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Dysregulation of IFN system can lead to poor response to pegylated interferon and ribavirin therapy in chronic hepatitis C.

Onomoto K, Morimoto S, Kawaguchi T, Toyoda H, Tanaka M, Kuroda M, Uno K, Kumada T, Matsuda F, Shimotohno K, Fujita T, Murakami Y - PLoS ONE (2011)

Bottom Line: The expression pattern of 31 IFN related-genes also differed significantly between NR and NL.IFN system dysregulation before treatment was associated with poor IFN therapy response.This method can be applied to establishing novel antiviral therapies and strategies for patients using a more individual approach.

View Article: PubMed Central - PubMed

Affiliation: Institute for Viral Research and Graduate School of Bioscience, Kyoto University, Kyoto, Japan.

ABSTRACT

Background: Despite being expensive, the standard combination of pegylated interferon (Peg-IFN)-α and ribavirin used to treat chronic hepatitis C (CH) results in a moderate clearance rate and a plethora of side effects. This makes it necessary to predict patient outcome so as to improve the accuracy of treatment. Although the antiviral mechanism of genetically altered IL28B is unknown, IL28B polymorphism is considered a good predictor of IFN combination treatment outcome.

Methodology: Using microarray, we quantified the expression profile of 237 IFN related genes in 87 CH liver biopsy specimens to clarify the relationship between IFN pathway and viral elimination, and to predict patients' clinical outcome. In 72 out of 87 patients we also analyzed IL28B polymorphism (rs8099917).

Principal findings: Five IFN related-genes (IFI27, IFI 44, ISG15, MX1, and OAS1) had expression levels significantly higher in nonresponders (NR) than in normal liver (NL) and sustained virological responders (SVR); this high expression was also frequently seen in cases with the minor (TG or GG) IL28B genotype. The expression pattern of 31 IFN related-genes also differed significantly between NR and NL. We predicted drug response in NR with 86.1% accuracy by diagonal linear discriminant analysis (DLDA).

Conclusion: IFN system dysregulation before treatment was associated with poor IFN therapy response. Determining IFN related-gene expression pattern based on patients' response to combination therapy, allowed us to predict drug response with high accuracy. This method can be applied to establishing novel antiviral therapies and strategies for patients using a more individual approach.

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The relationship among the expression of IFN-related genes, IL28B polymorphism and clinical outcome.(A) The relationship between expression of ISG and five related genes (MX1, OAS1, ISG15, IFI27, and IFI44) in the liver of CH patients and IL28B with the major (TT) or minor (TG or GG) genotype (rs8099917) is shown. The p-value of the relationship between gene expression level and IL28B genotype is also depicted. (B) The relationship among the expression level of the above five genes, clinical outcome, and IL28 genotype in individual cases. Red square, green circle, and blue rectangle represent TT, TG, and GG in IL28B genotype, respectively. The p value was calculated from a linear regression employing outcome as an explanatory variable (in which SVR, R and NR are encoded to 0, 1 and 2 respectively) and expression level as the response variable. We tested the  hypothesis that the coefficient of the outcome is 0. Summary table of the p-value is also shown. NS shows no significant difference.
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pone-0019799-g002: The relationship among the expression of IFN-related genes, IL28B polymorphism and clinical outcome.(A) The relationship between expression of ISG and five related genes (MX1, OAS1, ISG15, IFI27, and IFI44) in the liver of CH patients and IL28B with the major (TT) or minor (TG or GG) genotype (rs8099917) is shown. The p-value of the relationship between gene expression level and IL28B genotype is also depicted. (B) The relationship among the expression level of the above five genes, clinical outcome, and IL28 genotype in individual cases. Red square, green circle, and blue rectangle represent TT, TG, and GG in IL28B genotype, respectively. The p value was calculated from a linear regression employing outcome as an explanatory variable (in which SVR, R and NR are encoded to 0, 1 and 2 respectively) and expression level as the response variable. We tested the hypothesis that the coefficient of the outcome is 0. Summary table of the p-value is also shown. NS shows no significant difference.

Mentions: To examine the relationship between the genetic variation of IL28B and IFN related gene expression, we determined the IL28B polymorphism in 72 patients (Table 6). Patients with the minor genotype of IL28B displayed higher levels of hepatic ISGs expression, whereas patients with the major genotype showed significantly lower expression levels (Figure 2A). In order to further widen our understanding of the above relationship, we significantly identified individual genetic variations in IL28B at the clinical outcome (Figure 2B). We then individually compared the expression level of several IFN-lambda related genes at the clinical outcome with the genetic variation of IL28B. The expression level of interleukin 28A (IL28A), IL28B, interleukin 29 (IL29), interleukin 10 receptor, beta (IL10RB), signal transducer and activator of transcription 1 (STAT1), STAT5A, and tyrosine kinase 2 (TYK2) in IL28B genotype minor allele and major allele did not differ; however, the expression level of STAT5A and IRF9 was significantly higher in IL28B minor allele cases than in major allele (Figure 3A). The expression levels of these nine genes did not significantly differ among the clinical outcomes (NR, R, and SVR) (Figure 3B).


Dysregulation of IFN system can lead to poor response to pegylated interferon and ribavirin therapy in chronic hepatitis C.

Onomoto K, Morimoto S, Kawaguchi T, Toyoda H, Tanaka M, Kuroda M, Uno K, Kumada T, Matsuda F, Shimotohno K, Fujita T, Murakami Y - PLoS ONE (2011)

The relationship among the expression of IFN-related genes, IL28B polymorphism and clinical outcome.(A) The relationship between expression of ISG and five related genes (MX1, OAS1, ISG15, IFI27, and IFI44) in the liver of CH patients and IL28B with the major (TT) or minor (TG or GG) genotype (rs8099917) is shown. The p-value of the relationship between gene expression level and IL28B genotype is also depicted. (B) The relationship among the expression level of the above five genes, clinical outcome, and IL28 genotype in individual cases. Red square, green circle, and blue rectangle represent TT, TG, and GG in IL28B genotype, respectively. The p value was calculated from a linear regression employing outcome as an explanatory variable (in which SVR, R and NR are encoded to 0, 1 and 2 respectively) and expression level as the response variable. We tested the  hypothesis that the coefficient of the outcome is 0. Summary table of the p-value is also shown. NS shows no significant difference.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3094385&req=5

pone-0019799-g002: The relationship among the expression of IFN-related genes, IL28B polymorphism and clinical outcome.(A) The relationship between expression of ISG and five related genes (MX1, OAS1, ISG15, IFI27, and IFI44) in the liver of CH patients and IL28B with the major (TT) or minor (TG or GG) genotype (rs8099917) is shown. The p-value of the relationship between gene expression level and IL28B genotype is also depicted. (B) The relationship among the expression level of the above five genes, clinical outcome, and IL28 genotype in individual cases. Red square, green circle, and blue rectangle represent TT, TG, and GG in IL28B genotype, respectively. The p value was calculated from a linear regression employing outcome as an explanatory variable (in which SVR, R and NR are encoded to 0, 1 and 2 respectively) and expression level as the response variable. We tested the hypothesis that the coefficient of the outcome is 0. Summary table of the p-value is also shown. NS shows no significant difference.
Mentions: To examine the relationship between the genetic variation of IL28B and IFN related gene expression, we determined the IL28B polymorphism in 72 patients (Table 6). Patients with the minor genotype of IL28B displayed higher levels of hepatic ISGs expression, whereas patients with the major genotype showed significantly lower expression levels (Figure 2A). In order to further widen our understanding of the above relationship, we significantly identified individual genetic variations in IL28B at the clinical outcome (Figure 2B). We then individually compared the expression level of several IFN-lambda related genes at the clinical outcome with the genetic variation of IL28B. The expression level of interleukin 28A (IL28A), IL28B, interleukin 29 (IL29), interleukin 10 receptor, beta (IL10RB), signal transducer and activator of transcription 1 (STAT1), STAT5A, and tyrosine kinase 2 (TYK2) in IL28B genotype minor allele and major allele did not differ; however, the expression level of STAT5A and IRF9 was significantly higher in IL28B minor allele cases than in major allele (Figure 3A). The expression levels of these nine genes did not significantly differ among the clinical outcomes (NR, R, and SVR) (Figure 3B).

Bottom Line: The expression pattern of 31 IFN related-genes also differed significantly between NR and NL.IFN system dysregulation before treatment was associated with poor IFN therapy response.This method can be applied to establishing novel antiviral therapies and strategies for patients using a more individual approach.

View Article: PubMed Central - PubMed

Affiliation: Institute for Viral Research and Graduate School of Bioscience, Kyoto University, Kyoto, Japan.

ABSTRACT

Background: Despite being expensive, the standard combination of pegylated interferon (Peg-IFN)-α and ribavirin used to treat chronic hepatitis C (CH) results in a moderate clearance rate and a plethora of side effects. This makes it necessary to predict patient outcome so as to improve the accuracy of treatment. Although the antiviral mechanism of genetically altered IL28B is unknown, IL28B polymorphism is considered a good predictor of IFN combination treatment outcome.

Methodology: Using microarray, we quantified the expression profile of 237 IFN related genes in 87 CH liver biopsy specimens to clarify the relationship between IFN pathway and viral elimination, and to predict patients' clinical outcome. In 72 out of 87 patients we also analyzed IL28B polymorphism (rs8099917).

Principal findings: Five IFN related-genes (IFI27, IFI 44, ISG15, MX1, and OAS1) had expression levels significantly higher in nonresponders (NR) than in normal liver (NL) and sustained virological responders (SVR); this high expression was also frequently seen in cases with the minor (TG or GG) IL28B genotype. The expression pattern of 31 IFN related-genes also differed significantly between NR and NL. We predicted drug response in NR with 86.1% accuracy by diagonal linear discriminant analysis (DLDA).

Conclusion: IFN system dysregulation before treatment was associated with poor IFN therapy response. Determining IFN related-gene expression pattern based on patients' response to combination therapy, allowed us to predict drug response with high accuracy. This method can be applied to establishing novel antiviral therapies and strategies for patients using a more individual approach.

Show MeSH
Related in: MedlinePlus