Identification of a Single Nucleotide Polymorphism in the <i>MxA</i> Gene Promoter (G/T at nt –88) Correlated with the Response of Hepatitis C Patients to Interferon

Abstract

The interferon (IFN)-inducible MxA protein is known to play an important role in the host defense against certain viruses. We aimed to see if any genetic polymorphism in the promoter region of the MxA gene is associated with the IFN responsiveness of hepatitis C virus (HCV)-infected patients. Initially we sequenced the promoter region of the MxA gene in 12 subjects and found a polymorphic site. We then constructed a specific PCR-RFLP system for this site and subjected 63 samples from chronic hepatitis C patients who were nonresponders (NR) to IFN therapy to it, 52 with sustained response (SR), and 42 healthy controls. Subjects were all Japanese, and unrelated. A single nucleotide polymorphism (SNP) was identified in the MxA promoter region: G/T alleles at nt position –88. Interestingly, this SNP was involved in a genetic element highly homologous to the IFN-stimulated response element consensus sequence, and the G-to-T change there makes this homology a little greater. The rate of G·G homozygosity was 31% in the SR patients, significantly lower than in the NR patients (62%, p = 0.0009), while that of healthy controls was between the two groups (48%). Differences in HCV genotypes did not influence this result. Based on these findings, we propose that the SNP of the MxA promoter at nt –88 identified in this study affects the expression of MxA protein, and may thus be associated with the response of HCV patients to IFN.

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.…”

Single nucleotide polymorphisms and haplotypes in the IL10 region associated with HCV clearance

“…Polymorphisms in several genes including MxA, PKR, OAS, 11 HLA, KIR, TNF, 12 and MICA have been shown to be associated with HCV clearance or persistence. 13,14 Studies have indicated that single nucleotide polymorphisms (SNPs) in the IL10, CTLA, MxA, and LMP7 genes may influence the response to IFN-a treatment in patients with chronic HCV [15][16][17] along with variants in the HLA. 13,14 The strength of the immune response may influence HCV-mediated fibrogenesis 10 through cytokines that stimulate extracellular matrix deposition such as TNF.…”

Pharmacogenomic perspectives of chronic hepatitis C virus (HCV) infection

“…Substitution of À88T for À88G increases the sequence homology further, 8 and experimental analyses indicate that cloned MX1 promoter construct carrying À88T and À123A has a fourfold higher transcriptional activity compared with the À123G and À88G construct. 9 Other compelling evidence suggests that SR patients do have increased MX1 mRNA production and elevated MX1 protein level during treatment.…”

“…These studies also hold the promise of identifying additional molecular mechanisms that can be targeted for new, more effective interventions. The À88G/G genotype defined by a single-nucleotide polymorphism (SNP) in the MX1 promoter was found more frequently in the NR group among Japanese (n ¼ 115) 8 and British patients (n ¼ 171). 7 A related MX1 genotype, -123G/G has shown a similar effect due to tight linkage disequilibrium (LD) between À88G and À123G.…”

“…In those analyses of more than a single SNP or mutation in more than 100 patients, preliminary genetic markers include HLA and related variants on chromosome 6, 12,13 homozygosity for an extended haplotype (HHE) along the CCR2 to CCR5 loci on chromosome 3, 14 as well as cytokine gene and related polymorphisms mapped to various locations. [6][7][8] For example, HLA-DRB1*07 was associated with the NR phenotype in treated French (n ¼ 170), 12 while Japanese patients (n ¼ 175) with the LMP7 variant that changes amino acid 49Gln to 49Lys were more likely to be sustained responders (SRs). 13 In CTLA4, the 49G variant on the (À381)C-49G haplotype has been associated with SR in one study of European Americans (n ¼ 158).…”