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

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.

• Authors: Rikita Nakano, Toshiro Maekawa, Hiromi Abe, Yasufumi Hayashida, Hidenori Ochi, Tatsuhiko Tsunoda, Hiromitsu Kumada, Naoyuki Kamatani, Yusuke Nakamura, Kazuaki Chayama
• Journal: The Journal of general virology (J Gen Virol) Vol. 94 Issue Pt 1 Pg. 81-89 (Jan 2013) ISSN: 1465-2099 [Electronic] England
• PMID: 23034592 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antiviral Agents
• Ribavirin
• Interferons
• N-Acetylgalactosaminyltransferases

Topics

• Alleles
• Antiviral Agents (therapeutic use)
• Asian People
• Case-Control Studies
• Chromosomes, Human, Pair 12
• Female
• Genotype
• Hepatitis C, Chronic (drug therapy, enzymology, genetics, virology)
• Humans
• Interferons (therapeutic use)
• Introns
• Male
• Middle Aged
• N-Acetylgalactosaminyltransferases (genetics)
• Polymorphism, Single Nucleotide
• Ribavirin (therapeutic use)
• Transcription, Genetic
• Treatment Outcome
• Virus Replication (drug effects)
• Polypeptide N-acetylgalactosaminyltransferase