Genetic variation in the interleukin-28B gene is not associated with fibrosis progression in patients with chronic hepatitis C and known date of infection

Polymorphisms in the interleukin-28B (IL28B) region are associated with spontaneous and treatment-induced viral clearance in hepatitis C virus (HCV) infection. Nevertheless, it is unknown whether genetic variation at the IL28B locus influences the natural history of chronic HCV infection. Thus, we asked whether an association between IL28B polymorphisms and liver fibrosis progression existed. We studied 247 consecutive patients with chronic HCV, an accurate estimate of the date of infection, and a liver biopsy performed before any treatment. No patient had a history of alcohol abuse or coinfection with other viruses. We assessed the role of rs8099917 and rs12979860 polymorphisms and the effect of host and environmental factors on fibrosis progression. Blood transfusion (75%) was the main modality of infection. Median age at infection was 21 years, and median interval between infection and liver biopsy was 25 years. One hundred twenty-nine patients (52%) were infected by HCV-1, 74 (30%) by HCV-2, 34 (14%) by HCV-3, and 10 (4%) by HCV-4. Bridging fibrosis/cirrhosis (Ishak ≥ 4) was detected in 24% of patients. Age at infection had a marked effect on fibrosis progression by both a linear model and Cox proportional-hazard regression (P < 2E-16). A 12.1% increase in the hazard of advanced fibrosis was estimated for each additional year at infection, suggesting that this was the major explanatory variable in this cohort. Male gender (P < 0.05), HCV genotype 3 (P < 0.001) and steatosis (P < 0.05) were also associated with faster fibrosis progression. Conversely, the two IL28B polymorphisms had no impact on fibrosis progression. CONCLUSION: In HCV patients with a known date of infection, IL28B genotype was not associated with fibrosis progression rate or with the risk of developing advanced liver fibrosis.     

Association of IL28B SNP With Progression of Egyptian HCV Genotype 4 Patients to End Stage Liver Disease

Background

IL28B single nucleotide polymorphisms (SNPs) play important roles in the management of hepatitis C virus (HCV) infections and are strongly associated with spontaneous and treatment-induced HCV clearance.

Objectives

In the present study, the association between IL28B variants and the progression of HCV infection in Egyptian patients infected with type 4a virus will be examined.

Patients and Methods

Frequencies of the protective genotype C/C of SNP, rs12979860 were determined in healthy subjects, spontaneous resolvers, and chronic HCV type 4 patients with low F scores and in patients with end stage liver disease (ESLD). This study included a total of 404 subjects. Patients infected with HCV type 4a (n = 304) were divided into; chronic hepatitis C (CHC) with low F scores (CHC, n = 110), end stage liver disease (n = 110), liver cirrhosis (LC) (n = 35) and hepatocellular carcinoma (HCC) patients (n = 75), spontaneous resolvers of HCV infection (n = 84) were also included. A healthy group representing the Egyptian population (n = 100) was also included in the genotyping of IL28B. The later was typed via a polymerase chain reaction based restriction fragment length polymorphism (PCR-RFLP) assay analysis on purified genomic DNA extracted from all individuals.

Results

A significant increase (P < 0.0005) was observed in frequencies of IL-28B rs12979860 C/C genotypes in the healthy population, than in the CHC, LC and HCC groups (C/C = 48%, 13%, 0%.and 0% respectively). On the other hand the C/C genotype was significantly higher (P < 0.0005) in spontaneous resolvers than in healthy subjects. A comparable significant increase in the frequency of C/T allele accompanied by mild elevation of T/T allele frequency, were detected along the progression towards ESLD.

Conclusions

Genotype C/C is associated with viral clearance during acute infection. The sharp decline in the C/C genotype from healthy to CHC subjects and the total absence of the C/C genotype in ESLD suggests a central role of this genotype against HCV disease progression.     

The impact of human gene polymorphisms on HCV infection and disease outcome

In recent years, some genome-wide association studies have identified several single nucleotide polymorphisms (SNPs) associated with hepatitis C viral containment, treatment response, and disease progression. IL28B is a gene on chromosome 19, coding for interferon-λ3, and two polymorphisms upstream of this the gene have been strongly associated with clinical outcomes after treatment for the hepatitis C virus (HCV). The IL28B polymorphisms have additionally been associated with spontaneous clearance. The mechanism has yet to be clearly defined, but appears to involve differential responsiveness to interferon signaling between the favorable and unfavorable genotypes. ITPA is a gene on chromosome 20, coding for inosine triphosphatase, and polymorphisms on this gene have been associated with ribavirin-induced hemolytic anemia. Functional variants of ITPA have been identified that have decreased enzymatic activity, which appear to protect against anemia. Finally, PNPLA3 polymorphisms were initially described as predictors of nonalcoholic fatty liver disease, but have recently been associated with disease progression in HCV.     

Interleukin 28B polymorphisms are the only common genetic variants associated with low-density lipoprotein cholesterol (LDL-C) in genotype-1 chronic hepatitis C and determine the association between LDL-C and treatment response

Low-density lipoprotein cholesterol (LDL-C) levels and interleukin 28B (IL28B) polymorphism are associated with sustained viral response (SVR) to peginterferon/ribavirin (pegIFN/RBV) for chronic hepatitis C (CHC) infection. IL28B has been linked with LDL-C levels using a candidate gene approach, but it is not known whether other genetic variants are associated with LDL-C, nor how these factors definitively affect SVR. We assessed genetic predictors of serum lipid and triglyceride levels in 1604 patients with genotype 1 (G1) chronic hepatitis C virus (HCV) infection by genome-wide association study and developed multivariable predictive models of SVR. IL28B polymorphisms were the only common genetic variants associated with pretreatment LDL-C level in Caucasians (rs12980275, P = 4.7 × 10(-17), poor response IL28B variants associated with lower LDL-C). The association was dependent on HCV infection, IL28B genotype was no longer associated with LDL-C in SVR patients after treatment, while the association remained significant in non-SVR patients (P < 0.001). LDL-C was significantly associated with SVR for heterozygous IL28B genotype patients (P < 0.001) but not for homozygous genotypes. SVR modelling suggested that IL28B heterozygotes with LDL-C > 130 mg/dL and HCV RNA ≤600 000 IU/mL may anticipate cure rates >80%, while the absence of these two criteria was associated with an SVR rate of <35%. IL28B polymorphisms are the only common genetic variants associated with pretreatment LDL-C in G1-HCV. LDL-C remains significantly associated with SVR for heterozygous IL28B genotype patients, where LDL-C and HCV RNA burden may identify those patients with high or low likelihood of cure with pegIFN/RBV therapy.     

IL28B polymorphisms predict response to therapy among chronic hepatitis C patients with HCV genotype 4

Summary. Genetic polymorphisms near IL28B are associated with spontaneous and treatment‐induced clearance of hepatitis C virus (HCV). Our objective was to assess the predictive value of IL28B polymorphisms in the treatment of chronic hepatitis C of patients with HCV genotypes 4, for which data are currently limited. We analysed the association of IL28B polymorphisms with the virological response to treatment among 182 naïve chronic hepatitis C patients with HCV genotype 4, all from Syria. Associations of alleles with the response patterns were evaluated by univariate analysis and multivariate logistic regression, accounting for all relevant covariates. Sustained virological response (SVR) was achieved in 26% of rs8099917 TG/GG carriers compared with 60% of TT carriers (P < 0.0001) and 35% of rs12979860 CT/TT carriers compared with 62% of CC carriers (P = 0.0011). By multivariate analysis, the association between rs8099917 and SVR remained significant (OR = 0.19, 95% CI 0.07–0.50, for TG/GG vs TT, P = 0.0007), with the only significant covariate being advanced fibrosis (OR = 0.13, 95% CI 0.04–0.37, P = 0.0002). In conclusion, IL28B polymorphisms are the strongest predictors of response to therapy among chronic hepatitis C patients with HCV genotype 4.     

IL28B genetic variation and treatment response in patients with hepatitis C virus genotype 3 infection

Polymorphisms near the IL28B gene, which code for interferon (IFN)-λ3, predict response to pegylated interferon-α (PEG-IFN) and ribavirin treatment in hepatitis C virus (HCV) genotype 1 infected patients. Follow-up studies of the effect of IL28B gene in HCV non-genotype 1 infected patients have almost always used predominantly HCV genotype 2-infected or mixed genotype 2/3-infected cohorts with results partly conflicting with HCV genotype 1. We performed a retrospective analysis of 281 patients infected with HCV genotype 3 for association of response to therapy with IL28B polymorphisms. We found that the HCV genotype 1 responder genotypes at rs12979860 and rs8099917 did not associate with sustained virological response to PEG-IFN/ribavirin therapy. However, the responder genotypes of both SNPs showed association with rapid viral response measured at 4 weeks (rs12979860, P = 3 × 10(-5) ; rs8099917, P = 3 × 10(-4) ). In multivariate analysis, age (<40 years), baseline viral load (<4 × 10(5) IU/mL) and the responder genotypes of SNPs rs12979860 or rs8099917 remained significant independent predictors of rapid viral response to therapy. Furthermore, we show that IL28B polymorphisms are associated with relapse in patients who achieve rapid viral response to PEG-IFN/ribavirin therapy. The responder genotypes also showed association with markers of stage and activity of liver disease, namely high aspartate aminotransferase platelet ratio index (APRI, rs12979860, P = 0.018; rs8099917, not significant) and high alanine aminotransferase (ALT, rs12979860, P = 0.002; rs8099917, P = 0.001), in addition to a high baseline viral load (rs12979860, P = 1.4 × 10(-5) ; rs8099917, P = 7.3 × 10(-6) ). CONCLUSION: Polymorphisms near the IL28B gene show association with rapid viral response but not sustained viral response to PEG-IFN/ribavirin therapy in HCV genotype 3-infected patients.     

Distribution of IL28B Genotypes in Iranian Patients with Chronic Hepatitis C and Healthy Individuals

Background

IL28B polymorphism is recognized as one of the most prominent predictors of hepatitis C spontaneous and treatment-induced clearance. Interestingly, the favorable genotypes of IL28B are found to be more frequent in Asian ethnicity than Caucasian and African populations, respectively. A few studies reported that there is a mysterious association between the IL28B polymorphism and the hepatitis C virus (HCV) genotype in patients with chronic hepatitis C but they did not give any reason for this phenomenon.

Objectives

The foremost purpose of this study was to compare the distribution of IL28B genotypes between Iranian healthy individuals and patients with chronic hepatitis C.

Patients and Methods

In this study, 921 patients with chronic hepatitis C and 142 healthy individuals were included. The IL28B rs12979860 and rs8099917 polymorphisms were genotyped using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method.

Results

The frequency of IL28B rs12979860 CC, CT, and TT genotypes in chronic hepatitis C patients was 38%, 48.8%, and 13.2% and in healthy individuals was 43.7%, 48.6%, and 7.7%. Also, the frequency of IL28B rs8099917 TT, GT, and GG genotypes in chronic hepatitis C patients was 58.3%, 37.1%, and 4.6% and in healthy individuals was 64.1%, 32.4% and 3.5%. The differences in the distribution of IL28B rs12979860 and rs8099917 genotypes between patients with chronic hepatitis C and healthy individuals were not statistically significant. When we compared the distribution of IL28B genotypes between the healthy group and the HCV infected patients by HCV genotype, we found 9.8% higher frequency of rs12979860 CC genotype in the healthy individuals than HCV genotype 1 infected patients (P = 0.03) however there was no significant difference in the distribution of rs12979860 genotypes between the healthy and HCV genotype 3 infected groups (P = 0.46).

Conclusions

It seems that the impact of IL28B polymorphism on the spontaneous clearance of HCV genotype 1 is more prominent than HCV genotype 3 which results in the observation of higher rs12979860 C allele frequency in chronic hepatitis C patients with HCV genotype 3 than HCV genotype 1.     

Genetic polymorphism in cyclooxygenase-2 promoter affects hepatic inflammation and fibrosis in patients with chronic hepatitis C

Summary. Cyclooxygenase (COX)-2 is involved in inflammation, anti-apoptosis and carcinogenesis. The -1195GG genotype of single nucleotide polymorphism (SNP) in COX-2 promoter was associated with low platelet counts in patients with chronic hepatitis C. Polymorphism of patatin-like phospholipase domain-containing protein 3 (PNPLA3) gene (rs738409 C>G) have been reported to be associated with cirrhosis, and the major genotype of SNPs near interleukin (IL)28B are related to viral clearance. The present study was designed to assess the contribution of these SNPs to disease progression in patients with chronic hepatitis C. The study enrolled 220 Japanese patients with chronic hepatitis C. Three SNPs, -1195 COX-2, PNPLA3 and IL28B (rs8099917), were genotyped in order to analyze their association with hepatic fibrosis and inflammation. The -1195GG genotype in COX-2 was associated with advanced fibrosis and higher levels of inflammation in the liver tissues. The major genotype of IL28B was also associated with advanced fibrosis, but the polymorphism of PNPLA3 was neither associated with fibrosis nor inflammation. Multivariate analysis showed that -1195GG in COX-2 is an independent factor associated with advanced fibrosis, while the major genotype of IL28B and HCV genotype 2 were other independent factors. In conclusion, the -1195GG genotype in COX-2 is a genetic marker for liver disease progression, while the PNPLA3 genotypes are not associated with disease progression in Japanese patients with chronic hepatitis C.     

Interleukin-28B polymorphisms are associated with histological recurrence and treatment response following liver transplantation in patients with hepatitis C virus infection

Polymorphism in the interleukin-28B (IL28B) gene region, encoding interferon (IFN)-λ3, is strongly predictive of response to antiviral treatment in the nontransplant setting. We sought to determine the prevalence and impact on clinical outcomes of donor and recipient IL28B genotypes among liver transplant recipients. The cohort study included 189 consecutive patients infected with hepatitis C virus (HCV) who underwent liver transplantation between January 1, 1995, and January 1, 2005, at the Mayo Clinic, Rochester, MN. Genotyping of the polymorphism rs12979860 was performed on DNA collected from all donors and recipients in the cohort. Sixty-five patients received IFN-based antiviral therapy. The CC IL28B variant was less common in the chronic HCV-infected recipients than in non-HCV donor livers (33% versus 47%, P = 0.03). IL28B recipient genotype was significantly predictive of fibrosis stage, with TT genotype being associated with more rapid fibrosis (Pearson chi-square P = 0.024 for the comparison G versus A). Donor and recipient IL28B genotype were independently associated with sustained virologic response (P < 0.005). The presence of IL28B CC variant in either the recipient (R) or donor (D) liver was associated with increased rate of sustained virologic response (D-non-CC/R-non-CC = 3/19 [16%] versus D-CC/R-non-CC = 11/22 [50%] versus D-non-CC/R-CC = 5/12 [42%] versus R-CC/D-CC = 6/7 [86%], P = 0.0095). IL28B genotype was not significantly associated with survival (overall/liver-related). CONCLUSION: Recipient IL28B TT genotype is associated with more severe histological recurrence of HCV. Recipient and donor liver IL28B genotype are strongly and independently associated with IFN-based treatment response in patients after orthotopic liver transplantation. The data suggest that CC donor livers might be preferentially allocated to patients with HCV infection.     

IL-28B基因多态性与慢性丙型肝炎患者肝纤维化的相关性研究

目的探讨IL-28B基因多态性与慢性丙型肝炎(chronic hepatitisC,CHC)患者肝纤维化的相关性。方法选择65例CHC患者(男34例,女31例),检测患者rs12979860和rs8099917两个位点的基因型,并用瞬时弹性波扫描(FibroScan,FS)检测患者肝纤维化程度,分析这两个位点与肝纤维化的关系。结果 rs12979860和rs8099917两个位点的基因型与FS值的关系无统计学意义;但患者年龄(t=4.062,P=0.000)及感染时年龄(t=3.068,P=0.003)与FS值相关。结论 IL-28B基因对CHC患者肝纤维化的影响不显著。但患者年龄及感染时的年龄可能与CHC患者肝纤维化有关。     

HCV基因型对慢性丙型肝炎干扰素疗效的影响

目的 探讨HCV基因型对慢性丙型肝炎的干扰素（IFN）治疗效果的影响。方法 采用随机、开放和对照的多中心临床试验设计。208例受试者按1：1随机分到聚乙二醇干扰素α—2a(Peg-IFN）组和IFN-α-2a组。在治疗之前，用Simmonds基因分型法酶切分型，在治疗24周结束和完成24周的随访后检测患者的ALT和HCV RNA，以HCV RNA的阴转率作为主要评价指标，经ITT人群的统计学分析。结果 202例患者确定了HCV基因型，基因1型158例（78.2%），非基因1型44例（21.8%），治疗结束病毒应答率（ETVR）和持续病毒应答率（SVR）基因1型患者分别为53.8%和25.3%，非基因1型患者分别为61.4%和43.2%，SVR两组患者差异有显著性，x^2=5.313,P=0.021。Peg IFN组基因1型和非1型患者的ETVR分别为76.8%和81.0%，SVR分别为35.4%和66.7%，SVR两组患者差异有显著性，x^2=6.735,P=0.01。病毒复发率基因1型和非基因1型患者分别为55.6%和23.5%，差异有显著性，x^2=5.496,P=0.02.IFN-α-2a组，ETVR和SVR基因1型患者分别为29.0%和14.5%，非基因1型患者分别43.5%和21.7%，差异无显著性。病毒复发率基因1型患者为72.7%，非基因1型患者为50.0%，差异无显著性。结论 IFN对基因1型丙型肝炎患者的疗效低于非基因1型，HCV基因型主要影响IFN对慢性丙型肝炎的持续应答，也与药物和IFN的疗程相关。     

Genetic polymorphism in IL28B is associated with spontaneous clearance of hepatitis C virus genotype 4 infection in an Egyptian cohort

Single-nucleotide polymorphisms (SNPs) around IL28B are associated with spontaneous hepatitis C virus (HCV) clearance of genotypes 1 and 3 in white and African-American populations. This study investigated whether the IL28B SNP (rs12979860) is associated with spontaneous clearance of HCV, principally genotype 4, in 162 Egyptians (80 with clearance). The protective C allele was more common in those with spontaneous clearance (76.3% vs 57.9%; P = .0006). Individuals with clearance were 3.4 (95% confidence interval, 1.8-6.5) times more likely to have C/C genotype. Thus, IL28B plays a role in spontaneous clearance of HCV genotype 4 in North Africa.     

HCV genotype 3 is associated with a higher hepatocellular carcinoma incidence in patients with ongoing viral C cirrhosis

Liver steatosis is a main histopathological feature of Hepatitis C (HCV) infection because of genotype 3. Steatosis and/or mechanisms underlying steatogenesis can contribute to hepatocarcinogenesis. The aim of this retrospective study was to assess the impact of infection with HCV genotype 3 on hepatocellular carcinoma (HCC) occurrence in patients with ongoing HCV cirrhosis. Three hundred and fifty-three consecutive patients (193 men, mean age 58 ± 13 years), with histologically proven HCV cirrhosis and persistent viral replication prospectively followed and screened for HCC between 1994 and 2007. Log-rank test and Cox model were used to compare the actuarial incidence of HCC between genotype subgroups. The patients infected with a genotype 3 (n = 25) as compared with those infected with other genotypes (n = 328) had a lower prothrombin activity [78 (interquartile range 60-85) vs 84 (71-195) %, P = 0.03] and higher rate of alcohol abuse (48%vs 29%, P = 0.046). During a median follow-up of 5.54 years [2.9-8.6], 11/25 patients (44%) and 87/328 patients (26%) with a genotype 3 and non-3 genotype, respectively, develop a HCC. HCC incidences were significantly different among the genotype subgroups (P = 0.001). The 5-year occurrence rate of HCC was 34% (95% CI, 1.3-6.3) and 17% (95% CI, 5.7-9.2) in genotype 3 and non-3 genotype groups, respectively (P = 0.002). In multivariate analysis, infection with a genotype 3 was independently associated with an increased risk of HCC occurrence [hazard ratio 3.54 (95% CI, 1.84-6.81), P = 0.0002], even after adjustment for prothrombin activity and alcohol abuse [3.58 (1.80-7.13); P = 0.003]. For patients with HCV cirrhosis and ongoing infection, infection with genotype 3 is independently associated with an increased risk of HCC development.     

Hepatitis C virus (HCV) genotypes in Spanish patients with HCV infection: relationship between HCV genotype 1b, cirrhosis and hepatocellular carcinoma

Background/Aims: The influence of the infecting virus genotype on the progression of the underlying liver disease in patients with chronic hepatitis C virus (HCV) infection remains controversial. The aim of this study was to investigate the prevalence of HCV genotypes in Spanish patients with chronic HCV infection and to elucidate the relationship between the infecting genotype and severity of the disease.Methods: A cross-sectional, retrospective analysis of frequency distribution of HCV genotypes was carried out in 414 Spanish patients with chronic HCV infection, including 243 patients with asymptomatic or minimally symptomatic chronic hepatitis, 112 patients with cirrhosis and hepatocellular carcinoma and 59 patients with decompensated cirrhosis. HCV genotype was determined by restriction fragment length polymorphisms of the 5′ non-coding region.Results: Infection with HCV genotype 1b was found in 72% of patients with chronic hepatitis and in more than 90% of patients with cirrhosis, with or without hepatocellular carcinoma. Older age, infection with genotype 1b and absence of overt parenteral exposure as a possible source of infection were associated with cirrhosis and hepatocellular carcinoma by univariate analysis and this association was confirmed by regression analysis.Conclusions: HCV genotype 1b is associated with advanced liver disease in our geographical area. However, this may be related to a cohort-effect caused by over-representation of genotype 1b in older patients with more advanced disease, because, in our country, this HCV genotype appeared earlier in time and is therefore associated with more prolonged periods of infection.     

IL-28B基因多态性-丙型肝炎个体化治疗的新起点

众所周知,个体基因的差异在慢性丙型肝炎患者的治疗中有重要的影响.2009-08/201001,世界上4个独立的全基因关联研究发现白介素28B的基因型与长效干扰素-利巴韦林的治疗效果相关联.同时证实,rs8099917和rs12979860的单核苷酸多肽性(single nucleotide polymorphisms,SNP)与抗病毒治疗的持续病毒应答率(sustained virological response,SVR)联系最为密切.本综述旨在阐述白介素28B多态性与丙型肝炎治疗效果、丙型肝炎病毒自发清除及分子流行病学特点、部分药物不良反应之间的联系.这些研究提示我们,在不久的将来,一个以白介素28B基因型为基础的个体化治疗时代将会来到.     

Insulin resistance and steatosis in HBV-HCV co-infected patients: Role of PNPLA3 polymorphisms and impact on liver fibrosis progression

AIM:To evaluate steatosis,insulin resistance(IR)and patatin-like phospholipase domain-containing 3(PNPLA3) and their relation to disease progression in hepatitis B and C viruses(HCV-HBV) coinfected patients.METHODS:Three hundred and thirty patients with biopsy proven chronic hepatitis were enrolled:66 had HBV-HCV,66 HBV and 198 HCV infection.Prevalence of steatosis,IR and PNPLA3 polymorphisms and their relation to anthropometric,biochemical,virological and histological parameters were evaluated.RESULTS:Prevalence of steatosis in group HBV-HCV was similar to that in HCV(47.0% vs 49.5%,respec-tively);group HBV showed the lowest steatosis(33.3%).Group HBV-HCV had a lesser degree of steatosis than HCV(P = 0.016),lower HCV RNA levels(P = 0.025) and lower prevalence and degree of IR(P = 0.01).PNPLA3 polymorphisms were associated with steatosis.Group HBV-HCV showed higher levels of liver fibrosis than group HCV(P = 0.001),but similar to that ob-served in HBV group.In HBV-HCV group,liver fibrosis was not associated with steatosis,IR or PNPLA3.HBV infection was the independent predictor of advanced liver fibrosis.CONCLUSION:HBV-HCV co-infected patients have lower degree of hepatic steatosis,IR and HCV RNA than HCV mono-infected;co-infected patients showed a more rapid liver fibrosis progression that seems to be due to the double infection and/or HBV dominance.     

IL28B genetic variants and gender are associated with spontaneous clearance of hepatitis C virus infection

Summary. Single nucleotide polymorphisms (SNPs) near the IL28B gene have been shown to be associated with response to treatment for chronic hepatitis C and also with spontaneous clearance of hepatitis C virus (HCV) infection. We analysed the association between IL28B genetic variants and spontaneous clearance of HCV infection in 376 HCV‐infected Chinese paid plasma donors. Genotyping of eight SNPs near the IL28B region was performed by the iPLEX system (MassARRAY^® SNP Genotyping; Sequenom) in all donors, and sequencing was performed on all 80 donors who cleared HCV and on 160 of 296 donors who did not clear HCV to validate the genotypes. Eighty (21.3%) donors spontaneously cleared HCV. Four SNPs were significantly associated with spontaneous HCV clearance: rs8099917 TT (vs GT), rs8105790 TT (vs CT), rs12980275 AA (vs AG) and rs10853728 CC (vs CG or GG) with OR (95% CI) 15.27 (2.07–112.50), 14.88 (2.02–109.72), 7.92 (1.88–33.32) and 2.32 (1.22–4.42) respectively. No association between the other four IL28B SNPs including rs12979860 and spontaneous HCV clearance was found. Women had a higher rate of spontaneous HCV clearance than men [56/213 (26.3%) vs 24/163 (14.6%), P = 0.007], and this was true even after stratification for IL28B genotypes with OR of 1.9–2.2 among those with favourable genotypes. Our results confirmed that IL28B polymorphism is associated with spontaneous clearance of HCV in Chinese subjects, but the SNPs that predict HCV clearance in Chinese subjects were different from those reported in Caucasians. Women were more likely to clear HCV infection regardless of IL28B genotypes.     

Association of gene expression involving innate immunity and genetic variation in interleukin 28B with antiviral response

Innate immunity plays an important role in host antiviral response to hepatitis C viral (HCV) infection. Recently, single nucleotide polymorphisms (SNPs) of IL28B and host response to peginterferon α (PEG-IFNα) and ribavirin (RBV) were shown to be strongly associated. We aimed to determine the gene expression involving innate immunity in IL28B genotypes and elucidate its relation to response to antiviral treatment. We genotyped IL28B SNPs (rs8099917 and rs12979860) in 88 chronic hepatitis C patients treated with PEG-IFNα-2b/RBV and quantified expressions of viral sensors (RIG-I, MDA5, and LGP2), adaptor molecule (IPS-1), related ubiquitin E3-ligase (RNF125), modulators (ISG15 and USP18), and IL28 (IFNλ). Both IL28B SNPs were 100% identical; 54 patients possessed rs8099917 TT/rs12979860 CC (IL28B major patients) and 34 possessed rs8099917 TG/rs12979860 CT (IL28B minor patients). Hepatic expressions of viral sensors and modulators in IL28B minor patients were significantly up-regulated compared with that in IL28B major patients (≈ 3.3-fold, P < 0.001). However, expression of IPS-1 was significantly lower in IL28B minor patients (1.2-fold, P = 0.028). Expressions of viral sensors and modulators were significantly higher in nonvirological responders (NVR) than that in others despite stratification by IL28B genotype (≈ 2.6-fold, P < 0.001). Multivariate and ROC analyses indicated that higher RIG-I and ISG15 expressions and RIG-I/IPS-1 expression ratio were independent factors for NVR. IPS-1 down-regulation in IL28B minor patients was confirmed by western blotting, and the extent of IPS-1 protein cleavage was associated with the variable treatment response. CONCLUSION: Gene expression involving innate immunity is strongly associated with IL28B genotype and response to PEG-IFNα/RBV. Both IL28B minor allele and higher RIG-I and ISG15 expressions and RIG-I/IPS-1 ratio are independent factors for NVR.     

FAS promoter polymorphisms correlate with activity grade in hepatitis C patients

OBJECTIVE: Hepatocytes are susceptible to FAS-mediated apoptosis. The impact of polymorphisms in the FAS gene on histopathological features of HCV infection was therefore investigated. DESIGN/METHODS: Three single-nucleotide polymorphisms in the FAS promoter were assessed in 190 patients with chronic hepatitis C. Associations between FAS haplotypes and fibrosis stage and activity grade were tested by univariate and multivariate analyses. RESULTS: While there was no correlation between FAS promoter genotype and fibrosis stage, patients carrying the GCA haplotype (P=0.03, Fisher's exact test) and those homozygous for the GTG haplotype (P = 0.06) tended to have lower activity scores. Logistic regression showed that these associations were independent of patient age, sex and alcohol consumption. In a logistic regression model incorporating only male gender (odds ratio 2.1, 95% confidence interval 1.1-4.1 P = 0.04), the presence of the GCA haplotype (OR 0.31 95% CI 0.13-0.78 P = 0.01), and GTG homozygosity (OR 0.26 95% CI 0.08-0.83 P = 0.02), all three factors were independently correlated with activity grade. Furthermore, the GTG haplotype appeared to have lower promoter activity than the wild type GTA haplotype in a hepatocellular carcinoma cell line. CONCLUSIONS: Genetic polymorphism in the FAS gene may account for some of the histopathological variability in chronic hepatitis C.     

IL28B minor allele is associated with a younger age of onset of hepatocellular carcinoma in patients with chronic hepatitis C virus infection

Background

IL28B polymorphisms were shown to be associated with a response to peg-interferon-based treatment in chronic hepatitis C (CHC) and spontaneous clearance. However, little is known about how this polymorphism affects the course of CHC, including the development of hepatocellular carcinoma (HCC). We evaluated the influence of IL28B polymorphisms on hepatocarcinogenesis in CHC patients.

Methods

We genotyped the rs8099917 single-nucleotide polymorphism in 351 hepatitis C-associated HCC patients without history of IFN-based treatment, and correlated the age at onset of HCC in patients with each genotype.

Results

Frequencies of TT, TG, and GG genotypes were 74.3 % (261/351), 24.8 % (87/351), and 0.9 % (3/351), respectively. The mean ages at onset of HCC for TT, TG, and GG genotypes were 69.9, 67.5 and 66.8, respectively. In multivariate analysis, IL28B minor allele (TG and GG genotypes) was an independent risk factor for younger age at onset of HCC (P = 0.02) in males (P < 0.001) with higher body mass index (BMI; P = 0.009). The IL28B minor allele was also associated with a lower probability of having aspartate aminotransferase-to-platelet ratio index (APRI) >1.5 (minor vs. major, 46.7 vs. 58.6 %; P = 0.01), lower AST (69.1 vs. 77.7 IU/L, P = 0.02), lower ALT (67.8 vs. 80.9 IU/L, P = 0.002), higher platelet count (12.8 vs. 11.2 × 10⁴/μL, P = 0.002), and higher prothrombin time (79.3 vs. 75.4 %, P = 0.002).

Conclusions

The IL28B minor allele was associated with lower inflammatory activity and less progressed fibrosis of the liver; however, it constituted a risk factor for younger-age onset of HCC in CHC patients.