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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

Impact of IP10 expression on SVR response.SVR rate (%) in CHC patients was stratified according to pretreatment hepatic expression of IP10 (above versus below 0.035); IL28B rs12979860 genotype is shown. The threshold value of 0.035 demonstrated the relative unit of IP10 gene expression, normalized to GAPDH. Number of patients is shown as n, and SVR/n is the total subgroup. The P values were obtained by Fisher’s exact test.
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pone.0130899.g007: Impact of IP10 expression on SVR response.SVR rate (%) in CHC patients was stratified according to pretreatment hepatic expression of IP10 (above versus below 0.035); IL28B rs12979860 genotype is shown. The threshold value of 0.035 demonstrated the relative unit of IP10 gene expression, normalized to GAPDH. Number of patients is shown as n, and SVR/n is the total subgroup. The P values were obtained by Fisher’s exact test.

Mentions: To assess the potential predictive value of IP10 expression, we calculated the cut-off value with the best discriminatory ability, based on an receiver operating characteristic (ROC) curve analysis. In our dataset, a threshold expression of 0.035 (expressed in relative units according to GAPDH expression; in log scale, -1.45) revealed the optimal combination of specificity (89%) and sensitivity (52%) in predicting SVR. Using the 0.035 cutoff for pretreatment expression of IP10, the SVR rate was 76.9% (10/13) for the ones with low IP10 expression (< 0.035) and 26.5% (9/34) for those with a high IP10 level (> 0.035) (P = 0.003, OR = 9.26, 95% CI = 2.07–41.43). Modeling SVR as a function of IL28B genotype, treating IP10 expression as a qualitative variable (above or below 0.035) in a nominal logistic regression, showed a significant effect of IL28B genotype (P = 0.03) and IP10 expression (P = 0.01) in predicting SVR. Fig 7 demonstrates that combining IL28B genotype with pretreatment hepatic expression of IP10 clearly improves the predictive value of SVR in patients with CT or TT genotypes (P = 0.007). Although frequency analyses showed that the proportion of patients achieving SVR in the CT-TT subgroup is larger than SVR patients in the CC subgroup, it is an unreliable comparison due to the low number of patients in these subgroups.


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)

Impact of IP10 expression on SVR response.SVR rate (%) in CHC patients was stratified according to pretreatment hepatic expression of IP10 (above versus below 0.035); IL28B rs12979860 genotype is shown. The threshold value of 0.035 demonstrated the relative unit of IP10 gene expression, normalized to GAPDH. Number of patients is shown as n, and SVR/n is the total subgroup. The P values were obtained by Fisher’s exact test.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0130899.g007: Impact of IP10 expression on SVR response.SVR rate (%) in CHC patients was stratified according to pretreatment hepatic expression of IP10 (above versus below 0.035); IL28B rs12979860 genotype is shown. The threshold value of 0.035 demonstrated the relative unit of IP10 gene expression, normalized to GAPDH. Number of patients is shown as n, and SVR/n is the total subgroup. The P values were obtained by Fisher’s exact test.
Mentions: To assess the potential predictive value of IP10 expression, we calculated the cut-off value with the best discriminatory ability, based on an receiver operating characteristic (ROC) curve analysis. In our dataset, a threshold expression of 0.035 (expressed in relative units according to GAPDH expression; in log scale, -1.45) revealed the optimal combination of specificity (89%) and sensitivity (52%) in predicting SVR. Using the 0.035 cutoff for pretreatment expression of IP10, the SVR rate was 76.9% (10/13) for the ones with low IP10 expression (< 0.035) and 26.5% (9/34) for those with a high IP10 level (> 0.035) (P = 0.003, OR = 9.26, 95% CI = 2.07–41.43). Modeling SVR as a function of IL28B genotype, treating IP10 expression as a qualitative variable (above or below 0.035) in a nominal logistic regression, showed a significant effect of IL28B genotype (P = 0.03) and IP10 expression (P = 0.01) in predicting SVR. Fig 7 demonstrates that combining IL28B genotype with pretreatment hepatic expression of IP10 clearly improves the predictive value of SVR in patients with CT or TT genotypes (P = 0.007). Although frequency analyses showed that the proportion of patients achieving SVR in the CT-TT subgroup is larger than SVR patients in the CC subgroup, it is an unreliable comparison due to the low number of patients in these subgroups.

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