Genetic variation of the IL-28B promoter affecting gene expression.

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 polymorphi...

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Autores principales:	Masaya Sugiyama, Yasuhito Tanaka, Takaji Wakita, Makoto Nakanishi, Masashi Mizokami
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2011
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/e43f1a44991d43adadedf67633e8c03a
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spelling	oai:doaj.org-article:e43f1a44991d43adadedf67633e8c03a2021-11-18T07:35:48ZGenetic variation of the IL-28B promoter affecting gene expression.1932-620310.1371/journal.pone.0026620https://doaj.org/article/e43f1a44991d43adadedf67633e8c03a2011-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22046316/?tool=EBIhttps://doaj.org/toc/1932-6203The 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.Masaya SugiyamaYasuhito TanakaTakaji WakitaMakoto NakanishiMasashi MizokamiPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 6, Iss 10, p e26620 (2011)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Masaya Sugiyama Yasuhito Tanaka Takaji Wakita Makoto Nakanishi Masashi Mizokami Genetic variation of the IL-28B promoter affecting gene expression.
description	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.
format	article
author	Masaya Sugiyama Yasuhito Tanaka Takaji Wakita Makoto Nakanishi Masashi Mizokami
author_facet	Masaya Sugiyama Yasuhito Tanaka Takaji Wakita Makoto Nakanishi Masashi Mizokami
author_sort	Masaya Sugiyama
title	Genetic variation of the IL-28B promoter affecting gene expression.
title_short	Genetic variation of the IL-28B promoter affecting gene expression.
title_full	Genetic variation of the IL-28B promoter affecting gene expression.
title_fullStr	Genetic variation of the IL-28B promoter affecting gene expression.
title_full_unstemmed	Genetic variation of the IL-28B promoter affecting gene expression.
title_sort	genetic variation of the il-28b promoter affecting gene expression.
publisher	Public Library of Science (PLoS)
publishDate	2011
url	https://doaj.org/article/e43f1a44991d43adadedf67633e8c03a
work_keys_str_mv	AT masayasugiyama geneticvariationoftheil28bpromoteraffectinggeneexpression AT yasuhitotanaka geneticvariationoftheil28bpromoteraffectinggeneexpression AT takajiwakita geneticvariationoftheil28bpromoteraffectinggeneexpression AT makotonakanishi geneticvariationoftheil28bpromoteraffectinggeneexpression AT masashimizokami geneticvariationoftheil28bpromoteraffectinggeneexpression
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Genetic variation of the IL-28B promoter affecting gene expression.

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