunology 2013; 140:202-10. [PMID: 23710940 DOI: 10.1111/imm.12128] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2012] [Revised: 05/17/2013] [Accepted: 05/21/2013] [Indexed: 12/31/2022] Open
Abstract
A sudden upsurge of fever cases with joint pain was observed in the outpatient department, Community Health Centre, Rangat during July-August 2010 in Rangat Middle Andaman, India. The aetiological agent responsible for the outbreak was identified as chikungunya virus (CHIKV), by using RT-PCR and IgM ELISA. The study investigated the association of polymorphisms in the human leucocyte antigen class II genes with susceptibility or protection against CHIKV. One hundred and one patients with clinical features suggestive of CHIKV infection and 104 healthy subjects were included in the study. DNA was extracted and typed for HLA-DRB1 and DQB1 alleles. Based on the amino acid sequences of HLA-DQB1 retrieved from the IMGT/HLA database, critical amino acid differences in the specific peptide-binding pockets of HLA-DQB1 molecules were investigated. The frequencies of HLA-DRB1 alleles were not significantly different, whereas lower frequency of HLA-DQB1*03:03 was observed in CHIKV patients compared with the control population [P = 0·001, corrected P = 0·024; odds ratio (OR) = 0, 95% confidence interval (95% CI) 0·0-0·331; Peto's OR = 0·1317, 95% CI 0·0428-0·405). Significantly lower frequency of glutamic acid at position 86 of peptide-binding pocket 1 coding HLA-DQB1 genotypes was observed in CHIKV patients compared with healthy controls (P = 0·004, OR = 0·307, 95% CI 0·125-0·707). Computational binding predictions of CD4 epitopes of CHIKV by NetMHCII revealed that HLA-DQ molecules are known to bind more CHIKV peptides than HLA-DRB1 molecules. The results suggest that HLA-DQB1 alleles and critical amino acid differences in the peptide-binding pockets of HLA-DQB1 alleles might have role in influencing infection and pathogenesis of CHIKV.
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Role of HLA allele polymorphism in chronic hepatitis B virus infection and HBV vaccine sensitivity in patients from eastern Turkey. Biochem Genet 2010; 49:258-69. [PMID: 21188498 DOI: 10.1007/s10528-010-9404-6] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2010] [Accepted: 10/04/2010] [Indexed: 12/20/2022]
Abstract
Human leukocyte antigen (HLA) alleles have been associated with the clinical outcomes of hepatitis B virus (HBV) infection, which range from spontaneous recovery to hepatocellular carcinoma. In this study involving subjects from eastern Turkey, the frequencies of HLA-B35, HLA-CW4, HLA-DQ2, and HLA-DQ8 were markedly higher in the chronic HBV group than those in the spontaneously recovered group; the frequencies of HLA-A11 and HLA-A24 in the nonresponsive HBV vaccine group were markedly higher than those in the responsive HBV vaccine group; and the frequency of HLA-CW6 in the nonresponsive HBV vaccine group was significantly lower than in the responsive group. A complete understanding of HLA types associated with the progression to chronic HBV infection and their effects within the cell at the molecular level will be an important contribution in the development of new HBV vaccines and new treatment strategies for chronic HBV infection.
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Susceptible and protective HLA class 1 alleles against dengue fever and dengue hemorrhagic fever patients in a Malaysian population. PLoS One 2010; 5. [PMID: 20927388 PMCID: PMC2946915 DOI: 10.1371/journal.pone.0013029] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2010] [Accepted: 08/26/2010] [Indexed: 11/19/2022] Open
Abstract
Background The human leukocyte antigen alleles have been implicated as probable genetic markers in predicting the susceptibility and/or protection to severe manifestations of dengue virus (DENV) infection. In this present study, we aimed to investigate for the first time, the genotype variants of HLA Class 1(-A and -B) of DENV infected patients against healthy individuals in Malaysia. Methodology/Principal Findings This study was carried out with 92 dengue disease patients and 95 healthy controls from three different ethnic groups (Malay, Chinese and Indian) in Malaysia. All patients with clinical and laboratory confirmation of DENV infection were typed for the HLA-A and B loci, using polymerase chain reaction-sequence specific primer techniques. In our total population, a significant increase for HLA-B*53 (P = 0.042, Pc = 1.008) allele and a significant decrease for A*03 (P = 0.015, Pc = 0.18, OR = 5.23, 95% CI = 1.19–23.02) and B*18 (P = 0.017, Pc = 0.408) alleles were noted in DHF patients as compared to healthy donors. We also observed that in the Malay DHF patients, allele B*13 (P = 0.049, Pc = 1.176, OR = 0.18, 95% CI = 0.03–0.90) was present at a significantly higher frequency in this population while allele HLA-B*18 (P = 0.024, Pc = 0.576) was seen to be negatively associated with DHF. Conclusions/Significance These are the first findings on genetic polymorphisms in our population and we conclude that: (1) In our total population, HLA-B*53 probably involve in disease susceptibility, while the HLA-A*03 and HLA-B*18 may confer protection from progression to severe disease; (2) In the Malay population, HLA-B*13 and B*18 are probably associated in disease susceptibility and protection, respectively. These results could furnish as a valuable predictive tool to identify ethnically different individuals at risk and/or protection from severe forms of DENV infection and would provide valuable informations for the design of future dengue vaccine.
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Kim YJ, Lee HS. [Genetic epidemiological study on single nucleotide polymorphisms associated with hepatocellular carcinoma in patients with chronic HBV infection]. THE KOREAN JOURNAL OF HEPATOLOGY 2009; 15:7-14. [PMID: 19346781 DOI: 10.3350/kjhep.2009.15.1.7] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Hepatocellular carcinoma (HCC) is associated with hepatitis B virus (HBV) as an etiologic agent in 80% of cases, and is the major cause of death among HBV carriers. Family history of HCC is a known risk factor for the development of HCC among chronically HBV infected patients; therefore, genetic factors are likely to modify the risk of HCC. However, the genetic factors that determine progression to HCC remain mostly to be recovered. It is estimated that there are millions of single nucleotide polymorphisms (SNPs) within human genome and they are likely to explain much of the genetic diversity of individuals. In this review, the natural history of HBV infection and host genetic factors related to HCC, study design and target gene selection for the detection of SNPs related to the occurrence of HCC were discussed. Also, several SNPs or haplotypes, which were reportedly associated with increased or reduced risk of HCC occurrence in patients with chronic HBV infection, were reviewed. Especially, recent studies in Korea, one of the HBV endemic areas, were discussed. Screening of these polymorphisms might be useful in clinical practice to stratify the lower or higher risk group for HCC and might modify the design of HCC surveillance programs in patients with chronic HBV infection, if further genetic susceptibilities are identified. The ongoing studies of the distributions and functions of the implicated allele polymorphisms will not only provide insight into the pathogenesis of HCC, but may also provide a novel rationale for new methods of diagnosis and therapeutic strategies.
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Affiliation(s)
- Yoon Jun Kim
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea.
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Liu M, Cao B, Zhang H, Dai Y, Liu X, Xu C. Association of interferon-gamma gene haplotype in the Chinese population with hepatitis B virus infection. Immunogenetics 2006; 58:859-64. [PMID: 17033822 DOI: 10.1007/s00251-006-0161-y] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2006] [Accepted: 09/07/2006] [Indexed: 11/25/2022]
Abstract
In general, cytokines encoded by different genes of human genome might strongly influence host cell-mediated immune responses, which play an important role in the clearance of virus by the infected host. Interferon gamma (IFN-gamma) produced by T lymphocytes and natural killer cells plays an essential role in affecting cellular immune responses. A functional study demonstrated that two single nucleotide polymorphisms located in the IFN-gamma gene intron (at positions +874 and +2109) were involved in its transcriptional regulation. The aim of this study was to evaluate whether IFN-gamma gene polymorphisms or its haplotypes might be associated with predisposition to hepatitis B virus (HBV) infection in the Chinese population. The study included 181 cases with HBV infection and 272 gender, age-matched healthy controls. All genotyping were identified by polymerase chain reaction in association with the measurement of amplification refractory mutation system. A significant difference was observed between case and control groups. The frequency of +874A allele was significantly higher in patients than in controls (OR = 2.25, 95%CI = 1.69-2.99, P < 0.0001). However, no significant difference was found in the allelic frequencies of IFN-gamma +2109A/G between cases and controls (P > 0.05). By haplotype analysis, the frequency of haplotype AG (+874A and +2109G) revealed a significant difference in the cases in comparison to controls (P < 0.0001). Multiple logistic regression analysis showed that individuals possessing haplotype AG had an increased likelihood of HBV infection (OR = 8.14, 95%CI = 4.98-13.30). Our results suggest that haplotype AG containing +874A and +2109G may be a crucial risk factor of genetic susceptibility to HBV infection in the Chinese population.
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Affiliation(s)
- Meiqiang Liu
- Medical College, Shandong University, Jinan, Shandong Province, China
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Chaturvedi U, Nagar R, Shrivastava R. Dengue and dengue haemorrhagic fever: implications of host genetics. ACTA ACUST UNITED AC 2006; 47:155-66. [PMID: 16831202 DOI: 10.1111/j.1574-695x.2006.00058.x] [Citation(s) in RCA: 69] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Little is known of the role of human leucocyte antigen (HLA) alleles or non-HLA alleles in determining resistance, susceptibility or the severity of acute viral infections. Dengue fever (DF) and dengue haemorrhagic fever (DHF) are suitable models for immunogenetic studies, yet only superficial efforts have been made to study dengue disease to date. DF and DHF can be caused by both primary and secondary infection by any of the four serotypes of the dengue virus. Differences in host susceptibility to infectious disease and disease severity cannot be attributed solely to the virus virulence. Variations in immune response, often associated with polymorphism in the human genome, can now be detected. Data on the influence of human genes in DF and DHF are discussed here in relation to (1) associations between HLA polymorphism and dengue disease susceptibility or resistance, (2) protective alleles influencing progression to severe disease, (3) alleles restricting CD4(+) and CD8(+) T lymphocytes, and (4) non-HLA genetic factors that may contribute to DHF evolution. Recent discoveries regarding genetic associations in other viral infections may provide clues to understanding the development of end-stage complications in dengue disease. The scanty positive data presented here indicate a need for detailed genetic studies in different ethnic groups in different countries during the acute phase of DF and DHF on a larger number of patients.
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Affiliation(s)
- Umeshc Chaturvedi
- Department of Microbiology, K.G. Medical University, Lucknow, India.
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Kim YJ, Lee HS. Single Nucleotide Polymorphisms Associated with Hepatocellular Carcinoma in Patients with Chronic Hepatitis B Virus Infection. Intervirology 2005; 48:10-5. [PMID: 15785084 DOI: 10.1159/000082089] [Citation(s) in RCA: 36] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
It is estimated that there are millions of single nucleotide polymorphisms (SNPs) within human genome and there are likely to explain much of the genetic diversity of individuals. Hepatocellular carcinoma (HCC) is etiologically associated with hepatitis B virus (HBV) in 80% of cases, and is the dominant cause of death among HBV carriers. Among patients with chronic HBV infection, family history is a known risk factor for the development of HCC; therefore, genetic factors are likely to modify the risk of HCC. However, the genetic factors that determine progression to HCC remain mostly to be investigated. In this review, we discussed that the natural history of HBV infection and host genetic factors related to HCC, study design and target gene selection for the detection of SNPs related to the occurrence of HCC. Also, we reviewed that several SNPs or haplotypes, which were reportedly associated with increased or reduced risk of HCC occurrence in patients with chronic HBV infection. Screening of these polymorphisms might be useful in clinical practice to stratify the lower or higher risk group for HCC and might modify the design of HCC surveillance programs in patients with chronic HBV infection, if further genetic susceptibilities are identified.
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Affiliation(s)
- Yoon Jun Kim
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea
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Wang FS. Current status and prospects of studies on human genetic alleles associated with hepatitis B virus infection. World J Gastroenterol 2003; 9:641-4. [PMID: 12679901 PMCID: PMC4611419 DOI: 10.3748/wjg.v9.i4.641] [Citation(s) in RCA: 94] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Chronic hepatitis B virus (HBV) infection can cause a broad spectrum diseases, including from asymptomatic HBV carriers or cryptic hepatitis, to acute hepatitis, chronic hepatitis, Liver cirrhosis and primary hepatocellular carcinoma. The variable pattern and clinical outcome of the infection were mainly determined by virological itself factors, host immunological factors and genetic factors as well as the experimental factors. Among the human genetic factors, major candidate or identified genes involved in the process of HBV infection fall into the following categories: (1) genes that mediate the processes of viral entry into hepatocytes, including genes involved in viral binding, fusion with cellular membrane and transportation in target cells; (2) genes that modulate or control the immune response to HBV infection; (3) genes that participate in the pathological alterations in liver tissue; (4) genes involved in the development of liver cirrhosis and hepatocellular carcinoma associated with chronic HBV infection, including genes related to mother-to-infant transmission of HBV infection; and (5) those that contribute to resistance to antiviral therapies. Most of the reports of human genes associated with HBV infection have currently focused on HLA associations. For example, some investigators reported the association of the HLA class II alleles such as DRB1*1302 or HLA-DR13 or DQA1*0501-DQB1*0301-DQB1*1102 haplotypes with acute and/or chronic hepatitis B virus infection, respectively. Several pro-inflammatory cytokines such as Th1 cytokines (including IL-2 and IFN-γ) and TNF-α have been identified to participate the process of viral clearance and host immune response to HBV. In contrast, the Th2 cytokine IL-10 serves as a potent inhibitor of Th1 effector cells in HBV diseases. The MBP polymorphisms in its encoding region were found to be involved in chronic infection. Thus, reports from various laboratories have shown some inconsistencies with regard to the effects of host genetic factors on HBV clearance and persistence. Since genetic interactions are complex, it is unlikely that a single allelic variant is responsible for HBV resistance or susceptibility. However, the collective influence of several single nucleotide polymorphisms (SNPs) or haplotype (s) may underlie the natural combinational or synergistic protection against HBV. The future study including the multi-cohort collaboration will be needed to clarify these preliminary associations and identify other potential candidate genes. The ongoing study of the distributions and functions of the implicated allele polymorphisms will not only provide insight into the pathogenesis of HBV infection, but may also provide a novel rationale for new methods of diagnosis and therapeutic strategies.
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Affiliation(s)
- Fu-Sheng Wang
- Division of Bioengineering, Beijing Institute of Infectious Diseases, 100 Xi Si-Huan-Zhong Road, Beijing 100039, China.
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