A single nucleotide polymorphism in activated cdc42 associated tyrosine kinase 1 influences the interferon therapy in hepatitis C patients

作者：Fujimoto Yoshifumi; Ochi Hidenori; Maekawa Toshiro; Abe Hiromi; Hayes C Nelson; Kumada Hiromitsu; Nakamura Yusuke; Chayama Kazuaki^*

来源：Journal of Hepatology, 2011, 54(4): 629-639.

DOI：10.1016/j.jhep.2010.07.021

• ACK1
• HCV
• Tagging-SNP
• Interferon

Background 82 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 x 10(-4)). Replication analysis confirmed the association (p = 2.2 x 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. Overexpression 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-gamma-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.

• 出版日期2011-4
• 单位河北医科大学