Genetic polymorphism of the MxA gene promoter and interferon responsiveness of hepatitis C patients: revisited by analyzing two SNP sites (-123 and -88) in vivo and in vitro.
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.
Hijikata
M
M
Department of Medical Sciences, Toshiba General Hospital, Tokyo, Japan.
Mishiro
S
S
Miyamoto
C
C
Furuichi
Y
Y
Hashimoto
M
M
Ohta
Y
Y
D019204:GTP-Binding Proteins; D016174:Hepacivirus / Q000187:drug effects / Q000235:genetics*; D006526:Hepatitis C / Q000821:virology; D006801:Humans; D007372:Interferons / Q000494:pharmacology*; D064547:Myxovirus Resistance Proteins; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D011506:Proteins / Q000235:genetics*
C579071:MX1 protein, human; D064547:Myxovirus Resistance Proteins; D011506:Proteins; D007372:Interferons; D019204:GTP-Binding Proteins