Hepatic ISG expression is associated with genetic variation in interleukin 28B and the outcome of IFN therapy for chronic hepatitis C.
OBJECTIVE
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 (>or=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.
Honda
Masao
M
Department of Gastroenterology, Kanazawa University Graduate School of Medicine, Kanazawa, Japan.
Sakai
Akito
A
Yamashita
Tatsuya
T
Nakamoto
Yasunari
Y
Mizukoshi
Eishiro
E
Sakai
Yoshio
Y
Yamashita
Taro
T
Nakamura
Mikiko
M
Shirasaki
Takayoshi
T
Horimoto
Katsuhisa
K
Tanaka
Yasuhito
Y
Tokunaga
Katsushi
K
Mizokami
Masashi
M
Kaneko
Shuichi
S
D000328:Adult; D000368:Aged; D000998:Antiviral Agents / Q000627:therapeutic use*; D016000:Cluster Analysis; D004359:Drug Therapy, Combination; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation; D016174:Hepacivirus / Q000235:genetics; D019698:Hepatitis C, Chronic / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D050835:Interferon Regulatory Factors / Q000235:genetics*; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000627:therapeutic use*; D007372:Interferons; D007378:Interleukins / Q000235:genetics*; D008099:Liver / Q000187:drug effects* / Q000276:immunology / Q000821:virology; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D020411:Oligonucleotide Array Sequence Analysis; D011092:Polyethylene Glycols / Q000627:therapeutic use*; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D012367:RNA, Viral / Q000097:blood; D011994:Recombinant Proteins; D012254:Ribavirin / Q000627:therapeutic use*; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors; D016896:Treatment Outcome; D019562:Viral Load; D000095022:Interferon Lambda
D000998:Antiviral Agents; D050835:Interferon Regulatory Factors; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D007372:Interferons; D007378:Interleukins; D011092:Polyethylene Glycols; D012367:RNA, Viral; D011994:Recombinant Proteins; D012254:Ribavirin; C000624353:interferon-lambda, human; D000095022:Interferon Lambda; C417083:peginterferon alfa-2b