論文 - 詳細
| RRC ID | 38440 |
|---|---|
| 著者 | Fujimoto Y, Ochi H, Maekawa T, Abe H, Hayes CN, Kumada H, Nakamura Y, Chayama K. |
| タイトル | A single nucleotide polymorphism in activated Cdc42 associated tyrosine kinase 1 influences the interferon therapy in hepatitis C patients. |
| ジャーナル | J Hepatol |
| Abstract |
BACKGROUND & AIMS:Cdc42 is a Rho family GTPase protein and was recently implicated in mediating hepatitis C virus (HCV) infectivity. This study examines the association between Cdc42-related gene and interferon (IFN) therapy in HCV patients. METHODS:We analyzed the associations between the outcome of IFN therapy and 17 tagging single nucleotide polymorphisms (SNPs) within two genes involved in Cdc42 signaling (CDC42 and ACK1). A total of 295 out of the 409 study subjects were sustained responders (SR) and 114 were non-responders (NR). Replication was performed using an independent set of 794 IFN-treated patients. RESULTS:SNP rs2278034 [A/G] in intron 11 of activated Cdc42 associated tyrosine kinase (ACK) 1 was associated with the outcome of IFN therapy (p=6.4 × 10(-4)). Replication analysis confirmed the association (p=2.2 × 10(-3)) for patients treated with IFN monotherapy, but the association was not significant for pegylated-IFN-plus ribavirin therapy. Analysis using published HapMap expression data revealed that ACK1 expression correlates with IFN-stimulated gene (ISG) expression independently of ethnicity, but the relationship between rs2278034 and ACK1 expression was observed only within Asian populations. Over-expression of ACK1, but not the kinase-inactive mutant, increased ISG transcription in Huh7 cells. ACK1 expression enhanced the IFN-stimulated response element (ISRE) and interferon-γ-activated site (GAS) promoter activity through tyrosine phosphorylation of signal transducers and activators of transcription (STAT) 1. Furthermore, ACK1 over-expression in HCV-N replicon cells inhibited HCV replication. CONCLUSIONS:SNP rs2278034 in ACK1 is associated with IFN therapy outcome in patients with HCV. ACK1 may play a role in innate and IFN-induced antiviral action against HCV. |
| 巻・号 | 54(4) |
| ページ | 629-39 |
| 公開日 | 2011-4-1 |
| DOI | 10.1016/j.jhep.2010.07.021 |
| PII | S0168-8278(10)00809-3 |
| PMID | 21129804 |
| MeSH | Adult Aged Alleles Cell Line Female Gene Frequency Hepatitis C / drug therapy* Hepatitis C / enzymology Hepatitis C / genetics* Humans Interferon Type I / therapeutic use* Interferon alpha-2 Interferon-alpha / therapeutic use Male Middle Aged Polyethylene Glycols / therapeutic use Polymorphism, Single Nucleotide* Protein-Tyrosine Kinases / genetics* Protein-Tyrosine Kinases / metabolism RNA, Messenger / genetics RNA, Messenger / metabolism Recombinant Proteins / genetics Recombinant Proteins / metabolism Signal Transduction Transfection Treatment Outcome cdc42 GTP-Binding Protein / genetics |
| IF | 20.582 |
| 引用数 | 9 |
| WOS 分野 | GASTROENTEROLOGY & HEPATOLOGY |
| リソース情報 | |
| ヒト・動物細胞 | |