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

• Published in: Journal of hepatology Vol. 54; no. 4; pp. 629 - 639
• Main Authors: Fujimoto, Yoshifumi, Ochi, Hidenori, Maekawa, Toshiro, Abe, Hiromi, Hayes, C. Nelson, Kumada, Hiromitsu, Nakamura, Yusuke, Chayama, Kazuaki
• Format: Journal Article
• Language: English
• Published: Kidlington Elsevier B.V 01.04.2011; Elsevier
• Subjects: ACK1; Adult; Aged; Alleles; Biological and medical sciences; cdc42 GTP-Binding Protein - genetics; Cell Line; Female; Gastroenterology and Hepatology; Gastroenterology. Liver. Pancreas. Abdomen; Gene Frequency; HCV; Hepatitis C - drug therapy; Hepatitis C - enzymology; Hepatitis C - genetics; Human viral diseases; Humans; Infectious diseases; Interferon; Interferon Type I - therapeutic use; Interferon-alpha - therapeutic use; Male; Medical sciences; Middle Aged; Polyethylene Glycols - therapeutic use; Polymorphism, Single Nucleotide; Protein-Tyrosine Kinases - genetics; Protein-Tyrosine Kinases - metabolism; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; Signal Transduction; Tagging-SNP; Transfection; Treatment Outcome; Viral diseases; Viral hepatitis; OAS; OR; NR; CI; PTK; ACK; IFN; STAT; JAK; ACK1; MxA; GAS; LD; SNPs; Tagging-SNP; HCV; Interferon; IRF; ISG; BMI; ISRE; SR; sustained responders; odds ratio; signal transducer and activator of transcription; myxovirus resistance-A; single nucleotide polymorphisms; activated cdc42 associated tyrosine kinase; linkage disequilibrium; interferon-γ-activated site; body mass index; nonresponders; interferon; Janus-activated kinase; 2′-5′-oligoadenylate synthetase; protein tyrosine kinase; IFN-stimulated genes; interferon-stimulated response element; interferon regulatory factor; confidence interval; Human; Enzyme; Transferases; Cytokine; Hepatic disease; Infection; Treatment; Viral disease; Gastroenterology; Digestive diseases; Single nucleotide polymorphism; Protein-tyrosine kinase; Viral hepatitis C
• ISSN: 0168-8278; 1600-0641; 1600-0641
• DOI: 10.1016/j.jhep.2010.07.021

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. 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. 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. 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.