IL28b polymorphism is associated with intrahepatic ISG expression and peginterferon-a/ribavirin response rate in chronic HCV infection.


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Inproceedings: an article in a conference proceedings.
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Abstract (Abstract): shot summary in a article that contain essentials elements presented during a scientific conference, lecture or from a poster.
IL28b polymorphism is associated with intrahepatic ISG expression and peginterferon-a/ribavirin response rate in chronic HCV infection.
Title of the conference
45th Annual Meeting of the European Association for the Study of the Liver
Thompson A., Schuppan D., Urban T., Fellay J., Shianna K., McHutchison J., Goldstein D., Afdhal N.
Vienna, Austria, April 14-18, 2010
Publication state
Issued date
Journal of Hepatology
Background and Aims: Genetic variation of the IL28B gene
region has been associated with a 2-fold increase in SVR rate in
chronic hepatitis C (CHC) patients treated with peginterferon-alpha
(pegIFN) and ribavirin (RBV). The underlying mechanism remains
unclear. We hypothesized that IL28B polymorphism is associated
with intrahepatic expression levels of IFN-stimulated genes (ISGs),
known to influence treatment outcome.
Methods: 74 CHC patients with consent for genetic testing and
stored liver tissue were identified. 48 were treatment-naïve, 26
were non-responders (NR) to prior IFN therapy (off-treatment
for ≥6 months prior to biopsy). "IL28B-type" (rs12979860: CC,
CT, TT) was tested using the ABI TaqMan allelic discrimination
kit. Whole-genome expression data was measured using the
Illumina HumanHT-12 Expression BeadChip and differences in gene
expression by IL28B-type (CC vs non-CC) were analyzed using
Partek and Ingenuity Pathway Analysis, adjusting for HCV genotype,
gender, age and ethnicity. To declare significance, we used a false
discovery rate (FDR) threshold of 0.1.
Results: Data from 61 patients were suitable for analysis:
HCV-1 = 90%; male = 67%; median age = 52 yrs; ethnicity = 62%
Caucasian, 20% African American, 18% other; 70% were METAVIR
F0-2, none cirrhotic. In the comparison of differential intrahepatic
mRNA expression, 164 genes were significant. ISGs were heavily
over-represented and showed lower expression levels in CC livers
(OAS 1/2/3, MX1, IFIT 1/2/3 and ISG15 all had >3 fold lower
expression). IL28B and IL28A gene expression were detectable at
low levels; there was no difference by IL28B-type. The IFN signaling
pathway was the most enriched canonical pathway differentially
expressed by IL28B-type (P-value <10−5). In 25 patients PEG/RBV
response data was available (17 were NR prior to biopsy; 5/8 treated
post-biopsy attained SVR). IL28B-type was strongly associated with
SVR (P-value = 0.004). SVR was associated with lower intrahepatic
ISG expression levels.
Conclusions: The CC IL28B-type was strongly associated with
reduced expression of intrahepatic ISGs. In a subset, SVR was
associated with both CC IL28B-type and reduced ISG expression.
This suggests that genetic variation in IL28B regulates the innate
immune response to HCV in the liver, priming patients for a stronger
ISG response to exogenous IFN therapy.
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01/03/2012 16:14
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20/08/2019 16:15
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