Hepatic ISG Expression Is Associated With Genetic Variation in Interleukin 28B and the Outcome of IFN Therapy for Chronic Hepatitis C

Gastroenterology
Volume 139, Issue 2 , Pages 499-509, August 2010
 
Masao Honda, Akito Sakai, Tatsuya Yamashita, Yasunari Nakamoto, Eishiro Mizukoshi, Yoshio Sakai, Taro Yamashita, Mikiko Nakamura, Takayoshi Shirasaki, Katsuhisa Horimoto, Yasuhito Tanaka, Katsushi Tokunaga, Masashi Mizokami, Shuichi Kaneko, Hokuriku Liver Study Group

Received 9 October 2009; accepted 14 April 2010. published online 30 April 2010.

Abstract

Background & Aims
Multiple viral and host factors are related to the treatment response to pegylated-interferon and ribavirin combination therapy; however, the clinical relevance and relationship of these factors have not yet been fully evaluated.

Methods
We studied 168 patients with chronic hepatitis C who received pegylated-interferon and ribavirin combination therapy. Gene expression profiles in the livers of 91 patients were analyzed using an Affymetrix genechip (Affymetrix, Santa Clara, CA). The expression of interferon-stimulated genes (ISGs) was evaluated in all samples by real-time polymerase chain reaction. Genetic variation in interleukin 28B (IL28B; rs8099917) was determined in 91 patients.

Results
Gene expression profiling of the liver differentiated patients into 2 groups: patients with up-regulated ISGs and patients with down-regulated ISGs. A high proportion of patients with no response to treatment was found in the up-regulated ISGs group (P = .002). Multivariate logistic regression analysis showed that ISGs (<3.5) (odds ratio [OR], 16.2; P < .001), fibrosis stage (F1-F2) (OR, 4.18; P = .003), and ISDR mutation (≥2) (OR, 5.09; P = .003) were strongly associated with the viral response. The IL28B polymorphism of 91 patients showed that 66% were major homozygotes (TT), 30% were heterozygotes (TG), and 4% were minor homozygotes (GG). Interestingly, hepatic ISGs were associated with the IL28B polymorphism (OR, 18.1; P < .001), and its expression was significantly higher in patients with the minor genotype (TG or GG) than in those with the major genotype (TT).

Conclusions
The expression of hepatic ISGs is strongly associated with treatment response and genetic variation of IL28B. The differential role of host and viral factors as predicting factors may also be present.

Keywords: Pegylated Interferon, Ribavirin, Gene Expression, Single Nucleotide Polymorphism

Abbreviations used in this paper: aa, amino acid, AST, aspartate aminotransferase, cDNA, complementary DNA, CH-C, chronic hepatitis C, Down-ISGs, down-regulated ISGs, EVR, early virologic response, GWAS, genome-wide association studies, HCV, hepatitis C virus, IFN, interferon, IFI44, interferon-induced protein 44, IFIT1, interferon-induced protein with tetratricopeptide repeats 1, IL, interleukin, IL28B, interleukin 28B, ISDR, interferon sensitivity determining region, ISGs, interferon stimulated genes, Mx1, myxovirus (influenza virus) resistance 1 interferon-inducible protein p78 (mouse), NR, no response, Peg, pegylated, RBV, ribavirin, ROC, receiver operating characteristic, RTD, real-time detection, PCR, polymerase chain reaction, RTD-PCR, real-time detection-polymerase chain reaction, SNP, single nucleotide polymorphism, SVR, sustained viral response, TR, transient response, Up-ISGs, up-regulated ISGs

Participating investigators are listed in Appendix 1.

Conflicts of interest The authors disclose no conflicts.

Funding This work was supported in part by a grant-in-aid from the Ministry of Health, Labour and Welfare of Japan.

PII: S0016-5085(10)00657-8

doi:10.1053/j.gastro.2010.04.049

© 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.

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