| 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
|
| Resource |
| Human and Animal Cells |
HuH-7 |
