Susceptibility and Interferon Response in HBV Infection
A recent genome-wide association study discovered that two polymorphisms, interferon (IFN) alpha receptor 2 (IFNAR-2) F8S and interleukin 10 receptor (IL10RB) K47E, were associated with susceptibility to hepatitis B virus (HBV) infection in Africa. Here, we reevaluate the effects of the two polymorphisms on HBV susceptibility in the Chinese Han population, and extended the study to look at their association with IFN response in chronic hepatitis B (CHB). We included 341 patients with CHB and 341 unrelated controls presenting with asymptotic HBV self-limited infection, who were well matched in age and sex. In the CHB group, 101 patients had been treated with peg-IFN-alpha-2a for 48 weeks and followed up for 24 weeks to determine the clinical response, resulting 34 individuals with sustained virological response (SVR) and 67 individuals with nonsustained response (NR). Subgroups in the CHB group were divided according to the viral loads, HBeAg and maternal HBsAg status. The association with the susceptibility to HBV infection was only observed for IL10RB K47E when we compared the individuals with persistent HBV infection through nonmaternal transmission to the controls with asymptomatic self-limited HBV infection. Further, we found that the IFNAR2–8SS genotype was associated with HBeAg negative patients (OR = 0.316, 95% CI: 0.121–0.825, P = 0.019) and that the IFNAR2–8F allele was associated with the risk to high viral loads (OR = 1.667, 95% CI: 1.148–2.420, P = 0.007). In addition, the IFNAR2–8FF genotype predisposed to higher MxA gene induction and correlated with sustained IFN response (OR = 0.348, 95% CI: 0.129–0.935, P = 0.036). Haplotype analysis based on polymorphisms of three single-nucleotide polymorphisms, MxA −88 G/T, IFNAR-2 F8S and IL10RB K47E showed that the haplotype distribution was significantly different between the SVR and NR groups (P = 0.040). This study suggests that IFNAR2 may play an important role in determining IFN response and clinical phenotypes of HBV infection in the Chinese Han population.
Hepatitis B virus (HBV) is the most common cause of acute and chronic liver diseases in Asia and Africa with about 400 million people with chronic viral infection worldwide. The majority of individuals could clear the virus successfully, while only 5–10% develop to chronic hepatitis B (CHB) and present with a persistent viral infection state. Host genetic factors play an important role in determining differential susceptibility to HBV infection. Although twin studies and limited genetic association study data have supported that the genetic factors, such as HLA, polymorphisms in cytokines and immune response-related genes could influence the outcomes of HBV infection, major susceptibility loci have not yet been identified.
Frodsham et al. initially studied around 200 sibling pairs from The Gambia with chronic HBV infection through genome-wide approach, and identified a major susceptibility locus as a cluster of class II cytokine receptor genes on chromosome 21q22 with significant linkage peak (lod > 3.16). A strong haplotypic association was found comprising two nonsynonymous single-nucleotide polymorphisms (SNPs) in the interferon-alpha receptor-2 gene (IFNAR-2), F8S and the second chain of the IL-10 (IL10RB), K47E. However, the effects of the two SNPs in Chinese Han population were still unknown. Indeed, Chinese Han CHB patients were different from those in The Gambia in several epidemiological aspects. Most of Chinese CHB patients were infected during the early neonatal stage through maternal-to-infant transmission and clustered in the family, but this situation, known as vertical transmission was rare in Africa. In the viral aspects, the prevalent HBV viral genotypes in China were genotypes B and C rather than genotype E in The Gambia.
Considering the importance of IFN, type I IFN was found to inhibit various kinds of viruses, and adopted in the treatment of CHB for 20 years. Now, type I IFN is systematically recommended as the first-line drug to treat CHB, normalizing liver function and decreasing viral loads. Such desirable effects rely on the binding of type I IFN with its receptors, IFNAR-1 and IFNAR-2, which subsequently activate a JAK-STAT signalling cascade to initiate the transcription of 100s of IFN-dependent gene, such as MxA, OAS1 and PKR. Our previous data show that MxA induction could be a useful maker to predict sustained response to IFN treatment. Based on the two different clinical phenotypes, the susceptibility to chronic HBV infection and IFN treatment responses, we conduct the case–control association study and functional exploration for IFNAR2 F8S and IL10RB K47E.
Summary and Introduction
Summary
A recent genome-wide association study discovered that two polymorphisms, interferon (IFN) alpha receptor 2 (IFNAR-2) F8S and interleukin 10 receptor (IL10RB) K47E, were associated with susceptibility to hepatitis B virus (HBV) infection in Africa. Here, we reevaluate the effects of the two polymorphisms on HBV susceptibility in the Chinese Han population, and extended the study to look at their association with IFN response in chronic hepatitis B (CHB). We included 341 patients with CHB and 341 unrelated controls presenting with asymptotic HBV self-limited infection, who were well matched in age and sex. In the CHB group, 101 patients had been treated with peg-IFN-alpha-2a for 48 weeks and followed up for 24 weeks to determine the clinical response, resulting 34 individuals with sustained virological response (SVR) and 67 individuals with nonsustained response (NR). Subgroups in the CHB group were divided according to the viral loads, HBeAg and maternal HBsAg status. The association with the susceptibility to HBV infection was only observed for IL10RB K47E when we compared the individuals with persistent HBV infection through nonmaternal transmission to the controls with asymptomatic self-limited HBV infection. Further, we found that the IFNAR2–8SS genotype was associated with HBeAg negative patients (OR = 0.316, 95% CI: 0.121–0.825, P = 0.019) and that the IFNAR2–8F allele was associated with the risk to high viral loads (OR = 1.667, 95% CI: 1.148–2.420, P = 0.007). In addition, the IFNAR2–8FF genotype predisposed to higher MxA gene induction and correlated with sustained IFN response (OR = 0.348, 95% CI: 0.129–0.935, P = 0.036). Haplotype analysis based on polymorphisms of three single-nucleotide polymorphisms, MxA −88 G/T, IFNAR-2 F8S and IL10RB K47E showed that the haplotype distribution was significantly different between the SVR and NR groups (P = 0.040). This study suggests that IFNAR2 may play an important role in determining IFN response and clinical phenotypes of HBV infection in the Chinese Han population.
Introduction
Hepatitis B virus (HBV) is the most common cause of acute and chronic liver diseases in Asia and Africa with about 400 million people with chronic viral infection worldwide. The majority of individuals could clear the virus successfully, while only 5–10% develop to chronic hepatitis B (CHB) and present with a persistent viral infection state. Host genetic factors play an important role in determining differential susceptibility to HBV infection. Although twin studies and limited genetic association study data have supported that the genetic factors, such as HLA, polymorphisms in cytokines and immune response-related genes could influence the outcomes of HBV infection, major susceptibility loci have not yet been identified.
Frodsham et al. initially studied around 200 sibling pairs from The Gambia with chronic HBV infection through genome-wide approach, and identified a major susceptibility locus as a cluster of class II cytokine receptor genes on chromosome 21q22 with significant linkage peak (lod > 3.16). A strong haplotypic association was found comprising two nonsynonymous single-nucleotide polymorphisms (SNPs) in the interferon-alpha receptor-2 gene (IFNAR-2), F8S and the second chain of the IL-10 (IL10RB), K47E. However, the effects of the two SNPs in Chinese Han population were still unknown. Indeed, Chinese Han CHB patients were different from those in The Gambia in several epidemiological aspects. Most of Chinese CHB patients were infected during the early neonatal stage through maternal-to-infant transmission and clustered in the family, but this situation, known as vertical transmission was rare in Africa. In the viral aspects, the prevalent HBV viral genotypes in China were genotypes B and C rather than genotype E in The Gambia.
Considering the importance of IFN, type I IFN was found to inhibit various kinds of viruses, and adopted in the treatment of CHB for 20 years. Now, type I IFN is systematically recommended as the first-line drug to treat CHB, normalizing liver function and decreasing viral loads. Such desirable effects rely on the binding of type I IFN with its receptors, IFNAR-1 and IFNAR-2, which subsequently activate a JAK-STAT signalling cascade to initiate the transcription of 100s of IFN-dependent gene, such as MxA, OAS1 and PKR. Our previous data show that MxA induction could be a useful maker to predict sustained response to IFN treatment. Based on the two different clinical phenotypes, the susceptibility to chronic HBV infection and IFN treatment responses, we conduct the case–control association study and functional exploration for IFNAR2 F8S and IL10RB K47E.
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