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Polymorphism of OAS-1 determines liver fibrosis progression in hepatitis C by reduced ability to inhibit viral replication


Naoya Kato, MD, Unit of Disease Control Genome Medicine, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan
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Background: Progression of disease after hepatitis C virus (HCV) infection differs among individuals, indicating a possibility of participation of host genetic factors. 2′-5′-oligoadenylate synthetase 1 (OAS-1), an important component of the innate immune system, has an antiviral function, and may therefore have a certain relationship with progression of disease.

Aim: To evaluate single nucleotide polymorphisms (SNPs) of OAS-1 and its relationship with the disease status of HCV infection.

Methods: Six SNPs of OAS-1 were selected and examined in 409 Japanese patients with chronic HCV infection using the TaqMan PCR genotyping method. The relationship of SNP genotypes and clinical manifestations of patients was analysed. Then, a pair of OAS-1-expression plasmids mimicking the clinical-related SNPs were created and transfected into liver cells carrying the HCV subgenomic replicon or the full-length genome, JFH1, and HCV replication after transfection was compared.

Results: Patients with genotypes A/A, A/G and G/G of an SNP of OAS-1 at the exon 3 of its coding sequence were at gradient increased risks of suffering from higher serum alanine aminotransferase (P<0.001) and aspartate aminotransferase (P=0.001), higher degree of liver fibrosis (P=0.010) and higher presence of liver cirrhosis (P=0.001). By multivariate logistic regression analysis, genotype G/G was an independent factor associated with cirrhosis (P=0.013, odds ratio 3.11, 95% confidence interval 1.27–7.63). In liver cells, OAS-1 with the G allele showed lower ability to inhibit virus replication than OAS-1 with the A allele (P=0.004).

Conclusions: The SNP of OAS-1 at the exon 3 of its coding sequence was associated with progression of disease in Japanese patients with HCV infection.