Ethnic and geographical differences in HLA associations with the outcome of hepatitis C virus infection

Wang, H; Zheng, Xin; Ke, Xiaogang; Dorak, M. Tevfik; Shen, Jingjing; Boodram, Basmattee; O’Gorman, Maurice R.G.; Beaman, Kenneth D.; Cotler, Scott J.; Hershow, Ronald C.; Rong, Lijun

doi:10.1186/1743-422x-6-46

Cited by 37 publications

(46 citation statements)

References 30 publications

(46 reference statements)

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“…Other studies have also identified HLA-A*03 as a critical determinant of outcome in HCV and hepatitis B virus (HBV). Wang et al describe an association between viral clearance and HLA-A*03; however, this association was only identified in the non-Caucasian subgroup of the cohort 34. In a Korean study, HLA-A*03 was found significantly more frequently in chronic HCV carriers compared with healthy controls 35.…”

Section: Discussionmentioning

confidence: 96%

Molecular footprints reveal the impact of the protective HLA-A*03 allele in hepatitis C virus infection

Fitzmaurice

Petrović

Ramamurthy

et al. 2011

Gut

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Background and aimsCD8 T cells are central to the control of hepatitis C virus (HCV) although the key features of a successful CD8 T cell response remain to be defined. In a cohort of Irish women infected by a single source, a strong association between viral clearance and the human lecucocyte (HLA)-A*03 allele has been described, and the aim of this study was to define the protective nature of the associated CD8 T cell response.MethodsA sequence-led approach was used to identify HLA-A*03-restricted epitopes. We examine the CD8 T cell response associated with this gene and address the likely mechanism underpinning this protective effect in this special cohort, using viral sequencing, T cell assays and analysis of fitness of viral mutants.ResultsA strong ‘HLA footprint’ in a novel NS3 epitope (TVYHGAGTK) was observed. A lysine (K) to arginine (R) substitution at position 9 (K1088R) was seen in a significant number of A*03-positive patients (9/12) compared with the control group (1/33, p=0.0003). Threonine (T) was also substituted with alanine (A) at position 8 (T1087A) more frequently in A*03-positive patients (6/12) compared with controls (2/33, p=0.01), and the double substitution of TK to AR was also observed predominantly in HLA-A*03-positive patients (p=0.004). Epitope-specific CD8 T cell responses were observed in 60% of patients three decades after exposure and the mutants selected in vivo impacted on recognition in vitro. Using HCV replicons matched to the viral sequences, viral fitness was found to be markedly reduced by the K1088R substitution but restored by the second substitution T1087A.ConclusionsIt is proposed that at least part of the protective effect of HLA-A*03 results from targeting of this key epitope in a functional site: the requirement for two mutations to balance fitness and escape provides an initial host advantage. This study highlights the potential protective impact of common HLA-A alleles against persistent viruses, with important implications for HCV vaccine studies.

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Section: Discussionmentioning

confidence: 96%

Molecular footprints reveal the impact of the protective HLA-A*03 allele in hepatitis C virus infection

Fitzmaurice

Petrović

Ramamurthy

et al. 2011

Gut

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“…Studies also showed the importance of HLA molecules to the natural outcomes of HCV infection. Although it has been reported in a few sufficiently sampled and well-designed studies that some alleles have strong associations with HCV infection [10,16–18], many other studies were limited either due to a small study population, or an inappropriate population stratification, or the lack of correction for multiple comparisons, or a low resolution typing technique [5,19]. Moreover, racial differences in the studies of association between the HLA patterns and the outcomes of HCV infection were also identified [18–21].…”

Section: Introductionmentioning

confidence: 99%

HLA-B Alleles B15:01 and B15:02: Opposite Association with Hepatitis C Virus Infection in Chinese Voluntary Blood Donors

et al. 2015

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Background: Although human leukocyte antigens (HLA) have been shown in association with the outcomes of hepatitis C virus (HCV) infection among different ethnic groups, such studies remain absent in China, where the HCV prevalence is higher than the global average. Methods: In this study, 426 HCV-infected and 709 uninfected blood donors were analyzed, among whom the HLA alleles were sequenced using a high-resolution genotyping method. Results: At the 2-digit level, none of the alleles showed a statistical difference between the HCV-infected and uninfected groups. However, at the 4-digit level, the HLA-B alleles B*15:01 and B*15:02 showed an opposite association with HCV infection, i.e. B*15:01 was significantly higher in the HCV-infected group (odds ratio, OR = 1.561, p = 0.010), while B*15:02 was significantly higher in the uninfected group (OR = 0.778, p = 0.016). We also identified a higher frequency of B*13:02 in the HCV-infected group (OR = 1.515, p = 0.009) and a higher frequency of B*07:05 in the uninfected group (OR = 0.299, p = 0.001). Conclusions: The frequencies of four HLA alleles, B*07:05, B*13:02, B*15:01, and B*15:02, were found to be significantly different between the HCV-infected and uninfected blood donors in China, revealing an inverse relation of B*15:01 and B*15:02 with HCV infection. This finding suggests that the ethnic genetic variations of HLA may greatly affect the host immune responses against HCV.

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“…For analysis, liver fibrosis was also classified either being mild (0-2), moderate (3)(4) or severe (5-6). Activity was graded into minimal (0-4), mild (5-8), moderate (8)(9)(10)(11)(12) and severe (13)(14)(15)(16)(17)(18)). All patients were tested negative for both hepatitis B surface antigen (HBs antigen) and anti-HIV antibody.…”

Section: Methodsmentioning

confidence: 99%

“…on the associations between HLA Class II alleles and HCV infection [12]. In addition, the reported associations showed ethnic and geographical differences [13][14][15][16].…”

Section: Introductionmentioning

confidence: 99%

Association of Human Leucocyte Antigen Class I (HLA-A and HLA-B) With Chronic Hepatitis C Virus Infection in Egyptian Patients

Mosaad

Farag

Arafa

et al. 2010

Scandinavian Journal of Immunology

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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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Ethnic and geographical differences in HLA associations with the outcome of hepatitis C virus infection

Cited by 37 publications

References 30 publications

Molecular footprints reveal the impact of the protective HLA-A*03 allele in hepatitis C virus infection

Molecular footprints reveal the impact of the protective HLA-A*03 allele in hepatitis C virus infection

HLA-B Alleles B15:01 and B15:02: Opposite Association with Hepatitis C Virus Infection in Chinese Voluntary Blood Donors

Association of Human Leucocyte Antigen Class I (HLA-A and HLA-B) With Chronic Hepatitis C Virus Infection in Egyptian Patients

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Ethnic and geographical differences in HLA associations with the outcome of hepatitis C virus infection

Cited by 37 publications

References 30 publications

Molecular footprints reveal the impact of the protective HLA-A*03 allele in hepatitis C virus infection

Molecular footprints reveal the impact of the protective HLA-A*03 allele in hepatitis C virus infection

HLA-B Alleles B*15:01 and B*15:02: Opposite Association with Hepatitis C Virus Infection in Chinese Voluntary Blood Donors

Association of Human Leucocyte Antigen Class I (HLA-A and HLA-B) With Chronic Hepatitis C Virus Infection in Egyptian Patients

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HLA-B Alleles B15:01 and B15:02: Opposite Association with Hepatitis C Virus Infection in Chinese Voluntary Blood Donors