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

Details

Serval ID
serval:BIB_AB272EB7FCFF
Type
Inproceedings: an article in a conference proceedings.
Publication sub-type
Abstract (Abstract): shot summary in a article that contain essentials elements presented during a scientific conference, lecture or from a poster.
Collection
Publications
Title
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
Author(s)
Thompson A., Schuppan D., Urban T., Fellay J., Shianna K., McHutchison J., Goldstein D., Afdhal N.
Address
Vienna, Austria, April 14-18, 2010
ISBN
0168-8278
Publication state
Published
Issued date
2010
Peer-reviewed
Oui
Volume
52
Series
Journal of Hepatology
Pages
S2
Language
english
Abstract
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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Create date
01/03/2012 15:14
Last modification date
20/08/2019 15:15
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