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Artemova MG, Abdurakhmanov DT. [Cryoglobulinemic vasculitis in chronic hepatitis C: Genetic aspects]. TERAPEVT ARKH 2019; 89:110-114. [PMID: 28514410 DOI: 10.17116/terarkh2017894110-114] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Cryoglobulinemia (CG) is detected in more than 50% of patients with chronic hepatitis C (CHC); however, only 15-25% of them develop cryoglobulinemic vasculitis (CV) that is a systemic vasculitis due to the formation of immune deposits, which affects small (less than medium-sized) vessels and which is frequently fatal for the patient. The causes of CG only in some patients with CHC and the pathogenesis of CV remain unstudied; however, the accumulated data allow one to identify the special contribution of the patient's genetic factors to the development of the disease. The paper considers the genetic aspects of the development of CG and CV in CHC.
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Affiliation(s)
- M G Artemova
- M.V. Lomonosov Moscow State University, Moscow, Russia
| | - D T Abdurakhmanov
- I.M. Sechenov First Moscow State Medical University, Ministry of Health of Russia, Moscow, Russia
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Ponzetto A, Holton J, Vaira D. Letter: years of life that could be saved by preventing HCC. Aliment Pharmacol Ther 2017; 45:375-376. [PMID: 27933689 DOI: 10.1111/apt.13853] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/08/2022]
Affiliation(s)
- A Ponzetto
- Department of Medical Science, University of Turin, Torino, Italy
| | - J Holton
- National Mycobacterial Reference Unit, National Mycobacterium Reference Laboratory, Abernethy Building, Institute of Cell and Molecular Science, London, UK
| | - D Vaira
- Department of Medical and Surgical Sciences, S. Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
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Association between interleukin-18 gene promoter (- 607C/A and - 137G/C) polymorphisms and chronic hepatitis C virus infections: A meta-analysis. Meta Gene 2015; 5:21-31. [PMID: 26042207 PMCID: PMC4443429 DOI: 10.1016/j.mgene.2015.04.004] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2015] [Revised: 04/24/2015] [Accepted: 04/24/2015] [Indexed: 02/05/2023] Open
Abstract
Objective HCV infection has a chronicity rate of about 70%, several studies have shown that interleukin-18 (IL-18) was associated with etiology and progression of hepatitis C virus (HCV) infections. However, the association between single-nucleotide polymorphisms − 607C/A (rs1946518) and − 137G/C (rs187238) located in the IL-18 gene promoter and chronic hepatitis C virus infections was still controversial and ambiguous. To derive a more precise effect on the association between these polymorphisms and chronic hepatitis C virus infections, we performed this first meta-analysis based on the currently available evidence of the literature. Methods A total of 4 studies with 1222 cases and 1115 controls for − 607C/A polymorphism and 3 studies with 959 cases and 987 controls for − 137G/C polymorphism were identified to perform a meta-analysis. Summary ORs and corresponding 95% CIs for IL-18 polymorphisms and chronic hepatitis C virus infections were estimated using fixed- and random-effects models when appropriate. Heterogeneity, sensitivity analysis, and publication bias were evaluated. Results We found a significant association between − 137G/C polymorphism and chronic hepatitis C virus infections (CG + CC versus GG: OR = 2.157, 95% CI [1.822, 2.553]; CC versus CG + GG: OR = 2.007, 95% CI [1.441, 2.797]). However, no significant association was observed between − 607C/A polymorphism and chronic hepatitis C virus infections under different contrast models. Conclusions The present meta-analysis suggested that IL-18 − 137G/C polymorphism in promoter region was associated with chronic hepatitis C virus infections, but no evidence indicate association between − 607C/A polymorphism and chronic hepatitis C virus infections. High-quality studies with larger sample size and larger number are warranted.
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Houldsworth A, Metzner M, Hodgkinson A, Shaw S, Kaminski E, Demaine AG, Cramp ME. Haplotype analysis finds linkage disequilibrium in the IL-12 gene in patients with HCV. J Med Virol 2015; 87:1207-17. [PMID: 25908236 DOI: 10.1002/jmv.24179] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/30/2015] [Indexed: 12/27/2022]
Abstract
HCV is a major cause of liver disease worldwide. IL-12 plays an essential role in the balance of T helper 1 (Th1) differentiation versus a T helper 2 (Th2) driven response from its naïve precursor. Linkage disequilibrium measures the degree to which alleles at two loci are associated and the non-random associations between alleles at two loci. Haplotypes of the three IL-12B loci studied were determined in the patient cases and the normal healthy control subjects. The frequency of the 12 possible IL-12B haplotypes on the 3 loci was determined in subjects heterozygous at only one of the loci within the studied haplotype. Haplotype frequencies were compared between the patient groups and controls (n = 49) to determine if any preferential combination of markers occurred using chi-squared and applying the Bonferroni correction. 45 HCV RNA negative patients; 88 HCV RNA positive patients; and 15 uninfected cases at high risk of HCV infection (EU) were studied. The haplotype "C" SNP of the 3'UTR with the "E" 4 bp deletion of the intron 4 region was in linkage disequilibrium (χ(2) = 45.15, P < 0.001, 95% CL). The haplotype analysis of the insertion allele of the promoter with the deletion allele of the intron 4("E") IL-12B polymorphism showed linkage disequilibrium (χ(2) = 5.64, P = 0.02). Linkage disequilibrium of polymorphisms is reported in the IL-12 gene in patients with HCV infection and contributes to the understanding of patient genotype and expected production of IL-12, responding to infection.
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Affiliation(s)
- Annwyne Houldsworth
- Hepatology and Molecular Medicine Research Groups, Peninsula Medical School, Plymouth, United Kingdom
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Akıncı E, Bodur H, Muşabak U, Sağkan RI. The relationship between the human leukocyte antigen system and Crimean-Congo hemorrhagic fever in the Turkish population. Int J Infect Dis 2013; 17:e1038-41. [PMID: 23911239 DOI: 10.1016/j.ijid.2013.06.005] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2013] [Revised: 05/29/2013] [Accepted: 06/03/2013] [Indexed: 11/29/2022] Open
Abstract
OBJECTIVES The human leukocyte antigen (HLA) molecules have been shown to be important genetic factors in several diseases. In this study we aimed to evaluate the possible role of HLA genes in the course of Crimean-Congo hemorrhagic fever (CCHF) infection. METHODS A total of 57 adult patients with CCHF and 43 healthy controls living in the same regions as the patients were included in the study. Severe cases were defined according to previously reported severity criteria. RESULTS The frequency of HLA-A*02 was found to be significantly higher in the patients than in the healthy controls (p=0.021). However, a significantly lower frequency of HLA-B*27 was observed in the patients than in the healthy controls (p=0.01). The relative risk (RR) of HLA-A*02 allele for CCHF was found to be 1.93 (95% confidence interval 1.11 < RR < 3.36). With regard to severe and non-severe cases, there was a significantly greater frequency of HLA-A*23 in severe cases (p=0.014). CONCLUSIONS The results of this study indicate that while some HLA alleles could constitute a risk factor for acquiring CCHF infection, others could have a protective role against the disease. This study also presents the impact of genetic risk factors on the clinical course of the disease.
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Affiliation(s)
- Esragül Akıncı
- Ankara Numune Education And Research Hospital, Infectious Diseases and Clinical Microbiology Department, 06100 Sıhhiye, Ankara, Turkey.
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Ramezani A, Banifazl M, Mamishi S, Sofian M, Eslamifar A, Aghakhani A. The influence of human leukocyte antigen and IL-10 gene polymorphisms on hepatitis B virus outcome. HEPATITIS MONTHLY 2012; 12:320-5. [PMID: 22783343 PMCID: PMC3389357 DOI: 10.5812/hepatmon.6094] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 01/17/2012] [Revised: 03/18/2012] [Accepted: 04/29/2012] [Indexed: 12/11/2022]
Abstract
CONTEXT The clinical outcome of hepatitis B virus (HBV) infection is variable, ranging from spontaneous recovery to an inactive carrier state, chronic hepatitis, occult HBV infection, liver cirrhosis, or hepatocellular carcinoma. EVIDENCE ACQUISITION This variable pattern and clinical outcomes of the infection were mainly determined by virological and host genetic factors. Since the most of host genetic factors associated with HBV infection have currently focused on human leukocyte antigen (HLA) associations and interleukin (IL)-10 gene polymorphisms, this review focuses on the recent progresses in these issues to provide prognostic markers for the outcome of HBV infection. RESULTS A study on serum levels of IL-10 in occult HBV infected patients reported that the higher level of IL-10 production may suppress function of the immune system against HBV in patients with occult HBV infection. IL-10 promoter polymorphism at position -592 is associated with susceptibility to occult HBV infection. CONCLUSIONS Findings of this study suggest that the host HLA polymorphism is an important factor in determining outcome of HBV infection but regarding IL-10 gene promoter polymorphisms, we are still have a long way to achieve a definite conclusion.
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Affiliation(s)
- Amitis Ramezani
- Clinical Research Department, Pasteur Institute of Iran, Tehran, IR Iran
- Pediatric Infectious Disease Research Center, Tehran University of Medical sciences, Tehran, IR Iran
| | - Mohammad Banifazl
- Iranian Society for Support of Patients with Infectious Disease, Tehran, IR Iran
| | - Setareh Mamishi
- Pediatric Infectious Disease Research Center, Tehran University of Medical sciences, Tehran, IR Iran
| | - Masoomeh Sofian
- TPIRC (Tuberculosis and Pediatric Infectious Research Center), Arak University of Medical Sciences, Arak, IR Iran
| | - Ali Eslamifar
- Clinical Research Department, Pasteur Institute of Iran, Tehran, IR Iran
| | - Arezoo Aghakhani
- Clinical Research Department, Pasteur Institute of Iran, Tehran, IR Iran
- Corresponding author: Arezoo Aghakhani, Clinical Research Department., Pasteur Institute of Iran, Tehran, IR Iran. Tel.: +98-2166968852, Fax: +98-2166465147, E-mail:
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Cangussu LOF, Teixeira R, Campos EF, Rampim GF, Mingoti SA, Martins-Filho OA, Gerbase-DeLima M. HLA class II alleles and chronic hepatitis C virus infection. Scand J Immunol 2011; 74:282-287. [PMID: 21535077 DOI: 10.1111/j.1365-3083.2011.02568.x] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
The aim of this study was to investigate association of human leucocyte antigens (HLA)-DRB1 and DQB1 polymorphisms with hepatitis C virus (HCV) infection and with the occurrence of severe liver fibrosis/cirrhosis in chronically infected patients. Ninety-nine white patients, from southeast Brazil, with confirmed HCV chronic infection were included in the study. Severe fibrosis/cirrhosis (METAVIR scores F3-F4) was present in 49 patients. HLA-DRB1 specificities and DRB1*11 and DQB1* alleles were determined by PCR-SSP, and their frequencies were compared between patients and a control group of 103 healthy white Brazilian individuals. The results confirmed previous reports of the association of DRB1*11 and DQB1*03 with protection from chronic HCV infection, but did not confirm their association with protection from severe fibrosis/cirrhosis. Furthermore, the results suggested that the polymorphic sites on HLA molecules responsible for protection from chronic HCV infection are encoded not only by the DRB1*1101 and DQB1*0301, as suggested in the literature, but also by other DRB1*11 and DQB1*03 alleles. Thus, we hypothesized that the common polymorphic residues shared by different DRB1*11 and/or DQB1*03 alleles might be responsible for selection of viral epitopes for presentation to CD4(+) T cells, leading to an efficient immune response against the virus.
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Affiliation(s)
- L O F Cangussu
- Viral Hepatitis Division, Instituto Alfa de Gastroenterologia, Hospital das Clínicas/UFMG, Belo Horizonte, Minas Gerais, BrazilInternal Medicine Department, School of Medicine, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, BrazilImmunogenetics Division, Pediatrics Departament, Escola Paulista de Medicina, Federal University of São Paulo, São Paulo, São Paulo, BrazilInstituto de Ciencias Exatas, ICEX, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, BrazilLaboratório de Biomarcadores de Diagnóstico e Monitoração, Centro de Pesquisas René Rachou, Fundação Oswaldo Cruz, Belo Horizonte, Minas Gerais, Brazil
| | - R Teixeira
- Viral Hepatitis Division, Instituto Alfa de Gastroenterologia, Hospital das Clínicas/UFMG, Belo Horizonte, Minas Gerais, BrazilInternal Medicine Department, School of Medicine, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, BrazilImmunogenetics Division, Pediatrics Departament, Escola Paulista de Medicina, Federal University of São Paulo, São Paulo, São Paulo, BrazilInstituto de Ciencias Exatas, ICEX, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, BrazilLaboratório de Biomarcadores de Diagnóstico e Monitoração, Centro de Pesquisas René Rachou, Fundação Oswaldo Cruz, Belo Horizonte, Minas Gerais, Brazil
| | - E F Campos
- Viral Hepatitis Division, Instituto Alfa de Gastroenterologia, Hospital das Clínicas/UFMG, Belo Horizonte, Minas Gerais, BrazilInternal Medicine Department, School of Medicine, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, BrazilImmunogenetics Division, Pediatrics Departament, Escola Paulista de Medicina, Federal University of São Paulo, São Paulo, São Paulo, BrazilInstituto de Ciencias Exatas, ICEX, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, BrazilLaboratório de Biomarcadores de Diagnóstico e Monitoração, Centro de Pesquisas René Rachou, Fundação Oswaldo Cruz, Belo Horizonte, Minas Gerais, Brazil
| | - G F Rampim
- Viral Hepatitis Division, Instituto Alfa de Gastroenterologia, Hospital das Clínicas/UFMG, Belo Horizonte, Minas Gerais, BrazilInternal Medicine Department, School of Medicine, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, BrazilImmunogenetics Division, Pediatrics Departament, Escola Paulista de Medicina, Federal University of São Paulo, São Paulo, São Paulo, BrazilInstituto de Ciencias Exatas, ICEX, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, BrazilLaboratório de Biomarcadores de Diagnóstico e Monitoração, Centro de Pesquisas René Rachou, Fundação Oswaldo Cruz, Belo Horizonte, Minas Gerais, Brazil
| | - S A Mingoti
- Viral Hepatitis Division, Instituto Alfa de Gastroenterologia, Hospital das Clínicas/UFMG, Belo Horizonte, Minas Gerais, BrazilInternal Medicine Department, School of Medicine, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, BrazilImmunogenetics Division, Pediatrics Departament, Escola Paulista de Medicina, Federal University of São Paulo, São Paulo, São Paulo, BrazilInstituto de Ciencias Exatas, ICEX, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, BrazilLaboratório de Biomarcadores de Diagnóstico e Monitoração, Centro de Pesquisas René Rachou, Fundação Oswaldo Cruz, Belo Horizonte, Minas Gerais, Brazil
| | - O A Martins-Filho
- Viral Hepatitis Division, Instituto Alfa de Gastroenterologia, Hospital das Clínicas/UFMG, Belo Horizonte, Minas Gerais, BrazilInternal Medicine Department, School of Medicine, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, BrazilImmunogenetics Division, Pediatrics Departament, Escola Paulista de Medicina, Federal University of São Paulo, São Paulo, São Paulo, BrazilInstituto de Ciencias Exatas, ICEX, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, BrazilLaboratório de Biomarcadores de Diagnóstico e Monitoração, Centro de Pesquisas René Rachou, Fundação Oswaldo Cruz, Belo Horizonte, Minas Gerais, Brazil
| | - M Gerbase-DeLima
- Viral Hepatitis Division, Instituto Alfa de Gastroenterologia, Hospital das Clínicas/UFMG, Belo Horizonte, Minas Gerais, BrazilInternal Medicine Department, School of Medicine, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, BrazilImmunogenetics Division, Pediatrics Departament, Escola Paulista de Medicina, Federal University of São Paulo, São Paulo, São Paulo, BrazilInstituto de Ciencias Exatas, ICEX, Federal University of Minas Gerais, Belo Horizonte, Minas Gerais, BrazilLaboratório de Biomarcadores de Diagnóstico e Monitoração, Centro de Pesquisas René Rachou, Fundação Oswaldo Cruz, Belo Horizonte, Minas Gerais, Brazil
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Pár A. [Genetic polymorphisms as predictors of response to antiviral treatment in chronic hepatitis C virus infection]. Orv Hetil 2011; 152:876-81. [PMID: 21565755 DOI: 10.1556/oh.2011.29113] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
The review discusses the genetic polymorphisms involved in the pathogenesis of hepatitis C virus (HCV) infection, that may determine the outcome of disease. In this field earlier both certain major histocompatibility complex (MHC) alleles and some cytokine gene variants have also been studied. Recently, the genome-wide association study (GWAS) and targeted single nucleotide polymorphism (SNP) analysis have revealed that a variant in the promoter region of interleukin-28B (IL-28B) gene is strongly linked to viral clearance and it may be the strongest pretreatment predictor of treatment response in chronic hepatitis C. Last year it was shown that two genetic variants leading to inosine triphosphatase deficiency protect against haemolytic anemia in patients receiving ribavirin during antiviral treatment for chronic HCV infection.
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Affiliation(s)
- Alajos Pár
- Pécsi Tudományegyetem, Általános Orvostudományi Kar, Klinikai Központ I. Belgyógyászati Klinika Pécs Ifjúság u. 13. 7624.
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Mosaad YM, Farag RE, Arafa MM, Eletreby S, El-Alfy HA, Eldeek BS, Tawhid ZM. Association of human leucocyte antigen Class I (HLA-A and HLA-B) with chronic hepatitis C virus infection in Egyptian patients. Scand J Immunol 2011; 72:548-53. [PMID: 21044129 DOI: 10.1111/j.1365-3083.2010.02468.x] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
Egypt has the highest prevalence of hepatitis C virus (HCV) in the world, ranging from 6% to 28% with an average of approximately 13.8% in the general population. It has been reported that human leucocyte antigen (HLA) alleles are associated with the outcome of HCV infection, but this associations showed ethnic and geographical differences. The objective of this study is to investigate the association between the frequencies of HLA Class I and chronic HCV infection in Egyptian patients and to find out whether there is a relation between certain HLA Class I antigens and HCV viral load, degree of fibrosis, activity and alanine aminotransferase (ALT) level. A case control study was conducted on 100 patients with chronic HCV infection and 150 healthy controls. HLA-A and HLA-B typing by complement-dependent micro-lympho-cytotoxicity assay was performed for both groups. HLA-A11 antigen was significantly increased in patients with chronic HCV infection versus controls (OR 3.98; 95% CI = 1.85-8.89; P = 0.001; and Pc = 0.021). HLA-B12, HLA-B13, HLA-B17 and HLA-B40 were higher in patients, and HLA-A32 and HLA-B14 were higher in controls, although the significance was lost after correction for multiple testing. HLA-A9 was significantly associated with low viral load (P = 0.008, Pc = 0.048). The results of this work implicate that HLA-A11 antigen may influence chronic HCV infection and may play a role in viral persistence. Different HLA Class I antigens are not associated with degree of liver fibrosis, grades of activity or level of ALT. However, HLA-A9 is associated with low HCV viral load in chronic HCV Egyptian patients.
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Affiliation(s)
- Y M Mosaad
- Clinical Immunology Unit, Clinical Pathology Department, Mansoura Faculty of Medicine, Mansoura University, Mansoura, Egypt.
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Blair CS, Haydon GH, Hayes PC. Section Review Anti-infectives: Current perspectives on the treatment and prevention of hepatitis C infection. Expert Opin Investig Drugs 2008. [DOI: 10.1517/13543784.5.12.1657] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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Muratori P, Czaja AJ, Muratori L, Granito A, Guidi M, Ferri S, Volta U, Mantovani W, Pappas G, Cassani F, Lenzi M, Bianchi FB. Evidence of a genetic basis for the different geographic occurrences of liver/kidney microsomal antibody type 1 in hepatitis C. Dig Dis Sci 2007; 52:179-84. [PMID: 17160474 DOI: 10.1007/s10620-006-9495-4] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2006] [Accepted: 06/19/2006] [Indexed: 12/11/2022]
Abstract
Antibodies to liver/kidney microsome type 1 occur in Italian patients with hepatitis C, but rarely develop in North American patients. Our goals were to compare the frequencies of the HLA markers associated with autoimmune expression in Italian and North American patients with chronic hepatitis C and to determine genetic bases for regional differences in antibody production. HLA B8, DR3, DR4, DR7, DR11, DR13, DQ2, and the B8-DR3-DQ2 haplotype were determined by microlymphocytotoxicity and polymerase chain reaction in 105 Italian patients (50 with microsomal antibodies), 100 North American patients (none with microsomal antibodies), and Italian and North American healthy control subjects. Italian patients with microsomal antibodies differed from North American patients without these antibodies by having a higher frequency of HLA DR7 (54% vs. 27%, P=0.002). HLA DR7 occurred more frequently in seropositive Italian patients than in seronegative counterparts (54% vs. 11% P < 0.0001), Italian healthy control subjects (54% vs. 29%, P=0.0009), and North American healthy control subjects (54% vs. 19%, P < 0.0001). The frequency of HLA DR7 was similar in North American patients and controls (27% vs. 19%, P=0.2), but it was lower than in Italian controls (19% vs. 29%, P=0.059). Seropositive Italian patients had a lower frequency of HLA DR11 than seronegative Italian patients and Italian controls (18% vs. 34%, P=0.07, and 18% vs. 35%, P=0.02, respectively). In contrast to seropositive Italian patients, North American patients had HLA DR4 (30% vs. 12%, P=0.02), HLA DR13 (29% vs. 10%, P=0.01), and the B8-DR3-DQ2 haplotype (23% vs. 6%, P=0.01) more often. Similarly, HLA DR4 and the B8-DR3-DQ2 phenotype were more frequent in North American patients than in Italian controls (30% vs. 16%, P=0.005, and 23% vs. 7%, P=0.00002, respectively). HLA DR7 is associated with the development of microsomal antibodies in Italian patients with chronic hepatitis C. The lower frequency of HLA DR7 in North America could contribute to the rarity of these antibodies in this region. HLA DR11 may be protective against the development of microsomal antibodies in Italian patients, whereas HLA DR4, HLA DR13, and the B8-DR3-DQ2 haplotype may be protective in North American patients.
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Affiliation(s)
- Paolo Muratori
- Department of Internal Medicine, Cardioangiology, Hepatology, Policlinico Sant'Orsola-Malpighi, Bologna, Italy.
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El-Sayed HH, Amin Husse N, Yousef Gha L, Megeed Lot AA, Raouf Raaf MA. Clinical Spectrum of Hepatitis-Associated Cryoglobulinemia: Cross-Link between Hematological and Immunological Phenomena. JOURNAL OF MEDICAL SCIENCES 2006. [DOI: 10.3923/jms.2007.31.41] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
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Yoon SK, Han JY, Pyo CW, Yang JM, Jang JW, Kim CW, Chang UI, Bae SH, Choi JY, Chung KW, Sun HS, Choi HB, Kim TG. Association between human leukocytes antigen alleles and chronic hepatitis C virus infection in the Korean population. Liver Int 2005; 25:1122-7. [PMID: 16343061 DOI: 10.1111/j.1478-3231.2005.01105.x] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/13/2023]
Abstract
BACKGROUND/AIM Recent data have shown that the clinical outcome of hepatitis C virus (HCV) infection may be influenced by the host genetic factor. The aim of this study was to investigate whether particular human leukocytes antigen (HLA) molecules are associated with the susceptibility to HCV infection in the Korean population. METHODS One hundred and thirty-seven patients with chronic HCV infection and 206 normal individuals were examined for HLA class I and II molecules. RESULTS In class I antigens, the frequencies of HLA-A3 (relative risk (RR)=3.5, P<0.04), HLA-B35 (RR=2.0, P<0.03), and HLA-B46 (RR=2.5, P<0.02) significantly increased in chronic HCV carriers compared with the controls. The frequencies of DRB1*0803, DQB1*0601 and DQB1*0604 were significantly higher in chronic HCV carriers than in controls (RR=2.5, P<0.005; RR=1.8, P<0.05; RR=1.9, P<0.04, respectively). On the other hand, the frequencies of DRB1*0301, DQA1*0501 and DQB1*0201 were significantly lower in chronic HCV carriers than in normal controls (RR=0.2, P<0.03; RR=0.4, P<0.004; RR=0.5, P<0.02, respectively). The haplotype DRB1*0803-DQB1*0601 significantly increased (RR=2.5, P<0.02) while the DQA1*0501-DQB1*0201 significantly decreased (RR=0.2, P<0.03) in chronic HCV carriers compared with normal controls. In stratification analysis to investigate the interrelationships among the associated alleles, DRB1*0803 and DQB1*0601 were associated with HLA-B46, particularly in patients with chronic HCV carriers. CONCLUSIONS These results suggest that particular HLA alleles may have an influence on chronic HCV infection as a host genetic factor in the Korean population.
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Affiliation(s)
- Seung Kew Yoon
- Department of Internal Medicine, WHO Collaborating Center for Reference and Research on Viral Hepatitis, Seoul, Korea
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Abstract
In addition to viral and environmental/behavioural factors, host genetic diversity is believed to contribute to the spectrum of clinical outcomes in hepatitis C virus (HCV) infection. This paper reviews the literature with respect to studies of host genetic determinants of HCV outcome and attempts to highlight trends and synthesise findings. With respect to the susceptibility to HCV infection, several studies have replicated associations of the HLA class II alleles DQB1(*)0301 and DRB1(*)11 with self-limiting infection predominantly in Caucasian populations. Meta-analyses yielded summary estimates of 3.0 (95% CI: 1.8-4.8) and 2.5 (95% CI: 1.7-3.7) for the effects of DQB1(*)0301 and DRB1(*)11 on self-limiting HCV, respectively. Studies of genetics and the response to interferon-based therapies have largely concerned single-nucleotide polymorphisms and have been inconsistent. Regarding studies of genetics and the progression of HCV-related disease, there is a trend with DRB1(*)11 alleles and less severe disease. Studies of extrahepatic manifestations of chronic HCV have shown an association between DQB1(*)11 and DR3 with the formation of cryoglobulins. Some important initial observations have been made with respect to genetic determinants of HCV outcome. Replication studies are needed for many of these associations, as well as biological data on the function of many of these polymorphisms.
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Affiliation(s)
- L J Yee
- Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA.
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Airoldi A, Zavaglia C, Silini E, Tinelli C, Martinetti M, Asti M, Rossini A, Vangeli M, Salvaneschi L, Pinzello G. Lack of a strong association between HLA class II, tumour necrosis factor and transporter associated with antigen processing gene polymorphisms and virological response to alpha-interferon treatment in patients with chronic hepatitis C. ACTA ACUST UNITED AC 2004; 31:259-65. [PMID: 15548263 DOI: 10.1111/j.1365-2370.2004.00478.x] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
The aim of the study was to investigate whether polymorphisms of the HLA class II, tumour necrosis factor (TNF) and transporter associated with antigen processing (TAP) genes influence the response to alpha-interferon in patients with chronic hepatitis C. Twenty-seven sustained responders and 55 non-responders to alpha-interferon monotherapy were investigated. HLA-DRB1, DQA1, DQB1, TNFA, TNFB, TAP1 and TAP2 alleles were determined by PCR-based molecular techniques. Sustained virological response was defined as undetectable serum hepatitis C virus (HCV) RNA for at least 3 years after the end of treatment. Probability (P) values were corrected for the number of alleles tested (Pc). Viral genotype 1b was more frequent in responders than in non-responders (56% vs. 26%, P = 0.009). HLA-DQB1*02 occurred less frequently in responders than in non-responders (14.8% vs. 29%, Pc not significant). HLA-DRB1*11 and DQB1*0602 were found in 22.2% and 9.3% of responders and in 10.9% and 1.8% of non-responders, respectively (Pc not significant). There was no difference in the distribution of TNF alleles in the two groups. Twenty-four (88.8%) responder patients as compared with 34 (61.8%) non-responders were TAP1*0101 homozygous (Pc not significant). Thus, in European Caucasoids with chronic hepatitis C, we could not demonstrate a strong association between HLA class II, TNF, and TAP gene polymorphisms and response to interferon treatment.
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Affiliation(s)
- A Airoldi
- Department of Gastroenterology and Hepatology 'Crespi', Niguarda Hospital, Milan, Italy
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16
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Andrade Júnior DRD, Andrade DRD. The influence of the human genome on chronic viral hepatitis outcome. Rev Inst Med Trop Sao Paulo 2004. [DOI: 10.1590/s0036-46652004000300001] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
The mechanisms that determine viral clearance or viral persistence in chronic viral hepatitis have yet to be identified. Recent advances in molecular genetics have permitted the detection of variations in immune response, often associated with polymorphism in the human genome. Differences in host susceptibility to infectious disease and disease severity cannot be attributed solely to the virulence of microbial agents. Several recent advances concerning the influence of human genes in chronic viral hepatitis B and C are discussed in this article: a) the associations between human leukocyte antigen polymorphism and viral hepatic disease susceptibility or resistance; b) protective alleles influencing hepatitis B virus (HBV) and hepatitis C virus (HCV) evolution; c) prejudicial alleles influencing HBV and HCV; d) candidate genes associated with HBV and HCV evolution; d) other genetic factors that may contribute to chronic hepatitis C evolution (genes influencing hepatic stellate cells, TGF-beta1 and TNF-alpha production, hepatic iron deposits and angiotensin II production, among others). Recent discoveries regarding genetic associations with chronic viral hepatitis may provide clues to understanding the development of end-stage complications such as cirrhosis or hepatocellular carcinoma. In the near future, analysis of the human genome will allow the elucidation of both the natural course of viral hepatitis and its response to therapy.
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17
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Leone N, Pellicano R, Brunello F, Cutufia MA, Berrutti M, Fagoonee S, Rizzetto M, Ponzetto A. Helicobacter pylori seroprevalence in patients with cirrhosis of the liver and hepatocellular carcinoma. ACTA ACUST UNITED AC 2004; 27:494-7. [PMID: 14642558 DOI: 10.1016/j.cdp.2003.07.004] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND Infection by Helicobacter hepaticus causes chronic hepatitis and hepatocellular carcinoma (HCC) in mice, and Helicobacter pylori (H. pylori) genomic sequences have been demonstrated in the liver of patients with HCC. H. pylori infection reportedly occurs with high frequency in patients with cirrhosis but none of the studies has investigated it in subjects with cirrhosis and superimposed HCC. In this case-control study, we searched for the seroprevalence of H. pylori infection in patients with HCC. PATIENTS AND METHOD Forty-six patients (30 males, 16 females, mean age 69 years) with HCC and hepatitis C virus (HCV)-related cirrhosis were compared to 46 sex and age (+/-1 year) matched patients presenting consecutively to the Emergency Department of Molinette Hospital of Torino. All subjects were tested for presence in serum of IgG antibodies against H. pylori and the result was analyzed using the chi-square test. RESULTS H. pylori seropositivity was more prevalent among patients with HCC (36/46, 78.2%) than in controls (25/46, 54%) (P<0.05) (OR 3.02, 95% confidence interval ). Twenty-five out of 30 (83.3%) male patients showed seropositivity at a variance with 16/30 (53%) in the controls (P<0.05); 11 out of 16 (68.7%) female patients were seropositive versus 9 out of 16 (56.2%) control subjects (P=n.s.). CONCLUSION Seroprevalence of antibodies to H. pylori was found to be higher in patients with HCC than in controls.
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Affiliation(s)
- Nicola Leone
- Department of Gastro-Hepatology, Molinette Hospital, Via Chiabrera 34, 10126 Turin, Italy
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18
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Pellicano R, Mazzaferro V, Grigioni WF, Cutufia MA, Fagoonee S, Silengo L, Rizzetto M, Ponzetto A. Helicobacter species sequences in liver samples from patients with and without hepatocellular carcinoma. World J Gastroenterol 2004; 10:598-601. [PMID: 14966925 PMCID: PMC4716988 DOI: 10.3748/wjg.v10.i4.598] [Citation(s) in RCA: 79] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
AIM: Only a minority of patients carrying a defined viral aetiologic agent develop cirrhosis and ultimately hepatocellular carcinoma (HCC), the mechanism underlying the worsening is still undefined. Experimental infection by Helicobacter hepaticus in mice causes chronic hepatitis and HCC and recently, more Helicobacter species (Helicobacter spp.) have been detected in the liver of patients suffering from cholestatic diseases and HCC arising from non-cirrhotic liver. We investigated whether Helicobacter spp. sequences could be detected in the liver of patients with cirrhosis and HCC compared to subjects with metastasis to liver from colon cancer.
METHODS: Twenty-three liver samples from patients operated upon for HCC superimposed on hepatitis C virus (HCV)-related cirrhosis and 6 from patients with resected metastases from colorectal cancer, were tested by polymerase chain reaction for presence of genomic 16S rRNA of Helicobacter genus using specific primers. DNA sequencing and cag A gene analysis were also performed.
RESULTS: Genomic sequences of Helicobacter spp. were found in 17 of 20 (85%) liver samples from patients with HCC and in 2 of 6 samples from patients with liver metastasis. In three samples of the first group the result was uncertain. H pylori was revealed in 16 out of 17 positive samples and Helicobacter pullorum in the other.
CONCLUSION: Helicobacter spp., carcinogenic in mice, were found at a higher frequency in the liver of patients with HCV-related cirrhosis and HCC than those in patients without primary liver disease.
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Affiliation(s)
- Rinaldo Pellicano
- Ambulatorio di Gastroenterologia, Ospedale S Giovanni Battista, Via Chiabrera 34, III piano, 10126 Torino, Italy
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19
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Yoshizawa K, Ota M, Saito S, Maruyama A, Yamaura T, Rokuhara A, Orii K, Ichijo T, Matsumoto A, Tanaka E, Kiyosawa K. Long-term follow-up of hepatitis C virus infection: HLA class II loci influences the natural history of the disease. TISSUE ANTIGENS 2003; 61:159-65. [PMID: 12694584 DOI: 10.1034/j.1399-0039.2003.00015.x] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Hepatitis C virus (HCV) causes various grades of chronic liver disease, ranging from an asymptomatic state to cirrhosis. To assess genetic factors of disease severity, we selected two HCV patient groups according to the following stringent criteria: (i) asymptomatic carrier state (ASC) defined by HCV infection for more than 20 years, normal alanine aminotransferase levels for the past 5 years as well as normal liver histology and/or shape and (ii) liver cirrhosis (LC) as diagnosed by clinical symptoms, liver biopsy and/or ultrasonography. A total of 103 chronically infected Japanese HCV patients (43 ASC and 60 LC) were analyzed. HLA class I and II alleles were established using low resolution DNA typing. HLA-DRB1 and DQB1 genotypes were inferred upon polymerase chain reaction-restriction fragment length polymorphism analysis. Two hundred and one anti-HCV-negative ethnically matched controls were included. The frequencies of DRB1*12 (*1201 and *1202), DQB1*0301 and DRB3*03 alleles were higher in patients with ASC than in those with LC (odds ratio (OR) 11.23, OR 4.25, and OR 3.22, respectively). The frequency of DQB1*0503 were lower in ASC patients compared to LC patients (OR 0.05). No significant differences between groups were observed for age, sex, source of infection, HCV genotype or viral loads. Our findings establish that certain HLA class II alleles strongly influence disease progression following HCV infection.
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Affiliation(s)
- K Yoshizawa
- Second Department of Internal Medicine, Shinshu University School of Medicine, Matsumoto, Japan.
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20
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Matsumori A, Ohashi N, Ito H, Furukawa Y, Hasegawa K, Sasayama S, Naruse T, Inoko H. Genes of the Major Histocompability Complex Class II Influence the Phenotype of Cardiomyopathies Associated With Hepatitis C Virus Infection. DEVELOPMENTS IN CARDIOVASCULAR MEDICINE 2003. [DOI: 10.1007/978-1-4419-9264-2_39] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
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21
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Wiley TE, Brown J, Chan J. Hepatitis C infection in African Americans: its natural history and histological progression. Am J Gastroenterol 2002; 97:700-6. [PMID: 11922566 DOI: 10.1111/j.1572-0241.2002.05555.x] [Citation(s) in RCA: 127] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVE The aim of this retrospective analysis was to determine the natural history of hepatitis C virus infection in African Americans versus non-African Americans by evaluating the clinical, virological, and histological findings. METHODS We examined in a retrospective manner the demographics, mode of infection, virological features, and histological progression of HCV infection in African Americans versus non-African Americans. There were 355 patients who met criteria based on adequate liver biopsy specimens and exclusion of other hepatic diseases. RESULTS African Americans (n = 112) were significantly more likely to be infected with genotype 1 virus (88%) than were non-African Americans (n = 243; 67%; p < or = 0.001). Baseline HCV RNA levels were similar, although baseline ALT values were significantly lower in African Americans (80.0 microl +/- 5.5 vs 112.1 microl +/- 6.2; p < or = 0.001). African Americans were significantly older at the time of presentation and were significantly more likely to be women (p < or = 0.02). In African Americans, there was a trend toward less cirrhosis (22% vs 30%; p < or = 0.1) and significantly less piecemeal necrosis on liver biopsy. Non-African Americans had significantly higher fibrosis scores, ALT values, and piecemeal necrosis ratings, and tended to progress more rapidly to cirrhosis. This difference in histological progression between the two groups was not explained by differences in alcohol consumption. CONCLUSION The lower ALT, piecemeal necrosis scores, and slower progression of fibrosis in African Americans may reflect less immunological recognition of HCV-infected liver cells.
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Affiliation(s)
- Thelma E Wiley
- Department of Medicine, College of Pharmacy, University of Illinois at Chicago, USA
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22
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Abstract
A genetic basis for interindividual variation in susceptibility to human infectious diseases has been indicated by twin, adoptee, pedigree, and candidate gene studies. This has led to the identification of a small number of strong genetic associations with common variants for malaria, HIV infection, and infectious prion diseases. Numerous other genes have shown less strong associations with these and some other infectious diseases, such as tuberculosis, leprosy, and persistent hepatitis viral infections. Many immunogenetic loci influence susceptibility to several infectious pathogens. Recent genetic linkage analyses of measures of infection as well as of infectious disease, including some genome-wide scans, have found convincing evidence of genetic linkage to chromosomal regions wherein susceptibility genes have yet to be identified. These studies indicate a highly polygenic basis for susceptibility to many common infectious diseases, with some emerging examples of interaction between variants of specific polymorphic host and pathogen genes.
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Affiliation(s)
- A V Hill
- Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, United Kingdom.
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23
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Hwang SJ, Chu CW, Huang DF, Lan KH, Chang FY, Lee SD. Genetic predispositions for the presence of cryoglobulinemia and serum autoantibodies in Chinese patients with chronic hepatitis C. TISSUE ANTIGENS 2002; 59:31-7. [PMID: 11972876 DOI: 10.1034/j.1399-0039.2002.590106.x] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Chronic hepatitis C virus (HCV) infection may induce immunological disorders in the host such as the presence of cryoglobulinemia or serum autoantibodies. The pathogenesis of these phenomena remains unclear but may reflect the host's genetic predispositions. The aim of this study was to evaluate the association between these immunological manifestations and human leukocyte antigen (HLA) expression in Chinese patients with chronic hepatitis C. The presence of serum cryoglobulin and autoantibodies (antinuclear antibody, antismooth muscle antibody, antimitochondrial antibody, antiliver-kidney-microsomal antibody) was determined in 122 Chinese patients with chronic hepatitis C. HLA class I and class II antigens were measured by microlymphocytotoxicity assay or by DNA typing in 122 chronic hepatitis C patients and 228 healthy controls. Of the 122 patients with chronic hepatitis C, 52 (43%) had cryoglobulinemia and 48 (39%) had serum autoantibodies. A significant difference in HLA frequency was noted for DR3, which was found in 36.5% of patients with cryoglobulinemia compared with 8.6% of patients without cryoglobulinemia and 11.3% of healthy controls. A significant difference in HLA frequency was also noted for DR4, which was found in 45.8% of patients with serum autoantibodies compared with 17.6% of patients without serum autoantibodies and 19% of healthy controls. Our results suggest the existence of HLA-linked susceptibility genes (DR3 or DR4) for the development of cryoglobulinemia or serum autoantibodies in Chinese patients with chronic hepatitis C.
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Affiliation(s)
- S-J Hwang
- Department of Family Medicine, Veterans General Hospital-Taipei, National Yang-Ming University School of Medicine, Taipei, Taiwan, Republic of China.
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24
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Cacoub P, Renou C, Kerr G, Hüe S, Rosenthal E, Cohen P, Kaplanski G, Charlotte F, Thibault V, Ghillani P, Piette JC, Caillat-Zucman S. Influence of HLA-DR phenotype on the risk of hepatitis C virus-associated mixed cryoglobulinemia. ARTHRITIS AND RHEUMATISM 2001; 44:2118-24. [PMID: 11592376 DOI: 10.1002/1529-0131(200109)44:9<2118::aid-art364>3.0.co;2-x] [Citation(s) in RCA: 66] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
OBJECTIVE Circumstances predisposing hepatitis C virus (HCV)-infected patients to develop mixed cryoglobulinemia (MC), which may manifest as a small-vessel systemic vasculitis (MC vasculitis), remain unclear. Previous studies have failed to demonstrate a clear role of either viral factors (genotype, viral load) or host factors (lymphocytes or immunoglobulin subsets). This study was undertaken to examine a possible role of HLA class II alleles in HCV-associated MC. METHODS One hundred fifty-eight HCV-infected patients, of whom 76 had MC (56 with type II MC and 20 with type III MC) and 82 did not have MC, were studied prospectively. MC vasculitis was noted in 35 HCV-infected patients with type II IgMkappa-containing cryoglobulins. HLA-DRB1 and HLA-DQB1 polymorphism was analyzed by hybridization using allele-specific oligonucleotides, after gene amplification. The odds ratio (OR) was calculated with Woolf's method. Then, using multivariate analysis, demographic, biologic, immunologic, virologic, and liver histologic factors associated with the presence of MC and MC vasculitis were investigated. RESULTS HLA-DR11 was significantly more frequent in patients with type II MC than in those without MC (41.1% versus 17.1%; OR 3.4, corrected P [Pcorr] = 0.017), regardless of the presence of vasculitis accompanying the MC (37.1% of those with MC vasculitis, 34.1% of those with MC but no vasculitis). HLA-DR7 was less frequent in HCV-infected patients with MC than in those without MC (13.2% versus 30.5%; OR 0.34, P = 0.012, Pcorr not significant), with a particularly lower frequency in those with type II MC and those with MC vasculitis (12.5% and 8.6%, respectively). There was no significant difference in HLA-DQB1 distribution between the different patient groups. By univariate and multivariate analysis, HLA-DR11 was the only positive predictive factor, besides female sex and advanced age, for the presence of MC and HCV-associated MC vasculitis (OR 2.58). CONCLUSION Our results indicate that the presence of the DR11 phenotype is associated with a significantly increased risk for the development of type II MC in patients with chronic HCV infection. In contrast, HLA-DR7 appears to protect against the production of type II MC. These results suggest that the host's immune response genes may play a role in the pathogenesis of HCV-associated MC.
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Affiliation(s)
- P Cacoub
- Department of Internal Medicine, Hĵpital La Pitié-Salpêtrière, Paris, France
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25
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Akuta N, Chayama K, Suzuki F, Someya T, Kobayashi M, Tsubota A, Suzuki Y, Saitoh S, Arase Y, Ikeda K, Kumada H. Risk factors of hepatitis C virus-related liver cirrhosis in young adults: positive family history of liver disease and transporter associated with antigen processing 2(TAP2)*0201 Allele. J Med Virol 2001; 64:109-16. [PMID: 11360242 DOI: 10.1002/jmv.1025] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
The aim of this study was to clinically characterize young patients with hepatitis-C-related cirrhosis. We compared 27 patients with liver cirrhosis (Group LC) who were anti-HCV positive, aged 40 years or less at the time of diagnosis, with 323 consecutive patients with HCV-related chronic hepatitis (Group CH) matched for age and gender. Furthermore, Group LC was divided into two arbitrary groups (29-35 years, n = 8 /36-40 years, n = 19), based on the age of patients at the time of diagnosis of liver cirrhosis. Patients' characteristics and family history were investigated, and the frequency of transporter associated with antigen processing 2 (TAP2) was determined. A family history of liver disease was present in 40.7% of Group LC but in 18.0% of Group CH (P < 0.05). The younger the age of diagnosis of cirrhosis in Group LC, the higher the frequency of a positive family history (29-35 years, 87.5%; 36-40 years, 21.1%, P < 0.05). The frequency of TAP2*0201 was significantly higher in young adult patients with HCV-related liver cirrhosis than in HCV carriers with normal ALT (P < 0.05), and tended to be higher than in uninfected normal subjects (P = 0.05). The cumulative survival rate of cirrhosis patients with family history of liver diseases was significantly lower than that of cirrhosis patients without such history (P < 0.05). Our findings suggest that a positive family history of liver disease and TAP2*0201 polymorphism may be risk factors for HCV-related liver cirrhosis in young adults.
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Affiliation(s)
- N Akuta
- Division of Gastroenterology, Toranomon Hospital, 2-2-2 Toranomon, Minato-ku, Tokyo, 105-0001, Japan.
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26
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Nagayama K, Enomoto N, Izumi N, Kurosaki M, Miyasaka Y, Watanabe H, Itakura J, Chen CH, Tazawa J, Hoshino Y, Ikeda T, Marumo F, Sato C. Sequences in the NS5A protein of hepatitis C virus and the serum alanine aminotransferase response to interferon therapy in Japanese patients. Gut 2001; 48:830-5. [PMID: 11358904 PMCID: PMC1728341 DOI: 10.1136/gut.48.6.830] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/08/2022]
Abstract
BACKGROUND AND AIMS Chronic hepatitis C is a slowly progressive disease and eventually causes hepatocellular carcinoma in many patients. Although interferon (IFN) therapy has been used for viral eradication, its success rate is only about 30%. In patients in whom it has failed (non-responders), there are several patterns of serum alanine aminotransferase (ALT) values, and detection of serum HCV-RNA during and after IFN therapy and improved long term prognosis were reported in patients whose serum ALT values were normalised by IFN therapy even if HCV viraemia persisted. The present study sought to clarify the virological characteristics contributing to these differences. METHODS Complete or partial length dominant sequences of hepatitis C virus genotype 1b (HCV-1b) were determined by direct sequencing. Firstly, the complete sequences of HCV-1b genomes were determined in six non-responders; three showed normalisation of serum ALT values during IFN-alpha therapy and the other three did not. Subsequently, the amino acid residues that were different in the two groups were further analysed retrospectively in another 82 patients. RESULTS Comparison of the sequences suggested an association between amino acids 2154-2172 of HCV-1b and serum ALT normalisation. A retrospective analysis of 82 patients revealed that the number of amino acid substitutions in this region was the only statistically significant variable associated with ALT normalisation (odds ratio 31.0; 95% confidence interval 5.0-286) in multivariate analyses. CONCLUSIONS A HCV genomic region that correlates with the ALT response to IFN therapy appears to be present in virologically IFN ineffective patients.
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Affiliation(s)
- K Nagayama
- Second Department of Internal Medicine, Faculty of Medicine, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, Japan, 113-8519
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27
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Tillmann HL, Chen DF, Trautwein C, Kliem V, Grundey A, Berning-Haag A, Böker K, Kubicka S, Pastucha L, Stangel W, Manns MP. Low frequency of HLA-DRB1*11 in hepatitis C virus induced end stage liver disease. Gut 2001; 48:714-8. [PMID: 11302974 PMCID: PMC1728277 DOI: 10.1136/gut.48.5.714] [Citation(s) in RCA: 46] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Hepatitis C virus (HCV) infection becomes chronic in more than 70% of patients, leading to end stage liver disease in about 20-30% of these patients. Apart from the virus itself, host factors that modulate the immune response are likely to be involved in determining the outcome of HCV infection. Studies on the association of human leucocyte antigens (HLAs) and HCV infection have shown inconsistent results. Selection of patient subgroups may be crucial. However, any association relevant to HCV disease progression will become evident, especially in those patients with end stage liver disease. Therefore, we analysed the phenotype frequencies of HLA antigens in two groups of 69 and 39 patients with HCV induced liver cirrhosis who had received a transplant or were awaiting liver transplantation. The first group was typed serologically and compared with 331 blood and liver donors. The second group, prospectively HLA typed by a polymerase chain reaction-sequence specific oligonucleotide (PCR-SSO) procedure for HLA-DRB and DQB alleles, was compared with another 170 PCR-SSO typed and randomly selected blood donors. Decreased frequencies for HLA-DR5 and HLA-DQ3 were found in one group of patients with HCV induced liver cirrhosis compared with the control groups. In the second analysis comparing 39 patients with end stage liver cirrhosis with blood donors, we confirmed the significant decrease in HLA-DRB1*11 and HLA-DQB1*03, which corresponded to serological HLA-DR5 and HLA-DQ3 antigens, respectively. Our results show that the presence of HLA-DRB1*11 and HLA-DQB1*03 alleles is associated with a reduced risk for the development of HCV induced end stage liver disease.
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Affiliation(s)
- H L Tillmann
- Department of Gastroenterology and Hepatology, Medizinische Hochschule Hannover, Germany
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28
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Bergamini A, Bolacchi F, Cerasari G, Carvelli C, Faggioli E, Cepparulo M, Demin F, Uccella I, Bongiovanni B, Niutta P, Capozzi M, Lupi M, Piscitelli E, Rocchi G, Angelico M. Lack of evidence for the Th2 predominance in patients with chronic hepatitis C. Clin Exp Immunol 2001; 123:451-8. [PMID: 11298133 PMCID: PMC1906012 DOI: 10.1046/j.1365-2249.2001.01467.x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
A T helper (Th)1 to Th2 shift has been proposed to be a critical pathogenic determinant in chronic hepatitis C. Here, we evaluated mitogen-induced and hepatitis C virus (HCV) core antigen-induced cytokine production in 28 patients with biopsy-proven chronic hepatitis C. Flow cytometry demonstrated that after mitogenic stimulation the percentage of Th2 cells (IL-4 + or IL-13 +) and Th0 cells (IFN-gamma/IL-4 + or IL-2/IL-13 +) did not differ between patients and controls. In contrast, the percentage of Th1 cells (IFN-gamma + or IL-2 +) was significantly increased in CD4 +, CD8 +, 'naive'-CD45RA + and 'memory'-CD45RO + T-cell subsets from patients versus controls. Similar results were obtained by ELISA testing supernatants from mitogen-stimulated, unfractionated peripheral blood mononuclear cell (PBMC) cultures. Interferon-alpha treatment was associated with a reduction in the mitogen-induced Th1 cytokine response in those patients who cleared their plasma HCV-RNA. Analysis of cytokine expression by CD4 + T cells after HCV core antigen stimulation in a subgroup of 13 chronic hepatitis C patients demonstrated no cytokine response in 74% of these patients and an IFN-gamma-restricted response in 26%. Finally, no Th2 shift was found in lipopolysaccharide-stimulated monocytes. These data indicate that a Th1 to Th2 shift does not occur in chronic hepatitis C.
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Affiliation(s)
- A Bergamini
- Department of Public Health and Cellular Biology, University of Rome Tor Vergata, Rome, Italy.
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Proust B, Dubois F, Bacq Y, Le Pogam S, Rogez S, Levillain R, Goudeau A. Two successive hepatitis C virus infections in an intravenous drug user. J Clin Microbiol 2000; 38:3125-7. [PMID: 10921996 PMCID: PMC87209 DOI: 10.1128/jcm.38.8.3125-3127.2000] [Citation(s) in RCA: 39] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
We report the case of an occasional intravenous drug user who developed two successive hepatitis C virus (HCV) infections. The first infection led to seroconversion (anti-HCV antibodies detected) and the detection of HCV RNA in serum. After a spontaneous recovery (normalization of alanine aminotransferase levels and HCV RNA clearance), a second HCV infection was observed, with the recurrence of HCV viremia. Antibody directed against HCV serotype 1 was detected throughout the follow-up monitoring, but two different HCV strains were identified during the two infectious episodes: genotype 1a for the first and genotype 3a for the second. This observation shows that primary HCV infection does not confer protective immunity against subsequent infection with viruses of other genotypes. This may hamper the development of a vaccine. Conflicting results were obtained in genotyping and serotyping assays, suggesting that the serotyping method cannot be used to identify the HCV type in patients, such as intravenous drug users, who are exposed to successive HCV infections.
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Affiliation(s)
- B Proust
- Département de Microbiologie Médicale et Moléculaire, Unité de Virologie, Centre Hospitalier Universitaire Bretonneau, Tours, France
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Brandhagen DJ, Gross JB, Poterucha JJ, Germer JJ, Czaja AJ, Smith CI, Ribeiro AC, Guerrero RB, Therneau TM, Schiff E, Gordon FD, Wiesner RH, Persing DH. Human leukocyte antigen DR markers as predictors of progression to liver transplantation in patients with chronic hepatitis C. Am J Gastroenterol 2000; 95:2056-60. [PMID: 10950057 DOI: 10.1111/j.1572-0241.2000.02137.x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVE Because many patients with chronic viral hepatitis do not progress to end-stage liver disease, it is possible that host factors such as human leukocyte antigen (HLA) differences are important. Our aims were to determine HLA marker-specific rates of progression to liver transplantation among patients with chronic hepatitis C; and to determine if polymerase chain reaction (PCR)-based HLA DRB1 typing can be performed on stored serum samples. METHODS Forty-two hepatitis C virus RNA-positive liver transplant patients and 87 untransplanted patients were included in a Cox proportional hazards model to test whether the occurrence of certain HLA DRB1 markers were associated with progression to liver transplantation. HLA DRB1 typing was performed on stored serum samples using a PCR method. RESULTS There were no differences among the HLA DRB1 markers with regard to the HLA marker-specific rate of progression to transplantation among patients with chronic hepatitis C. CONCLUSIONS HLA DRB1 markers do not appear to be associated with progression of disease in chronic viral hepatitis C. It is possible to perform PCR-based HLA DRB1 typing on stored frozen serum samples.
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Affiliation(s)
- D J Brandhagen
- Department of Health Sciences Research, Mayo Clinic and Foundation, Rochester, Minnesota, USA
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Zein NN. Tumor necrosis factor gene promoter polymorphism and recurrent hepatitis C after liver transplantation: the missing link to pathogenesis or a casual association? Liver Transpl 2000; 6:381-3. [PMID: 10827247 DOI: 10.1002/lt.500060329] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Affiliation(s)
- N N Zein
- Division of Gastroenterology and Hepatology Mayo Clinic and Mayo Foundation, Rochester, MN 55905, USA
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32
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Haruna Y, Miyamoto T, Yasunami R, Kanda T, Fushimi H, Kotoh K. Human leukocyte antigen DRB1 1302 protects against bile duct damage and portal lymphocyte infiltration in patients with chronic hepatitis C. J Hepatol 2000; 32:837-42. [PMID: 10845672 DOI: 10.1016/s0168-8278(00)80254-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND/AIMS To confirm the immune reaction of hosts in chronic hepatitis C, we examined the association of human leukocyte antigen (HLA) DR with the histopathological outcome including bile duct damage and steatosis, which are characteristic of hepatitis C virus (HCV) infection. METHODS One hundred and fifty-five patients with chronic HCV infection were examined. The pathological appearance of liver biopsy specimens was evaluated by both Knodell's histological activity index and examination of bile duct damage and steatosis. HLA DRB1 was determined by the polymerase chain reaction sequence-specific oligonucleotide probe method. RESULTS HLA DRB1 1302 was found with significantly higher frequency in patients without than with bile duct damage (34.8% vs. 4.7%, p=0.0001, p corrected by Bonferroni's inequality method=0.002). It was also found more frequently in patients without marked portal lymphocyte infiltration (28.6% vs. 7.7%, p=0.0015, p corrected by Bonferroni's method=0.03). HLA DRB1 1101 was found more frequently in patients without than with piecemeal necrosis (p=0.004). In contrast, the frequency of HLA DRB1 1502 tended to be higher in patients with than without piecemeal necrosis and marked portal lymphocyte infiltration (p=0.015 and p=0.03, respectively). HLA DRB1 1201 and 0802 were seen more frequently in bile duct damage-negative (p=0.02) and piecemeal necrosis-negative patients (p=0.03), respectively. Interestingly, serum HCV levels of HLA DRB1 1302-positive patients were significantly higher than those of 1302-negative patients (mean: 7.7 Meq/ml vs. 3.1 Meq/ml, p=0.0007). CONCLUSION These findings suggest that some histopathological changes in chronically HCV-infected livers could be caused by the host's immune reaction regulated by HLA DR.
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Affiliation(s)
- Y Haruna
- Department of Gastroenterology & Diabetology, Osaka Prefectural General Hospital, Japan
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Affiliation(s)
- C L Thio
- Division of Infectious Diseases, The Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.
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Tai DI, Tsai SL, Chen YM, Chuang YL, Peng CY, Sheen IS, Yeh CT, Chang KS, Huang SN, Kuo GC, Liaw YF. Activation of nuclear factor kappaB in hepatitis C virus infection: implications for pathogenesis and hepatocarcinogenesis. Hepatology 2000; 31:656-64. [PMID: 10706556 DOI: 10.1002/hep.510310316] [Citation(s) in RCA: 140] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
The hepatitis C virus (HCV) core protein is a multifunctional protein. It may bind to the death domain of tumor necrosis factor receptor 1 (TNFR1) and to the cytoplasmic tail of lymphotoxin-beta receptor, implying that it may be involved in the apoptosis and anti-apoptosis signaling pathways. In vitro studies have been inconclusive regarding its ability to inhibit or enhance TNF-alpha-induced apoptosis. To address this issue, electrophoretic mobility shift assay (EMSA) and immunohistochemical studies were used to show the activation of nuclear factor kappaB (NF-kappaB) in HCV-infected liver tissues and in HCV core-transfected cells. The activation of NF-kappaB was correlated with the apoptosis assays. The results showed that NF-kappaB activation could be shown in HCV-infected livers and HCV core-transfected cells. The data of EMSA correlated with those of immunohistochemical studies, which revealed a higher frequency of NF-kappaB nuclear staining in HCV-infected than in normal livers. NF-kappaB activation conferred resistance to TNF-alpha-induced apoptosis in HCV core-transfected cells. Inhibition of NF-kappaB activation by pyrrolidine dithiocarbamate sensitized them to TNF-alpha-induced apoptosis. These findings suggest that HCV infection may cause anti-apoptosis by activation of NF-kappaB and implicate a mechanism by which HCV may evade the host's immune surveillance leading to viral persistence and possibly to hepatocarcinogenesis.
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Affiliation(s)
- D I Tai
- Graduate Institute of Clinical Medicine, Chang Gung University College of Medicine, Taipei, Taiwan
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35
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Vejbaesya S, Songsivilai S, Tanwandee T, Rachaibun S, Chantangpol R, Dharakul T. HLA association with hepatitis C virus infection. Hum Immunol 2000; 61:348-53. [PMID: 10689128 DOI: 10.1016/s0198-8859(99)00131-7] [Citation(s) in RCA: 48] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
Hepatitis is one of the most important infectious diseases in Thailand. The knowledge of host factors that influence the course of the disease is still limited. In this study, the HLA class I and class II phenotypes were analyzed in the 2 groups of HCV-infected Thai populations. The first group included 43 individuals with transient HCV infection (HCV antibody positive, HCV RNA PCR negative), and the second included 57 individuals with persistent chronic HCV infection (HCV antibody positive, PCR positive). HLA class I typing was performed by 2-stage microlymphocytotoxicity test, and HLA class II typing, by PCR-SSO. No significant difference in the frequencies of HLA-A and -B antigens was observed between the 2 groups of HCV-infected individuals. The frequency of DRB1*0301 and DQB1*0201 was significantly higher in the persistent-infection group than in the transient-infection group (Pc = 0.03, Pc = 0.04, respectively). In addition, DRB1*0701 and DQA1*0201 were significantly decreased in all the HCV-infected patients compared with levels in the normal controls (Pc = 0.003, Pc = 0.001, respectively). This study demonstrated that DRB1*0301 and DQB1*0201 are associated with persistent HCV infection, whereas DRB1*0701 and DQA*0201 are associated with protection against HCV infection.
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Affiliation(s)
- S Vejbaesya
- Department of Transfusion Medicine, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand.
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36
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Ponzetto A, Pellicano R, Leone N, Cutufia MA, Turrini F, Grigioni WF, D'Errico A, Mortimer P, Rizzetto M, Silengo L. Helicobacter infection and cirrhosis in hepatitis C virus carriage: is it an innocent bystander or a troublemaker? Med Hypotheses 2000; 54:275-7. [PMID: 10790764 DOI: 10.1054/mehy.1999.0987] [Citation(s) in RCA: 60] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Since it has been shown that Helicobacter hepaticus causes both chronic hepatitis and hepatocellular carcinoma (HCC) in mice, it is suggested that differences in the progression of chronic hepatitis C may be due to a cofactor stemming from co-infection by bacteria, especially Helicobacter pylori, and/or other Helicobacter species. An assessment was made of the prevalence of H. pylori infection in HCV-positive cirrhotic patients. The presence of Helicobacter species (spp). was evaluated in resected liver tissue from HCC patients. Serum anti-H. pylori IgG antibodies were determined in 70 males with a clinical and/or histological diagnosis of cirrhosis and HCV infection and in 310 age-matched male blood donors. The prevalences of H. pylori antibody were 77% (54/70) and 59% (183/310) (P 0.004). Primers identifying 26 Helicobacter species were used to determine the presence of the genomic 16S rRNA of this genus in liver tissue resected from 25 cirrhotic HCC patients. Genomic sequences corresponding to H. pylori and H. pullorum were identified in 23 of these 25 livers. Together, these findings support the proposal that H. pylori is implicated in the pathogenesis and progression of cirrhosis, particularly in HCV-infected individuals. Involvement of Helicobacter spp. in HCC also seems highly possible.
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Affiliation(s)
- A Ponzetto
- Department of Gastroenterology, Hospital San Giovanni Battista, Torino, Italy.
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37
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Thursz M, Yallop R, Goldin R, Trepo C, Thomas HC. Influence of MHC class II genotype on outcome of infection with hepatitis C virus. The HENCORE group. Hepatitis C European Network for Cooperative Research. Lancet 1999; 354:2119-24. [PMID: 10609818 DOI: 10.1016/s0140-6736(99)91443-5] [Citation(s) in RCA: 219] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND The outcome of infection with hepatitis C virus (HCV) varies substantially among individuals. Host genetic factors are likely to give rise to some of this variability. Polymorphisms in the MHC class II loci may influence the outcome of HCV infection; however, reports of MHC class II allele associations have been inconsistent. We aimed to confirm these associations in a cohort of European patients with different clinical outcomes. METHODS The distribution of MHC class II alleles was compared between patients with self-limiting infection (n=85) and matched patients with persistent infection (n=170); between patients with mild (n=321) and severe (n=321) histological injury; and between patients who responded to interferon (n=96) and those who did not (n=192). The results of these comparisons were confirmed with a second-stage study of self-limiting infection (n=52) versus persistent infection (n=152). FINDINGS Self-limiting HCV infection was associated with HLA-DRB1*1101 (odds ratio 2.14 [95% CI 1.11-4.12]; p=0.013) and HLA-DQB1*0301 (2.22 [1.24-3.96], p=0.004). Persistent HCV infection was associated with HLA-DRB1*0701 (2.04 [1.03-4.17], p=0.027), and HLA-DRB4*0101 (2.38 [1.29-4.35], p=0.002). These results were confirmed in the second-stage study. No significant associations (p<0.05 after Bonferroni correction) were found between MHC class II alleles and severe histological injury or response to interferon therapy. INTERPRETATION Specific MHC class II alleles influence susceptibility or resistance to persistent HCV infection.
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Affiliation(s)
- M Thursz
- Division of Medicine A, Imperial College, School of Medicine at St Mary's Hospital, London, UK.
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38
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Kallinowski B, Scherer S, Mehrabi A, Theilmann L, Stremmel W. Clinical impact of HLA DR B1 genotypes in chronic hepatitis C virus infection. Transplant Proc 1999; 31:3346-9. [PMID: 10616501 DOI: 10.1016/s0041-1345(99)00820-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Affiliation(s)
- B Kallinowski
- Department of Internal Medicine, University of Heidelberg, Germany
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39
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Tuncer M, Sarikaya M, Yegin O, Süleymanlar G, Ersoy F, Yakupoglu G. Relationship between hepatitis C virus infection and human leucocyte antigens in renal transplant patients. Transplant Proc 1999; 31:3343-5. [PMID: 10616500 DOI: 10.1016/s0041-1345(99)00819-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Affiliation(s)
- M Tuncer
- Department of Medicine, Akdeniz University Medical School, Antalya, Turkey.
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40
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Abstract
Hepatitis C virus (HCV) infection is widespread with an estimated 3% of the world population being infected. Acute infection is usually mild but chronicity develops in as many as 70% of patients, of whom at least 20% will eventually develop cirrhosis. A further 1-4% of cirrhotic individuals will develop hepatocellular carcinoma. Infection with HCV may have effects on various organs other than the liver. HCV has been causally associated with a remarkable array of extrahepatic manifestations, some of which remain unproven. This review discusses the evidence implicating HCV in the aetiology of two important oral conditions, namely Sjögren's syndrome and lichen planus.
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Affiliation(s)
- K Roy
- Infection Research Group, University of Glasgow Dental School, Glasgow, Scotland
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41
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Zein NN, Arslan M, Li H, Charlton MR, Gross JB, Poterucha JJ, Therneau TM, Kolbert CP, Persing DH. Clinical significance of TT virus infection in patients with chronic hepatitis C. Am J Gastroenterol 1999; 94:3020-7. [PMID: 10520863 DOI: 10.1111/j.1572-0241.1999.01457.x] [Citation(s) in RCA: 21] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVE The TT virus (TTV) is a novel DNA virus that has recently been identified. The clinical significance of TTV infection in patients with chronic hepatitis C has not been determined. The aim of this study was to determine the prevalence and possible role of TTV in a well characterized population with chronic hepatitis C infection. METHODS Ninety patients with chronic HCV and known time of HCV acquisition were selected from approximately 250 patients followed at our institution. Characteristics including age, sex, histology, and length of disease were recorded. Direct sequencing of the NS5 region was used for HCV genotyping. TTV DNA detection was based on PCR. RESULTS TTV infection was present in 24 of 90 (27%) HCV patients. Patients were divided into four groups based on stage of disease; chronic hepatitis (CH, 29 patients), compensated cirrhosis (CC, 17 patients), decompensated cirrhosis (DC, 28 patients), and hepatocellular carcinoma (HCC, 16 patients). TTV was present in 2/29 (7%), 2/17 (12%), 11/28 (39%), and 9/16 (56%) in those with CAH, CC, DC, and HCC respectively. TTV was significantly more prevalent among those with advanced disease (DC and HCC) compared to those with stable disease (CH and CC; p = 0.001). Mean age, sex, and the time from exposure to HCV to development of complications were similar in TTV-positive and -negative patients. TTV infection was more common in patients infected with HCV genotype 1b. Univariate analysis showed that length of HCV infection, HCV genotype 1b, and TTV infection were important in predicting the stage of liver disease in HCV patients. However, after adjusting for length of HCV infection, TTV but not HCV genotype was important in predicting the stage of liver disease. CONCLUSIONS We conclude that 1) TTV infection is common in patients with chronic HCV; 2) TTV infection is more prevalent among patients with advanced HCV-associated liver disease (DC and HCC) than in those with stable disease (CH and CC); and 3) TTV infection is more common in patients with HCV genotype 1b but is independent from genotype in predicting the stage of HCV-associated liver disease.
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Affiliation(s)
- N N Zein
- Department of Laboratory Medicine and Pathology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota 55905, USA
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42
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Barrett S, Ryan E, Crowe J. Association of the HLA-DRB1*01 allele with spontaneous viral clearance in an Irish cohort infected with hepatitis C virus via contaminated anti-D immunoglobulin. J Hepatol 1999; 30:979-83. [PMID: 10406173 DOI: 10.1016/s0168-8278(99)80249-9] [Citation(s) in RCA: 70] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
BACKGROUND/AIMS The host's immune response may influence the course of hepatitis C virus (HCV) infection. The aim of this study was to examine the distribution of HLA Class II DRB1* alleles in a homogeneous cohort of individuals who were infected with HCV-contaminated anti-D immunoglobulin, and to compare frequencies of alleles in individuals with spontaneous viral clearance to those with chronic HCV infection. METHODS HLA DRB1* typing was performed on whole blood or serum from 157 females. Of these, 73 had spontaneously recovered from infection (persistently HCV RNA negative), while 84 had chronic HCV infection (persistently HCV RNA positive). A group of 5000 healthy bone marrow donors served as a control population. RESULTS No significant differences were observed between individuals with spontaneous viral clearance or chronic HCV infection for age, sex, alcohol consumption, source or duration of infection. The DRB1*01 allele was found significantly more frequently in individuals with viral clearance compared to those with chronic infection (27.4% vs. 7.1% p = 0.001, odds ratio OR = 4.9, pc = 0.01). No significant association was shown between severity of liver disease and DRB1* alleles. CONCLUSIONS DRB1*01 is associated with spontaneous viral clearance in an Irish cohort infected with HCV via contaminated anti-D immunoglobulin. HLA-DRB1* genes do not appear to influence severity of liver disease. These results suggest that host HLA-DRB1* alleles are important contributors to disease outcome.
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Affiliation(s)
- S Barrett
- Liver Unit, Mater Misericordiae Hospital, Dublin, Ireland
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Matsumori A, Ohashi N, Nishio R, Kakio T, Hara M, Furukawa Y, Ono K, Shioi T, Hasegawa K, Sasayama S. Apical hypertrophic cardiomyopathy and hepatitis C virus infection. JAPANESE CIRCULATION JOURNAL 1999; 63:433-8. [PMID: 10406581 DOI: 10.1253/jcj.63.433] [Citation(s) in RCA: 21] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
The familial form of hypertrophic cardiomyopathy (HCM) is attributed to mutations in the genes for contractile proteins, but the etiology of non-familial form remains unknown. This study was designed to examine the clinical features, histopathologic changes, and hepatitis C virus (HCV) genomes in patients with HCM associated with HCV infection. Anti-HCV antibody was present in the sera of 9 of 65 patients (13.8%) with HCM versus 2.41% in a control population of voluntary blood donors in Japan, a statistically significant difference (p<0.0001). Among these 9 patients, 6 had ace-of-spades-shaped deformities of the left ventricle with apical hypertrophy. Myocardial fibrosis was found in all patients, and mild cellular infiltration was observed in 5 patients. Type 1b HCV RNA was present in the sera of 5 of the 9 patients. The copy number of HCV was 5.5x10(3)-8.6x10(5) genomes/ml serum, and multiple clones of HCV were detected in the sera of each patient by an analysis of the hypervariable regions using fluorescent single-strand conformation polymorphism. Positive strands of HCV were found in the hearts of 5 patients, and negative strands in the hearts of 2 patients. A high prevalence of HCV infection was found in patients with HCM, particularly of the apical variety, suggesting that HCV is an important causal agent in the pathogenesis of the disease.
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Affiliation(s)
- A Matsumori
- Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Japan.
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44
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Mangia A, Gentile R, Cascavilla I, Margaglione M, Villani MR, Stella F, Modola G, Agostiano V, Gaudiano C, Andriulli A. HLA class II favors clearance of HCV infection and progression of the chronic liver damage. J Hepatol 1999; 30:984-9. [PMID: 10406174 DOI: 10.1016/s0168-8278(99)80250-5] [Citation(s) in RCA: 84] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/04/2022]
Abstract
BACKGROUND/AIMS This study was aimed to determine whether host-dependent genetic factors modulate the outcome of HCV infection. METHODS HLA class II DRB and DQB typing was performed in 184 infected patients and 200 healthy volunteers. Among the patients, 149 subjects had persistent HCV viremia (Group 1) and 35 subjects underwent spontaneous viral clearance (Group 2). Group 1 included cirrhotic patients with transfusion-acquired infections (n = 79), asymptomatic HCV carriers (n = 42), and patients with chronic hepatitis C responsive to interferon therapy (n = 28). RESULTS Spontaneous viral clearance was associated with HLA DRB1*1104 (pc = 0.054, OR = 4.51, 95% C.I. 2.02-10.1) and HLA DQB1*0301 (pc = 0.0039, OR = 4.52, 95% C.I. 2.15-9.51). In Group 1 the haplotype DRB1*1104/DQB1*0301 was less frequent (4.8%) than in Group 2 (18.3%) (pc = 0.009, OR = 7.38, 95% C.I. 2.58-21.59). At the HLA level, cirrhotic patients were not different from asymptomatic HCV carriers and patients with interferon-induced viral clearance. In cirrhotic patients infected with genotype 1b, the DQB1*0502 allele was more frequently found in those with rapidly progressive liver damage (OR = 8.15, 95% C.I. 1.49-44.44), but the corrected p-value was not significant (pc = 0.09). CONCLUSIONS The HLA haplotype DRB1*1104/DQB1*0301 appears to contribute to the spontaneous clearance of HCV infection. The predominance of the DQB1*0502 allele in cirrhotic patients with a rapidly progressive disease possibly reflects an influence of this allele on the progression of the HCV-related liver disease.
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Affiliation(s)
- A Mangia
- Division of Gastroenterology, Hospital Casa Sollievo della Sofferenza IRCCS, San Giovanni Rotondo, Italy.
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45
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Kuzushita N, Hayashi N, Kanto T, Takehara T, Tatsumi T, Katayama K, Ohkawa K, Ito A, Kasahara A, Moribe T, Sasaki Y, Hori M. Involvement of transporter associated with antigen processing 2 (TAP2) gene polymorphisms in hepatitis C virus infection. Gastroenterology 1999; 116:1149-54. [PMID: 10220507 DOI: 10.1016/s0016-5085(99)70018-1] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
BACKGROUND & AIMS Transporter associated with antigen processing (TAP) has essential roles in the antigen-presenting systems, translocating antigenic peptides from the cytosol into the endoplasmic reticulum. The aim of this study was to clarify whether TAP polymorphisms are involved in hepatitis C virus (HCV) infection. METHODS The 145 HCV-infected Japanese patients examined in this study were categorized into two groups: 36 carriers with persistently normal alanine transaminase (ALT) values and 109 patients with chronic liver disease (CLD). TAP2 gene phenotypes were determined by means of polymerase chain reaction-restriction fragment length polymorphism, and their frequencies were compared between the two groups. RESULTS Frequencies of TAP2*0101, *0102, and *0201 were not different between the two groups. However, TAP2*0103 frequency in carriers with normal ALT levels was significantly higher than that in patients with CLD (44% vs. 16%; P = 0.00064, Pc < 0.005). Although the TAP2*0103 allele was tightly linked with class II DRB1*1302-DQB1*0604 haplotype in this study, the TAP2*0103 frequency in the normal ALT group was also significantly higher than that in the CLD group even in DRB1*1302-DQB1*0604-negative patients (31% vs. 10%; P = 0.0076, Pc < 0.05). CONCLUSIONS These findings suggest that TAP2*0103 may be closely associated with low serum ALT activity in HCV-infected Japanese patients.
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Affiliation(s)
- N Kuzushita
- Department of Internal Medicine and Therapeutics, Osaka University School of Medicine, Osaka, Japan
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46
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Affiliation(s)
- P T Donaldson
- Institute of Liver Studies, King's College Hospital, Denmark Hill London SE5 9RS, UK
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47
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Asti M, Martinetti M, Zavaglia C, Cuccia MC, Gusberti L, Tinelli C, Cividini A, Bruno S, Salvaneschi L, Ideo G, Mondelli MU, Silini EM. Human leukocyte antigen class II and III alleles and severity of hepatitis C virus-related chronic liver disease. Hepatology 1999; 29:1272-9. [PMID: 10094975 DOI: 10.1002/hep.510290445] [Citation(s) in RCA: 70] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Hepatitis C outcome is likely related both to viral factors and host's immune responses. We correlated the severity of liver disease with human leukocyte antigen (HLA) genes (C4A, C4B, TNFA, TNFB, DRB1, DRB3, DRB4, DRB5, DQA1, DQB1, TAP1, and TAP2) in three groups of subjects: 99 patients with chronic hepatitis, 41 asymptomatic carriers, and 179 uninfected controls. Patients with grade/stage 3 to 4 hepatitis significantly differentiated for their low frequency of alleles TNFB*1, DRB1*1104, and DRB3*03, which had a protective role, and high frequency of allele DRB1*1001, which was associated with disease severity. HLA-DRB*11 subtypes were differentially distributed: DRB1*1104 was most frequent in carriers, whereas DRB1*1101 was more frequent in patients. The TAP1C,2A haplotype was also underrepresented in patients with respect to controls. Finally, a decrease of heterozygous subjects was observed in patients with respect to carriers at the DQB1 locus. Multivariate analysis by correspondence analysis and multiple logistic regression indicated that age, sex, and hepatitis C virus (HCV) type were the strongest risk factors; however, some immunogenetic variables (TNFB*1, DRB1*1104, and DRB3*03) showed an independent contribution, especially in comparing patients with extreme manifestations of disease. The involvement of different genes in various HLA subregions suggests that anti-HCV responses are modulated by a complex gene interplay rather than by single alleles.
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Affiliation(s)
- M Asti
- Department of Pathology, Università and IRCCS Policlinico San Matteo, Pavia, Italy
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48
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Affiliation(s)
- F Lunel
- Laboratoire de Bactério-Virologie, CHU Angers, France
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Tsai SL, Chen YM, Chen MH, Huang CY, Sheen IS, Yeh CT, Huang JH, Kuo GC, Liaw YF. Hepatitis C virus variants circumventing cytotoxic T lymphocyte activity as a mechanism of chronicity. Gastroenterology 1998; 115:954-65. [PMID: 9753499 DOI: 10.1016/s0016-5085(98)70268-9] [Citation(s) in RCA: 106] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS High rate of chronicity after acute hepatitis C virus (HCV) infection cannot be explained in the presence of a multispecific cytotoxic T lymphocyte (CTL) response. The aim of this study was to investigate the effect of virus variants on CTL activity in patients in whom chronicity developed. METHODS CTL clones specific to a decapeptide epitope derived from hypervariable region 1 were generated from 5 HLA-A2-positive patients with acute hepatitis C by in vitro stimulation with synthetic peptides. The sequential change of this CTL epitope and its influence on the CTL recognition were examined. RESULTS Virus variants did not appear in 3 patients with recovery, whereas variants with altered peptide ligands capable of antagonizing CTL activity emerged rapidly in the remaining 2 patients in whom chronicity developed. Importantly, these HLA-A2-restricted, hypervariable region 1-specific CTL clones shared the use of T-cell receptor (TCR) genes AV6 and BV17. CONCLUSIONS These data suggest that there is only a narrow T-cell repertoire responding to a single viral peptide/HLA ligand. The emergence of HCV variants with altered peptide ligands as TCR antagonists accompanied by a limited TCR repertoire may provide a mechanism for HCV chronicity.
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Affiliation(s)
- S L Tsai
- Liver Research Unit, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan
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Czaja AJ, Carpenter HA, Santrach PJ, Moore SB. Host- and disease-specific factors affecting steatosis in chronic hepatitis C. J Hepatol 1998; 29:198-206. [PMID: 9722200 DOI: 10.1016/s0168-8278(98)80004-4] [Citation(s) in RCA: 177] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
BACKGROUND/AIM Steatosis is commonly present in chronic hepatitis C. Our aim was to evaluate host- and disease-specific factors associated with its occurrence. METHODS Histologic findings in 60 patients were correlated with body mass index, human leukocyte antigens, and other conventional parameters. Comparisons were made with 41 patients who had nonalcoholic steatohepatitis and 18 patients who had chronic hepatitis B. RESULTS Patients with chronic hepatitis C and steatosis had lower serum concentrations of gamma-globulin (p=0.01) and immunoglobulin G (p=0.05) than their counterparts without steatosis, and they had a lower frequency of antinuclear antibodies (19% versus 52%, p=0.01). They also had a higher mean body mass index (p=0.002) and a greater frequency of risk factors for steatosis (70% versus 34%, p=0.009). These risk factors, however, occurred more commonly in patients with nonalcoholic steatosis (p=0.007). Furthermore, fat deposition occurred more often in chronic hepatitis C than in chronic hepatitis B (52% versus 22%, p=0.03), despite comparable metabolic findings. The degree of steatosis in chronic hepatitis C was not associated with individual metabolic features. CONCLUSIONS Steatosis in chronic hepatitis C is mainly a viral effect, and host-dependent metabolic factors may potentiate the manifestation. Fat deposition is associated with less immunoreactivity and it may connote a distinctive pathogenic mechanism.
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Affiliation(s)
- A J Czaja
- Division of Gastroenterology and Hepatology, Mayo Clinic and Mayo Foundation, Rochester, Minnesota 55905, USA
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