title: 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.affiliation: Laboratory for Digestive Diseases, RIKEN Center for Genomic Medicine, Hiroshima, Japan.|Pharmacology Research Laboratories, Drug Research Division, Dainippon Sumitomo Pharma Co., Osaka, Japan.
authors.forename: Rikita
authors.initials: R
authors.lastname: Nakano
authors.affiliation: Laboratory for Digestive Diseases, RIKEN Center for Genomic Medicine, Hiroshima, Japan.
authors.forename: Toshiro
authors.initials: T
authors.lastname: Maekawa
authors.affiliation: Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Abe
authors.affiliation: Laboratory for Digestive Diseases, RIKEN Center for Genomic Medicine, Hiroshima, Japan.
authors.forename: Yasufumi
authors.initials: Y
authors.lastname: Hayashida
authors.affiliation: Laboratory for Digestive Diseases, RIKEN Center for Genomic Medicine, Hiroshima, Japan.|Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.
authors.forename: Hidenori
authors.initials: H
authors.lastname: Ochi
authors.affiliation: Laboratory for Medical Informatics, RIKEN Center for Genomic Medicine, Yokohama, Japan.
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Tsunoda
authors.affiliation: Department of Hepatology, Toranomon Hospital, Tokyo, Japan.
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Kumada
authors.affiliation: Laboratory for International Alliance, RIKEN Center for Genomic Medicine, Yokohama, Japan.
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Kamatani
authors.affiliation: Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Nakamura
authors.affiliation: Laboratory for Digestive Diseases, RIKEN Center for Genomic Medicine, Hiroshima, Japan.|Department of Gastroenterology and Metabolism, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Chayama
mesh_terms: D000483:Alleles; D000998:Antiviral Agents / Q000627:therapeutic use*; D044466:Asian People; D016022:Case-Control Studies; D002881:Chromosomes, Human, Pair 12; D005260:Female; D005838:Genotype; D019698:Hepatitis C, Chronic / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics* / Q000821:virology; D006801:Humans; D007372:Interferons / Q000627:therapeutic use*; D007438:Introns; D008297:Male; D008875:Middle Aged; D017350:N-Acetylgalactosaminyltransferases / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012254:Ribavirin / Q000627:therapeutic use; D014158:Transcription, Genetic; D016896:Treatment Outcome; D014779:Virus Replication / Q000187:drug effects; D000097763:Polypeptide N-acetylgalactosaminyltransferase
chemical_list: D000998:Antiviral Agents; D007372:Interferons; D017350:N-Acetylgalactosaminyltransferases; D012254:Ribavirin; D000097763:Polypeptide N-acetylgalactosaminyltransferase