RRC ID 79342
Author Nakano R, Maekawa T, Abe H, Hayashida Y, Ochi H, Tsunoda T, Kumada H, Kamatani N, Nakamura Y, Chayama K.
Title Single-nucleotide polymorphisms in GALNT8 are associated with the response to interferon therapy for chronic hepatitis C.
Journal J Gen Virol
Abstract New anti-hepatitis C virus (HCV) therapeutics developed recently are more effective and lead to improvements in sustained viral response. However, interferon (IFN) monotherapy is still used to a limited extent for fear of adverse effects. This study investigated host genetic factors affecting the IFN response in patients with chronic hepatitis C (CHC). Using a two-step design, a large-scale association screening including 1088 Japanese CHC patients treated with IFN was performed employing ~70 000 gene-based single-nucleotide polymorphisms (SNPs). Replication was tested in an independent Japanese cohort of 328 patients. Fine-mapping and functional analyses were also performed. Through two-step screening, it was found that rs2286580 in intron 6 of the gene encoding N-acetylgalactosaminyltransferase 8 (GALNT8) on chromosome 12 was significantly associated with a sustained viral response (combined P = 3.9×10(-6), odds ratio 1.52, 95 % confidence interval 1.29-1.82). 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 genotype. By contrast, the outcome of pegylated IFN 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 an unfavourable allele of the variant. A luciferase reporter assay demonstrated that overexpression of GALNT8 attenuated IFN-α-induced gene transcription via the IFN-stimulated response element. These results suggest that GALNT8 variants contribute to the response to IFN therapy against CHC, providing a new insight into antiviral mechanisms of IFN.
Volume 94(Pt 1)
Pages 81-89
Published 2013-1-1
DOI 10.1099/vir.0.044396-0
PMID 23034592
MeSH Alleles Antiviral Agents / therapeutic use* Asian People Case-Control Studies Chromosomes, Human, Pair 12 Female Genotype Hepatitis C, Chronic / drug therapy* Hepatitis C, Chronic / enzymology Hepatitis C, Chronic / genetics* Hepatitis C, Chronic / virology Humans Interferons / therapeutic use* Introns Male Middle Aged N-Acetylgalactosaminyltransferases / genetics* Polymorphism, Single Nucleotide Polypeptide N-acetylgalactosaminyltransferase Ribavirin / therapeutic use Transcription, Genetic Treatment Outcome Virus Replication / drug effects
IF 3.376
Human and Animal Cells HuH-7