Article

Single nucleotide polymorphisms in GALNT8 are associated with response to interferon therapy for chronic hepatitis C.

Graduate School of Biomedical Science, Hiroshima University, Japan
Journal of General Virology (Impact Factor: 3.53). 10/2012; 94. DOI: 10.1099/vir.0.044396-0
Source: PubMed

ABSTRACT SUMMARY New anti-HCV therapeutics developed recently are more effective and lead to improvements in sustained viral response. However, interferon mono-therapy is still used to a limited extent for fear of adverse effects. We investigated host genetic factors affecting interferon response in patients with chronic hepatitis C. Using a two-step design, a large scale association screening including 1088 Japanese chronic hepatitis C patients treated with interferon was performed employing approximately 70,000 gene-based SNPs. Replication was tested in an independent Japanese cohort of 328 patients. Fine mapping and functional analyses were also performed. Through two-step screening, we found that rs2286580 in intron 6 of polypeptide N-acetylgalactosaminyltransferase 8 (GALNT8) on chromosome 12 was significantly associated with sustained viral response (combined p = 3.9 x 10-6, OR 1.52, 95%CI 1.27-1.82). The association was replicated in an additional cohort of 328 Japanese patients. In subgroup analysis, GALNT8 variants were associated with treatment outcome independently of HCV genotypes. By contrast, the outcome of pegylated-interferon and ribavirin combined therapy was not affected by the SNP. Fine mapping analysis revealed that the association peak was at rs10849138 in intron 6 of GALNT8. Allele-specific transcription analysis demonstrated that GALNT8 expression was upregulated by unfavorable allele of the variant. Luciferase reporter assay demonstrated that overexpression of GALNT8 attenuated IFN-α-induced gene transcription via ISRE elements. Our results suggest that GALNT8 variants contribute to response to interferon therapy against chronic hepatitis C, providing a new insight into antiviral mechanisms of interferon.

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