IL28b polymorphism is associated with intrahepatic ISG expression and peginterferon-a/ribavirin response rate in chronic HCV infection.
Détails
ID Serval
serval:BIB_AB272EB7FCFF
Type
Actes de conférence (partie): contribution originale à la littérature scientifique, publiée à l'occasion de conférences scientifiques, dans un ouvrage de compte-rendu (proceedings), ou dans l'édition spéciale d'un journal reconnu (conference proceedings).
Sous-type
Abstract (résumé de présentation): article court qui reprend les éléments essentiels présentés à l'occasion d'une conférence scientifique dans un poster ou lors d'une intervention orale.
Collection
Publications
Institution
Titre
IL28b polymorphism is associated with intrahepatic ISG expression and peginterferon-a/ribavirin response rate in chronic HCV infection.
Titre de la conférence
45th Annual Meeting of the European Association for the Study of the Liver
Adresse
Vienna, Austria, April 14-18, 2010
ISBN
0168-8278
Statut éditorial
Publié
Date de publication
2010
Peer-reviewed
Oui
Volume
52
Série
Journal of Hepatology
Pages
S2
Langue
anglais
Résumé
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.
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.
Web of science
Création de la notice
01/03/2012 16:14
Dernière modification de la notice
20/08/2019 16:15
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