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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 fibrosis stage and IL28B genotype on hepatic IP10 expression.Levels of IP10 expression were determined by rs12979860 (A) and rs8099917 (B) IL28B genotypes in patients, stratified by fibrosis F0-1 and F2-4 groups. Conversely, levels of IP10 expression were also determined according to the F0-1 and F2-4 fibrosis grouping in patients stratified by rs12979860 (C) and rs8099917 (D) IL28B genotypes. 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. n = number of patients in each group.
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pone.0130899.g004: Impact of fibrosis stage and IL28B genotype on hepatic IP10 expression.Levels of IP10 expression were determined by rs12979860 (A) and rs8099917 (B) IL28B genotypes in patients, stratified by fibrosis F0-1 and F2-4 groups. Conversely, levels of IP10 expression were also determined according to the F0-1 and F2-4 fibrosis grouping in patients stratified by rs12979860 (C) and rs8099917 (D) IL28B genotypes. 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. n = number of patients in each group.

Mentions: To exclude the effect of progression of fibrosis on IP10 expression, we also separately analyzed the fibrosis in F0-1 and F2-4 groups for an association between IP10 expression and the IL28B genotype. We observed no significant differences between them (Fig 4A and 4B). When we separately analyzed the IL28B stratification groups for an association between ISG expression and the fibrosis stage, however, we found that IP10 expression was different between F0-1 and F2-4 groups only in the subgroup of patients carrying the CT-TT rs12979860 and TG-GG rs8099917 genotypes (P = 0.009, P = 0.02, respectively; Fig 4C and 4D). In the CC rs12979860 and TT rs8099917 genotype groups, the statistical analysis revealed no significant association; however, we observed the same tendency between IP10 expression and F0-1 and F2-4 status in these genotype groups.


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 fibrosis stage and IL28B genotype on hepatic IP10 expression.Levels of IP10 expression were determined by rs12979860 (A) and rs8099917 (B) IL28B genotypes in patients, stratified by fibrosis F0-1 and F2-4 groups. Conversely, levels of IP10 expression were also determined according to the F0-1 and F2-4 fibrosis grouping in patients stratified by rs12979860 (C) and rs8099917 (D) IL28B genotypes. 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. n = number of patients in each group.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0130899.g004: Impact of fibrosis stage and IL28B genotype on hepatic IP10 expression.Levels of IP10 expression were determined by rs12979860 (A) and rs8099917 (B) IL28B genotypes in patients, stratified by fibrosis F0-1 and F2-4 groups. Conversely, levels of IP10 expression were also determined according to the F0-1 and F2-4 fibrosis grouping in patients stratified by rs12979860 (C) and rs8099917 (D) IL28B genotypes. 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. n = number of patients in each group.
Mentions: To exclude the effect of progression of fibrosis on IP10 expression, we also separately analyzed the fibrosis in F0-1 and F2-4 groups for an association between IP10 expression and the IL28B genotype. We observed no significant differences between them (Fig 4A and 4B). When we separately analyzed the IL28B stratification groups for an association between ISG expression and the fibrosis stage, however, we found that IP10 expression was different between F0-1 and F2-4 groups only in the subgroup of patients carrying the CT-TT rs12979860 and TG-GG rs8099917 genotypes (P = 0.009, P = 0.02, respectively; Fig 4C and 4D). In the CC rs12979860 and TT rs8099917 genotype groups, the statistical analysis revealed no significant association; however, we observed the same tendency between IP10 expression and F0-1 and F2-4 status in these genotype groups.

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