Host genetic determinants in hepatitis C virus infection

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 selflimiting 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.

Patient HLA-DRB1* and -DQB1* allele and haplotype association with hepatitis C virus persistence and clearance

“…However, when the non-SVR group was compared with the SVR group, the HLA-DQB1*0301 allele was found to be associated with virus clearance and HLA-DRB1*07 with virus persistence following IFN therapy, the former being consistent with previous findings (Cursino-Santos et al, 2007;Hong et al, 2005;Thio et al, 2001;Yee, 2004). In addition, Cramp et al (1998) observed a significantly higher frequency of HLA-DQB1*0301 in patients who spontaneously cleared the virus as opposed to chronically infected patients, although we did not see any statistically significant difference in the frequency of this allele in patients and normal controls.…”

Impact of the genetic restriction of virus-specific T-cell responses in hepatitis C virus infection

“…In two independent metaanalyses, the association between DRB1*1101 and viral clearance had an OR of 2.5 (95% CI 1.7-3.7) and 2.02 (95% CI 1.6-2.6), respectively, whereas the association between DQB1*03 and viral clearance was estimated at an OR of 3.0 (95% CI 1.8-4.8) and 2.4 (95% CI 1.6-3.4), respectively. 95,96 Notably, different factors may have contributed to an overinterpretation of the protective role of DRB1*11 and DQB1*0301 in both metaanalyses. First, there might be a bias towards the publication of studies with positive HLA associations, whereas studies showing no significant association with any HLA allele are probably less likely published.…”

Mechanisms of action of interferon and ribavirin in chronic hepatitis C: Summary of a workshop

“…In small studies done in patients with hepatitis C receiving antiviral therapy in clinical trials, genes associated with a higher likelihood of response have included major histocompatibility complex alleles, polymorphisms in ISGs such as Mx1, 41 and heterozygosity for HFE H63D , 42 but these associations need to be reproduced in other populations and independently confirmed. In a cross-sectional study of a large cohort of persons with chronic hepatitis C, a polymorphism in the promoter region of IFN-γ (−764G) was found to be more common in persons who spontaneously recovered from HCV infection compared to those who developed chronic infection (4.2% versus 1.6%) and in patients who had an SVR compared to nonresponse (11.2% versus 4.3%) to IFN-α-based therapy.…”

“…The candidates include those involved in the IFN-α/β pathway, including ISGs, genes encoding immunomodulatory cytokines, genes of the major histocompatibility complex regions, and genes involved in cell death and stress responses. In these studies, confounding and spurious associations can affect results, particularly when we are dealing with racially diverse and genetically heterogeneous populations.In small studies done in patients with hepatitis C receiving antiviral therapy in clinical trials, genes associated with a higher likelihood of response have included major histocompatibility complex alleles, polymorphisms in ISGs such as Mx1, 41 and heterozygosity for HFE H63D , 42 but these associations need to be reproduced in other populations and independently confirmed. In a cross-sectional study of a large cohort of persons with chronic hepatitis C, a polymorphism in the promoter region of IFN-γ (−764G) was found to be more common in persons who spontaneously recovered from HCV infection compared to those who developed chronic infection (4.2% versus 1.6%) and in patients who had an SVR compared to nonresponse (11.2% versus 4.3%) to IFN-α-based therapy.…”