A single nucleotide polymorphism in activated Cdc42 associated tyrosine kinase 1 influences the interferon therapy in hepatitis C patients.
OBJECTIVE
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.
The Institute of Physical and Chemical Research, Katsumi, Minami-ku, Hiroshima, Japan.
Yoshifumi
Y
Fujimoto
Hidenori
H
Ochi
Toshiro
T
Maekawa
Hiromi
H
Abe
C Nelson
CN
Hayes
Hiromitsu
H
Kumada
Yusuke
Y
Nakamura
Kazuaki
K
Chayama
D000328:Adult; D000368:Aged; D000483:Alleles; D002460:Cell Line; D005260:Female; D005787:Gene Frequency; D006526:Hepatitis C / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics*; D006801:Humans; D007370:Interferon Type I / Q000627:therapeutic use*; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D011092:Polyethylene Glycols / Q000627:therapeutic use; D020641:Polymorphism, Single Nucleotide; D011505:Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014162:Transfection; D016896:Treatment Outcome; D020764:cdc42 GTP-Binding Protein / Q000235:genetics
D007370:Interferon Type I; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D012333:RNA, Messenger; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; D011505:Protein-Tyrosine Kinases; C403262:TNK2 protein, human; D020764:cdc42 GTP-Binding Protein; C417083:peginterferon alfa-2b