期刊
PLOS ONE
卷 6, 期 10, 页码 -出版社
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0026620
关键词
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资金
- Ministry of Health Labor and Welfare of Japan
- Ministry of Education, Culture, Sports, Science, and Technology of Japan [271000]
- National Center for Global Health and Medicine [22-302]
- Grants-in-Aid for Scientific Research [23240124, 22118003, 23390117] Funding Source: KAKEN
The current standard of care for the treatment of chronic hepatitis C is pegylated interferon-alpha (PEG-IFN-alpha) and ribavirin (RBV). The treatment achieves a sustained viral clearance in only approximately 50% of patients. Recent whole genome association studies revealed that single nucleotide polymorphisms (SNPs) around IL-28B have been associated with response to the standard therapy and could predict treatment responses at approximately 80%. However, it is not clear which SNP is most informative because the genomic region containing significant SNPs shows strong linkage disequilibrium. We focused on SNPs in close proximity to the IL-28B gene to evaluate the function of each and identify the SNP affecting the IL-28B expression level most. The structures of IL-28A/B from 5' to 3'-UTR were determined by complete cDNA cloning. Both IL-28A and 28B genes consisted of 6 exons, differing from the CCDS data of NCBI. Two intron SNPs and a nonsynonymous SNP did not affect IL-28B gene function and expression levels but a SNP located in the proximal promoter region influenced gene expression. A (TA) dinucleotide repeat, rs72258881, located in the promoter region was discovered by our functional studies of the proximal SNPs upstream of IL-28B; the transcriptional activity of the promoter increased gradually in a (TA)(n) length-dependent manner following IFN-alpha and lipopolysaccharide stimulation. Healthy Japanese donors exhibited a broad range of (TA) dinucleotide repeat numbers from 10 to 18 and the most prevalent genotype was 12/12 (75%), differing from the database (13/13). However, genetic variation of IL-28A corresponding to that of IL-28B was not detected in these Japanese donors. These findings suggest that the dinucleotide repeat could be associated with the transcriptional activity of IL-28B as well as being a marker to improve the prediction of the response to interferon-based hepatitis C virus treatment.
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