The Impact of IL28B Genotype and Liver Fibrosis on the Hepatic Expression of IP10, IFI27, ISG15, and MX1 and Their Association with Treatment Outcomes in Patients with Chronic Hepatitis C.
ABSTRACT: The strong impact of interleukin 28B (IL28B) polymorphisms on sustained virological response (SVR) after peginterferon and ribavirin treatment in patients with chronic hepatitis C (CHC) is well-known. We investigated IL28B variability and hepatic expression of IP10, IFI27, ISG15, and MX1 in CHC patients, the relation of each with their clinical characteristics, and how they associated with responses to combined therapy. Genotyping and gene expression analysis were conducted in a selected cohort of treatment-naïve patients who underwent interferon and ribavirin treatment. Differential expression of IP10, IFI27, ISG15, and MX1 genes was assessed from pretreatment liver biopsies using quantitative PCR. Histopathological evaluation of liver specimens was performed on the basis of the Scheuer's modified scale. We showed that hepatic IFI27, ISG15, and MX1 expression was lower in the IL28B CC 12979860 and TT rs8099917 groups than in the CT-TT rs12979860 and TG-GG rs8099917 groups (P < 0.001). We found no differences in IP10 expression between the IL28B genotypes (P > 0.05); in contrast, IP10 expression was significantly affected by the progression of fibrosis (P = 0.007). We showed that the rs12979860 CC genotype was associated with successful treatment when compared to the rs12979860 CT-TT genotype (P = 0.004). Additionally, the expression levels of IP10, IFI27 and ISG15, but not MX1, were significantly higher in non-SVR patients than in SVR patients. The effect of variation in IL28B on the results of IFN-based treatment may be associated with changes in IFI27 and ISG15, but not with IP10. Silencing of IP10 is positive and independent from IL28B prediction of SVR, which is strongly associated with liver fibrosis in CHC patients.
Project description:AIM:To analyze the role of rs12979860 and rs8099917 polymorphisms in hepatitis C virus (HCV) genotype 1 infection of Brazilians. METHODS:A total of 145 adult patients diagnosed with genotype 1 chronic hepatitis C (CHC) who had completed a 48-wk regimen of pegylated-interferon α-2a or -2b plus ribavirin combination therapy were recruited from six large urban healthcare centers and 199 healthy blood donors (controls) from a single site between January 2010 and January 2012. Data on the patients' response to treatment was collected. Polymerase chain reaction-restriction fragment length polymorphism genotyping of the interleukin (IL)28B gene fragment encompassing the single nucleotide polymorphisms (SNPs) rs12979860 (C/T) and rs8099917 (T/G) was carried out for 79 of the CHC patients and 199 of the controls. Bi-directional amplicon sequencing of the two SNPs was carried out for the remaining 66 CHC patients. RESULTS:SNP rs12979860 genotyping was successful in 99.5% of the controls and 97.2% of the CHC patients, whereas the SNP rs8099917 genotyping was successful in 95.5% of the controls and 100% of the CHC patients. The genotype and allele distributions for both rs12979860 and rs8099917 were significantly different between the control and CHC patient groups, with significantly higher genotype frequencies of CC and TT in the controls (P = 0.037 and 0.046, respectively) and of TT and GG in the CHC patients (P = 0.0009 and 0.0001, respectively). Analysis of the CHC patients who achieved sustained virological response (SVR) to treatment (n = 55) indicated that the rs12979860 C allele and CC genotype were predictors of SVR (P = 0.02). No significant correlation was found between rs8099917 genotypes and treatment response, but carriers of the T allele showed significantly higher rates of SVR (P = 0.02). Linkage disequilibrium analysis of the group that achieved SVR showed a significant association between rs12979860 and rs8099917 (P = 0.07). CONCLUSION:The higher allele frequency of rs12979860 C and rs8099917 T observed in non-HCV-infected individuals may indicate a potential protective role for these IL28B-related polymorphisms.
Project description:BACKGROUND:The aim of this study was to determine whether two polymorphisms of the human interferon lambda 4 (IFNL4) gene (rs12979860 and rs8099917) can predict sustained virologic response (SVR) following antiviral therapy in patients with inherited bleeding disorder and chronic hepatitis C (CHC). METHODS:This retrospective study was conducted on 294 patients with congenital bleeding disorder and CHC who were treated with Peg-Interferon-? (PegIFN) and Ribavirin (RBV). Baseline patient and viral parameters were measured and analyzed statistically to assess their combined and individual contributions to SVR prediction. RESULTS:The most prevalent variants of rs12979860 and rs8099917 identified among the study patients were CT (45.9%) and TT (57.6%), respectively. Overall, SVR was achieved in 69% of the study patients. The rate of SVR was lower in patients with HCV genotype-1 than in those with HCV genotype-3 (62% vs 88%; P<.001; OR=0.23). Multivariate analysis of SVR predictors in patients with HCV genotype-1 infection included age (<24 years), BMI (<25), absence of cirrhosis, HCV RNA level (<400 000 IU/mL), rs8099917 TT and rs12979860 CC, all of which were associated with a higher SVR rate. In HCV genotype-3 infection, only rs12979860 CC was significantly associated with SVR. CONCLUSION:These results demonstrate that polymorphisms of the IFNL4 gene are highly associated with SVR to PegIFN and RBV combination therapy in patients with a congenital bleeding disorder and CHC. Assessment of rs12979860 and rs8099917 genotypes can guide physicians in choosing an optimal treatment regimen, including less expensive therapies that may only be available in many geographic locales.
Project description:BACKGROUND:A dinucleotide variant rs368234815 in interferon lambda 4 (IFNL4) gene was recently found to be associated with the hepatitis C virus (HCV) treatment response. This study aimed to assess the impact of IFNL4 rs368234815 polymorphism on treatment response to pegylated-IFN alpha (Peg-IFN-?) and ribavirin (RBV) in hemophilic patients with chronic hepatitis C (CHC). MATERIALS AND METHODS:In this retrospective study, 92 hemophilic patients with CHC who were treated with Peg-IFN-?/RBV were investigated. Single-nucleotide polymorphisms (SNPs) in IFNL genomic region including rs368234815, rs12979860, and rs8099917 were analyzed by DNA sequencing. RESULTS:Of the 92 patients, 63 (68.5%) achieved sustained virological response (SVR). Of the 43 patients with rs368234815 TT/TT genotype, 36 (83.7%) achieved SVR, while in 49 patients with non-TT/TT genotypes, 27 (55.1%) achieved SVR. Other pretreatment parameters predicted SVR were patients' body mass index, HCV genotype, rs12979860, and rs8099917 SNPs. In multivariate analysis, all above-mentioned parameters except rs8099917 remained as predictors of SVR. IFNL4 rs368234815 was a strong predictor of SVR; however, the prediction power of this SNP was the same as that of rs12979860 SNP in the patients of the current study. CONCLUSION:IFNL4 rs368234815 SNP can be considered for decision-making in the treatment of HCV-infected patients.
Project description:BACKGROUND & AIMS:IL28B polymorphisms were shown to be strongly associated with the response to interferon therapy in chronic hepatitis C (CHC) and spontaneous viral clearance. However, little is known about how these polymorphisms affect the natural course of the disease. Thus, we conducted the present meta-analysis to assess the impact of IL28B polymorphisms on disease progression. METHODS:A literature search was conducted using MEDLINE, EMBASE, and the Cochrane Library. Integrated odds ratios (OR) were calculated with a fixed-effects or random-effects model based on heterogeneity analyses. RESULTS:We identified 28 studies that included 10,024 patients. The pooled results indicated that the rs12979860 genotype CC was significantly associated (vs. genotype CT/TT; OR, 1.122; 95%CI, 1.003-1.254; P?=?0.044), and that the rs8099917 genotype TT tended to be (vs. genotype TG/GG; OR, 1.126; 95%CI, 0.988-1.284; P?=?0.076) associated, with an increased possibility of severe fibrosis. Both rs12979860 CC (vs. CT/TT; OR, 1.288; 95%CI, 1.050-1.581; P?=?0.015) and rs8099917 TT (vs. TG/GG; OR, 1.324; 95%CI, 1.110-1.579; P?=?0.002) were significantly associated with a higher possibility of severe inflammation activity. Rs8099917 TT was also significantly associated with a lower possibility of severe steatosis (vs. TG/GG; OR, 0.580; 95%CI, 0.351-0.959; P?=?0.034), whereas rs12979860 CC was not associated with hepatic steatosis (vs. CT/TT; OR, 1.062; 95%CI, 0.415-2.717; P?=?0.901). CONCLUSIONS:IL28B polymorphisms appeared to modify the natural course of disease in patients with CHC. Disease progression seems to be promoted in patients with the rs12979860 CC and rs8099917 TT genotypes.
Project description:BACKGROUND:Hepatitis C is a global health problem and represents a major cause of liver disease and socioeconomic burden. Effective antiviral therapy may prevent these complications, but the current treatment for patients with chronic hepatitis C virus (HCV) infection does not produce sustained virologic response. Therefore, identification of the determinants of response to treatment is a high priority. A number of host and viral factors have been associated with treatment outcomes. OBJECTIVES:To assess the associations of single nucleotide polymorphisms (SNP) of the IL28B and sustained virologic response (SVR) of patients with chronic hepatitis C to PEG-interferon/ribavirin therapy. MATERIALS AND METHODS:We searched PubMed, Medline and Cochrane Library, and found 7 eligible papers involved in this study. Then we performed a meta-analysis comparing the SVR rate at SNP of the IL28B in individuals with PEG-interferon/ribavirin therapy. Meanwhile, the SVR rate between different races and HCV genotypes was studied. RESULTS:The sustained virologic response rate was higher in patients with the rs12979860 CC and rs8099917 TT alleles in the IL28B SNP, comparing with the rs12979860 CT, or TT and rs8099917 TG or GG. Furthermore, a higher SVR was observed in the Caucasians than in Afro-Americans (OR = 3.85, 95% CI: 3.06-4.83); the percentage of rs12979860 TT genotype was lower in Caucasians (OR = 0.25, 95% CI: 0.20-0.31) and the percentage of rs12979860 CC genotype was higher in Caucasians than that of Afro-Americans (OR = 3.45, 95% CI = 2.68-4.44). Between different HCV genotypes, the SVR was much lower in those with HCV genotype 1 than those with genotype 2/3 (OR = 0.16, 95% CI: 0.11-0.24). CONCLUSIONS:IL28B is significantly associated with response to PEG-interferon/ribavirin therapy of patients with chronic HCV infection. Both the rs12979860 and rs8099917 alleles could be used as independent predictors of the treatment response. The rs12979860 allele in particular, is more important from our study. The polymorphism even explains part the difference in response rate between different ethnic groups and HCV genotypes.
Project description:Pretreatment serum levels of interferon-?-inducible protein-10 (IP-10, CXCL10) and dipeptidyl peptidase-4 (DPP IV) predict treatment response in chronic hepatitis C (CHC). The association between functional genetic polymorphisms of CXCL10 and DPP4 and treatment outcome has not previously been studied. This study aimed to determine the association between genetic variations of CXCL10 and DPP4 and the outcome of treatment with pegylated interferon-? (PEG-IFN-?) based therapy in Thai patients with CHC. 602 Thai patients with CHC treated using a PEG-IFN-? based regimen were genotyped for CXCL10 rs56061981 G>A and IL28B rs12979860 C>T. In addition, in patients infected with CHC genotype 1, DPP4 (rs13015258 A>C, rs17848916 T>C, rs41268649 G>A, and rs 17574 T>C) were genotyped. Correlations between single nucleotide polymorphisms, genotype, and treatment response were analyzed. The rate of sustained virologic response (SVR) was higher for the CC genotype of IL28B rs12979860 polymorphisms than for non-CC in both genotype 1 (60.6% vs. 29.4%, P < 0.001) and non-genotype 1 (69.4% vs. 49.1%, P < 0.05) CHC. SVR was not associated with the CXCL10 gene variant in all viral genotypes or DPP4 gene polymorphisms in viral genotype1. Multivariate analysis revealed IL28B rs12979860 CC genotype (OR = 3.12; 95% CI, 1.72-5.67; P < 0.001), hepatitis C virus RNA < 400,000 IU/ml (OR = 2.21; 95% CI, 1.22-3.99, P < 0.05), age < 45 years (OR = 2.03; 95% CI, 1.11-3.68; P < 0.05), and liver fibrosis stage 0-1 (OR = 1.64; 95% CI, 1.01-2.65, P < 0.05) were independent factors for SVR. Unfavorable IL28B rs12979860 CT or TT genotypes with the CXCL10 rs56061981 non-GG genotype were associated with a higher SVR than GG genotype (66.7% vs. 33.0%, P = 0.004) in viral genotype 1. In Thai CHC genotype 1 infected patients with an unfavorable IL28B rs12979860 CT/TT genotype, the complementary CXCL10 polymorphism strongly enhances prediction of treatment response.
Project description:BACKGROUND/AIMS:There are few available data regarding the association between the single nucleotide polymorphisms (SNPs) of the gene encoding interleukin 28B (IL28B) and a sustained virologic response (SVR) to peginterferon (PEG-IFN) plus ribavirin (RBV) therapy in Korean chronic hepatitis C patients. METHODS:This was a retrospective cohort study of 156 patients with chronic hepatitis C virus (HCV) infection who received combination treatment of PEG-IFN plus RBV. Blood samples from these patients were analyzed to identify the IL28B SNPs at rs12979860, rs12980275, rs8099917, and rs8103142. Association analyses were performed to evaluate the relationships between each IL28B SNP and SVRs. RESULTS:Seventy six patients with HCV genotype 1 and 80 with genotype non-1 were enrolled. The frequencies of rs12979860 CC and CT genotypes were 90.4% and 9.6%, respectively; those of rs12980275 AA and AG genotypes were 87.2% and 12.8%, respectively; those of rs8099917 TT and TG genotypes were 92.3% and 7.7%, respectively; and those of rs8103142 TT and CT genotypes were 90.4% and 9.6%, respectively. Among the patients with HCV genotype 1, the SVR rates were 69.7% and 80.0% for rs12979860 CC and CT, respectively (P=0.71). Among the HCV genotype non-1 patients, SVR rates were 88.0% and 100% for rs12979860 CC and CT (P=1.00), respectively. CONCLUSIONS:Genotypes of the IL28B SNP that are known to be favorable were present in most of the Korean patients with chronic hepatitis C in this study. Moreover, the IL28B SNP did not influence the SVR rate in either the HCV genotype 1 or non-1 patients. Therefore, IL28B SNP analysis might be not useful for the initial assessment, prediction of treatment outcomes, or treatment decision-making of Korean chronic hepatitis C patients.
Project description:BACKGROUND:In 2009, 3 genome-wide association studies implicated IL28B single-nucleotide polymorphisms (SNPs) as the strongest genetic pretreatment predictor of sustained virological response (SVR) in hepatitis C infection. Recently, the American Association for the Study of Liver Diseases (AASLD) and the European Association for the Study of the Liver (EASL) included IL28B testing in their guidelines. OBJECTIVES:The main aim of this study was to develop and validate a simple, rapid, and inexpensive polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method for genotyping of common IL28B polymorphisms (rs12979860 and rs8099917). PATIENTS AND METHODS:Two methods were developed to genotype common IL28B polymorphisms: 1) PCR-sequencing as a reference method and 2) PCR-RFLP as a rapid and inexpensive method. Both polymorphisms were genotyped in 104 Iranian hepatitis C patients by both methods simultaneously. To validate the PCR-RFLP method, the PCR-RFLP genotyping results should be 100% concordant with the PCR-sequencing results. RESULTS:Genotyping of rs12979860 and rs8099917 by PCR-RFLP was concordant with PCR-sequencing in 104 (100%) individuals. The analytical sensitivity and specificity of the PCR-RFLP method for genotyping of both SNPs are 100%. Among these 104 patients with chronic hepatitis C, the frequency of the rs12979860 CC, CT and TT genotypes were 40.4%, 47.1% and 12.5% and the frequency of the rs8099917 TT, GT and GG genotypes were 59.6%, 35.6% and 4.8%, respectively. Also, three IL28B haplotypes (rs12979860-rs8099917) were found among our patients including C-T, T-G and T-T with 63.9%, 22.6% and 13.5% frequency, respectively. C-G haplotype was absent in all of our patients. CONCLUSIONS:We have developed a validated, fast, and simple PCR-RFLP method for genotyping of common IL28B SNPs that is more cost-effective than sequencing.
Project description:The genome-wide association studies have identified a strong association between interleukin 28B (IL28B) gene polymorphisms and the response to treatment in patients with hepatitis C virus (HCV) infection. The aim of the study was to evaluate the association between three most widely studied IL28B gene polymorphisms and the response to antiviral treatment of chronic hepatitis C. We performed the genotyping of the three IL28B gene polymorphisms: rs12979860, rs8099917, and rs12980275 in 72 Caucasian patients with chronic hepatitis C, previously treated with the combination therapy of pegylated interferon alpha (PEGIFN ?) and ribavirin (RBV). The patients included in the study had finished the treatment regimen at least 6 months before enrolling in the study. We used the sustained viral response (SVR) for the evaluation of the effectiveness of the antiviral treatment, and it was tested with an assay with a sensitivity of 20 IU/mL. An SVR was achieved in 59.7% (43/72) of the treated patients. The three IL28B gene polymorphisms (CC genotype of rs12979860, TT genotype of rs8099917, and AA genotype of rs12980275) were associated with the SVR (p=0.029, p=0.016, and p=0.028, respectively) in the study patients with chronic hepatitis C treated with the combination therapy of PEGIFN ? and RBV. The association of IL28B gene polymorphisms with the treatment response points to the possibility of personalized medicine for the treatment of HCV infection.
Project description:BACKGROUND:IL28B gene polymorphism is the best baseline predictor of response to interferon alfa-based antiviral therapies in chronic hepatitis C. Recently, a new IFN-L4 polymorphism was identified as first potential functional variant for induction of IL28B expression. Individualization of interferon alfa-based therapies based on a combination of IL28B/IFN-L4 polymorphisms may help to optimize virologic outcome and economic resources. METHODS:Optimization of treatment outcome prediction was assessed by combination of different IL28B and IFN-L4 polymorphisms in patients with chronic HCV genotype 1 (n?=?385), 2/3 (n?=?267), and 4 (n?=?220) infection treated with pegylated interferon alfa (PEG-IFN) and ribavirin with (n?=?79) or without telaprevir. Healthy people from Germany (n?=?283) and Egypt (n?=?96) served as controls. RESULTS:Frequencies of beneficial IL28B rs12979860 C/C genotypes were lower in HCV genotype 1/4 infected patients in comparison to controls (20-35% vs. 46-47%) this was also true for ss469415590 TT/TT (20-35% vs. 45-47%). Single interferon-lambda SNPs (rs12979860, rs8099917, ss469415590) correlated with sustained virologic response (SVR) in genotype 1, 3, and 4 infected patients while no association was observed for genotype 2. Interestingly, in genotype 3 infected patients, best SVR prediction was based on IFN-L4 genotype. Prediction of SVR with high accuracy (71-96%) was possible in genotype 1, 2, 3 and 4 infected patients who received PEG-IFN/ribavirin combination therapy by selection of beneficial IL28B rs12979860 C/C and/or ss469415590 TT/TT genotypes (p<0.001). For triple therapy with first generation protease inhibitors (PIs) (boceprevir, telaprevir) prediction of high SVR (90%) rates was based on the presence of at least one beneficial genotype of the 3 IFN-lambda SNPs. CONCLUSION:IFN-L4 seems to be the best single predictor of SVR in genotype 3 infected patients. For optimized prediction of SVR by treatment with dual combination or first generation PI triple therapies, grouping of interferon-lambda haplotypes may be helpful with positive predictive values of 71-96%.