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Interferon (IFN) regulatory factor 7 (IRF-7) has been shown to play an essential role in the transcriptional activation of virus-inducible cellular genes, especially IFN genes. Polymorphisms of the IRF-7 gene may probably affect both the quality and the quantity of IRF-7. We investigated the role of IRF-7 polymorphisms in Japanese patients with chronic hepatitis C virus (HCV) infection.We studied a total of nine polymorphisms of the IRF-7 gene including SNP1047A/G (Lys/Glu) and SNP2157A/G (Gln/Arg) using the Taqman allelic discrimination and sequencing techniques in 406 Japanese patients with chronic HCV infection. We further performed functional analysis of SNP1047 and SNP2157 by transcriptional activation of the IFNA promoter.We found that SNP1047AG and SNP2157AG genotypes were in complete linkage disequilibrium and were present in a significantly higher proportion in HCV-infected patients with cirrhosis (5.6%) than in those without cirrhosis (1.7%) (P=0.03). Multivariate analysis also revealed that SNP1047 and SNP2157 were independently associated with cirrhosis at an odds ratio of 2.5. Functional analysis revealed that SNP1047G and SNP2157G alleles increased IFNA expression.SNP1047AG and SNP2157AG genotypes were strongly associated with cirrhosis. SNP1047G and SNP2157G alleles might be used as markers of host factors associated with a higher risk of cirrhosis in Japanese patients with chronic HCV infection.