Single nucleotide polymorphism of the MxA gene promoter influences the response to interferon monotherapy in patients with hepatitis C viral infection

Abstract

The biological activity of interferon (IFN) is mediated by the induction of intracellular antiviral proteins, such as 2'-5' oligoadenylate synthetase, dsRNA-activated protein kinase and MxA protein. Among these, MxA protein is assumed to be the most specific surrogate parameter for IFN action. This study was performed to elucidate whether a single nucleotide polymorphism (SNP) (G/T at nt-88) in the promoter region of the MxA gene influences the response to IFN therapy in patients with chronic hepatitis C virus (HCV) infection. Polymorphisms of the MxA gene in 235 HCV patients were determined by polymerase chain reaction-restriction fragment length polymorphism. The frequency of SNP was compared between sustained-responders (n = 78) and nonresponders (n = 157), as determined by biochemical and virological responses to IFN. Multivariate analysis showed that among all patients, HCV genotype, HCV RNA level and the SNP of the MxA gene were independent and significant determinants of the outcome of IFN therapy [odds ratio 3.8 (95% confidence interval 2.0-7.0), P < 0.0001; 0.27 (0.15-0.50), P < 0.0001; 1.8 (1.0-3.4), P = 0.0464, respectively]. Furthermore, among patients with a low viral load (< or =2.0 Meq/mL), MxA-T-positive patients were more likely to show a sustained response compared with MxA-T-negative patients [2.87 (1.3-6.3); 62%vs 36%; P = 0.0075]. Our findings suggested that the SNP of the MxA gene is one of the important host factors that independently influences the response to IFN in patients with chronic HCV infection, especially those with a low viral load.

Association of single nucleotide polymorphisms in interferon signaling pathway genes and interferon-stimulated genes with the response to interferon therapy for chronic hepatitis C

“…Furthermore, association studies have suggested that polymorphisms in these genes may play a role in differential drug response [12,13].…”

The Impact of Host Factors on Management of Hepatitis C Virus

“…The -88T SNP in the MxA gene was found to be associated with lower MxA activity. In patients with low viral load, sustained viral response (SVR) was significantly higher (62%) in -88T patients than in patients bearing the -88A allele (32%) (11). The 5`2` OAS plays a major role in the clearance of the virus.…”

Genetic Variation of Host Immune Response Genes and Their Effect on Hepatitis C Infection and Treatment Outcome

“…Three SNPs in the IFN induced 2'-5' oligoadenylated synthetase -like gene (OASL) (rs3213545 T , rs1169279 A and rs2859398 C alleles) were found to be associated with SVR (Su, Yee et al 2008). The T allele in the promoter (-88) of MxA was also associated with SVR (Suzuki, Arase et al 2004). Although these association studies highlight the relevance of IFN and ISG variants in HCV treatment, additional gene expression studies have been carried out to directly correlated expression levels with treatment outcome.…”

“…Underlined HLA alleles appear in more than one study. References: (Thio, Gao et al 2002;McKiernan, Hagan et al 2004;Wang, Zheng et al 2009), (Thio, Thomas et al 2001;Yee 2004;Yoon, Han et al 2005;Ksiaa, Ayed-Jendoubi et al 2007;Harris, Sugimoto et al 2008), (Ishida, Ikebuchi et al 2011), (Falleti, Fabris et al 2010), (Haas, Weiß et al 2009), (Mueller, Mas-Marques et al 2004), (Yee, Tang et al 2001) (Morgan, Lambrecht et al 2008), (Thio, Goedert et al 2004;Paladino, Fainboim et al 2006), (Knapp, Hennig et al 2003;Lio, Caruso et al 2003;Kimura, Saito et al 2006;An, Thio et al 2008), (Schott, Witt et al 2008), (Huang, Yang et al 2007), (Ge, Fellay et al 2009;Mangia, Thompson et al 2010), (Tanaka, Nishida et al 2009;Rauch, Kutalik et al 2010), (Vejbaesya, Nonnoi et al 2011), (Khakoo, Thio et al 2004;Montes-Cano, Caro-Oleas et al 2005), (Persico, Capasso et al 2008), (Su, Yee et al 2008), (Suzuki, Arase et al 2004), (Knapp, Yee et al 2003), (Dai, Chuang et al 2010). The innate immune system has a critical role in detecting pathogens and triggering the immune response.…”