title: Genetic variation of the IL-28B promoter affecting gene expression.
abstract: The current standard of care for the treatment of chronic hepatitis C is pegylated interferon-α (PEG-IFNα) 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-α 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.
authors: The Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Chiba, Japan.
authors: Masaya
authors: M
authors: Sugiyama
authors: Yasuhito
authors: Y
authors: Tanaka
authors: Takaji
authors: T
authors: Wakita
authors: Makoto
authors: M
authors: Nakanishi
authors: Masashi
authors: M
authors: Mizokami
mesh_terms: D018900:Dinucleotide Repeats; D015870:Gene Expression; D014644:Genetic Variation; D019698:Hepatitis C, Chronic; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology / Q000627:therapeutic use; D007372:Interferons; D007378:Interleukins / Q000235:genetics*; D008969:Molecular Sequence Data; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D012254:Ribavirin / Q000494:pharmacology / Q000627:therapeutic use; D000095022:Interferon Lambda
chemical_list: D016898:Interferon-alpha; D007372:Interferons; D007378:Interleukins; D012254:Ribavirin; C000624353:interferon-lambda, human; D000095022:Interferon Lambda