Genetic Polymorphism of the <i>MxA</i> Gene Promoter and Interferon Responsiveness of Hepatitis C Patients: Revisited by Analyzing Two SNP Sites (–123 and –88) in vivo and in vitro

Abstract

We have previously reported a single nucleotide polymorphism (SNP) at nucleotide (nt) position –88 (G or T) within an interferon-stimulated response element-like sequence in the promoter region of the MxA gene, which correlated with responsiveness of hepatitis C patients to interferon. Upstream of it, we then identified another SNP (C or A at nt –123) and investigated whether this SNP also correlates with interferon responsiveness. The two SNPs showed a high linkage to each other: all the individuals having G at –88 had C at –123, and 73% of those having T at –88 had A at –123. As was expected from this observation, the SNP at –123 also exhibited a correlation with interferon responsiveness (C/C homozygotes were more frequent among nonresponders than among responders: 65% of 107 vs. 40% of 52, p = 0.0028). These in vivo data from patients were further supported by results from in vitro experiments. The MxA promoter sequence with A at –123 and T at –88 showed about 4-fold higher activity of upregulating the downstream reporter gene than that with C at –123 and G at –88, in a luciferase reporter assay.

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

“…Generally speaking, the present study supports previous reports that polymorphisms in ISGs may be important in the clearance of hepatitis C virus, both naturally and in the context of therapy [12,20,21]. In addition to the OASL gene, we also observed statistically significant associations with SVR in either AA or CA alone for several SNPs in the ISPs as well as the ISGs.…”

Polymorphisms in interferon-induced genes and the outcome of hepatitis C virus infection: roles of MxA, OAS-1 and PKR

“…This observation is consistent with a previous report in a Japanese population in which the GG genotype was associated with nonresponse to interferon. 20,23 Interestingly, the allele frequency of the T allele is much lower in our Caucasian population than in the Japanese population (14.5% in Caucasians and 29.0% in Japanese). The apparent effect of the T-allele is supported by in vitro functional work, suggesting that this variant has higher transcriptional activity than the G allele when stimulated with interferon-a.…”

Host genetic determinants in hepatitis C virus infection

“…The Japanese group examined the role of polymorphisms in the MxA gene and response to interferon monotherapy in a Japanese population and observed the À88MxA-(G/ G) genotype to be correlated with nonresponse and the À123MxA-(C/C) genotype to be correlated with nonresponse. 71,72 Studies of HCV progression or severity of disease A total of 44 studies were found to address the topic of host genetics and HCV progression, severity or activity of disease, and have largely been inconsistent. 16,18,27,29,32,34,37,39,47,[68][69][70]80, There is a trend with DRB1*11 alleles and less severe liver disease.…”