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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.

Domagalski K, Pawłowska M, Kozielewicz D, Dybowska D, Tretyn A, Halota W - PLoS ONE (2015)

Bottom Line: 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).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.

View Article: PubMed Central - PubMed

Affiliation: Centre For Modern Interdisciplinary Technologies, Nicolaus Copernicus University, Toruń, Poland.

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.

No MeSH data available.


Related in: MedlinePlus

Relationship between hepatic expression of IP10, IFI27, ISG15, and MX1 and treatment outcome in individual cases.Empty circles, rectangles, and filled diamonds represent TT, CT, and CC rs12979860 genotypes, respectively. The y-axis shows the relative unit of a given gene, normalized to GAPDH in log scale, as a box plot displaying the 10th, 25th, 50th, 75th, and 90th percentiles of gene expression levels. Each dot represents one sample. The P values were obtained by the Mann-Whitney test (for SVR, n = 19; non-SVR [nSVR], n = 28).
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pone.0130899.g005: Relationship between hepatic expression of IP10, IFI27, ISG15, and MX1 and treatment outcome in individual cases.Empty circles, rectangles, and filled diamonds represent TT, CT, and CC rs12979860 genotypes, respectively. The y-axis shows the relative unit of a given gene, normalized to GAPDH in log scale, as a box plot displaying the 10th, 25th, 50th, 75th, and 90th percentiles of gene expression levels. Each dot represents one sample. The P values were obtained by the Mann-Whitney test (for SVR, n = 19; non-SVR [nSVR], n = 28).

Mentions: Finally, gene expression analysis of four investigated genes showed that the expression levels of IP10, IFI27, and ISG15 were significantly higher in non-SVR patients than in SVR patients, but the expression level of MX1 was similar in non-SVR and SVR patients (Fig 5). As shown, rs12979860 affects the final therapeutic outcome and the expression of IP10 was not related to the IL28B genotype (Fig 1). The lack of correlation between IP10 expression and IL28B genotype indicates that the association with SVR observed for both of these markers is independent; however, IL28B genotype affects the gene expression of IFI27, ISG15, and MX1. In order to further our understanding of the above relationship, we individually compared the expression levels of four investigated genes, according to clinical outcome, with the genetic variation of IL28B. Fig 5 showed SVR enrichment in patients with the IL28B favorable genotype and a lack of SVR in those patients with the unfavorable genotype. To eliminate the effects of variation in IL28B on clinical outcome, gene expression was analyzed by dividing patients into CC and CT-TT IL28B genotype groups. When the patients were stratified by IL28B genotype, we found that there were no differences in median ISG expression between SVR and non-SVR subsets (Fig 6). Although there were no statistically significant differences in IP10 expression according to SVR, only IP10 expression behaved similarly in IL28B subgroups of patients and the sample population as a whole.


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.

Domagalski K, Pawłowska M, Kozielewicz D, Dybowska D, Tretyn A, Halota W - PLoS ONE (2015)

Relationship between hepatic expression of IP10, IFI27, ISG15, and MX1 and treatment outcome in individual cases.Empty circles, rectangles, and filled diamonds represent TT, CT, and CC rs12979860 genotypes, respectively. The y-axis shows the relative unit of a given gene, normalized to GAPDH in log scale, as a box plot displaying the 10th, 25th, 50th, 75th, and 90th percentiles of gene expression levels. Each dot represents one sample. The P values were obtained by the Mann-Whitney test (for SVR, n = 19; non-SVR [nSVR], n = 28).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4482747&req=5

pone.0130899.g005: Relationship between hepatic expression of IP10, IFI27, ISG15, and MX1 and treatment outcome in individual cases.Empty circles, rectangles, and filled diamonds represent TT, CT, and CC rs12979860 genotypes, respectively. The y-axis shows the relative unit of a given gene, normalized to GAPDH in log scale, as a box plot displaying the 10th, 25th, 50th, 75th, and 90th percentiles of gene expression levels. Each dot represents one sample. The P values were obtained by the Mann-Whitney test (for SVR, n = 19; non-SVR [nSVR], n = 28).
Mentions: Finally, gene expression analysis of four investigated genes showed that the expression levels of IP10, IFI27, and ISG15 were significantly higher in non-SVR patients than in SVR patients, but the expression level of MX1 was similar in non-SVR and SVR patients (Fig 5). As shown, rs12979860 affects the final therapeutic outcome and the expression of IP10 was not related to the IL28B genotype (Fig 1). The lack of correlation between IP10 expression and IL28B genotype indicates that the association with SVR observed for both of these markers is independent; however, IL28B genotype affects the gene expression of IFI27, ISG15, and MX1. In order to further our understanding of the above relationship, we individually compared the expression levels of four investigated genes, according to clinical outcome, with the genetic variation of IL28B. Fig 5 showed SVR enrichment in patients with the IL28B favorable genotype and a lack of SVR in those patients with the unfavorable genotype. To eliminate the effects of variation in IL28B on clinical outcome, gene expression was analyzed by dividing patients into CC and CT-TT IL28B genotype groups. When the patients were stratified by IL28B genotype, we found that there were no differences in median ISG expression between SVR and non-SVR subsets (Fig 6). Although there were no statistically significant differences in IP10 expression according to SVR, only IP10 expression behaved similarly in IL28B subgroups of patients and the sample population as a whole.

Bottom Line: 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).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.

View Article: PubMed Central - PubMed

Affiliation: Centre For Modern Interdisciplinary Technologies, Nicolaus Copernicus University, Toruń, Poland.

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.

No MeSH data available.


Related in: MedlinePlus