Impact of Interferon-α Receptor-1 Promoter Polymorphisms on the Transcriptome of the Hepatitis B Virus-Associated Hepatocellular Carcinoma
Background and aimsGenetic polymorphisms within the promoter of interferon-α receptor type-1 (IFNAR1) have been associated with the susceptibility to and the outcome of chronic hepatitis B virus (HBV) infection. However, the impact of these polymorphisms in the transcriptome of the HBV-associated he...
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Frontiers Media S.A.
2018-04-01
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| Series: | Frontiers in Immunology |
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| Online Access: | http://journal.frontiersin.org/article/10.3389/fimmu.2018.00777/full |
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| author | Timokratis Karamitros Timokratis Karamitros George Papatheodoridis Dimitrios Paraskevis Angelos Hatzakis Jean L. Mbisa Urania Georgopoulou Paul Klenerman Gkikas Magiorkinis Gkikas Magiorkinis |
| author_facet | Timokratis Karamitros Timokratis Karamitros George Papatheodoridis Dimitrios Paraskevis Angelos Hatzakis Jean L. Mbisa Urania Georgopoulou Paul Klenerman Gkikas Magiorkinis Gkikas Magiorkinis |
| author_sort | Timokratis Karamitros |
| collection | DOAJ |
| description | Background and aimsGenetic polymorphisms within the promoter of interferon-α receptor type-1 (IFNAR1) have been associated with the susceptibility to and the outcome of chronic hepatitis B virus (HBV) infection. However, the impact of these polymorphisms in the transcriptome of the HBV-associated hepatocellular carcinoma (HCC) remains largely unexplored.MethodsUsing whole-genome and exome sequencing data from The Cancer Genome Atlas project, we characterized three single-nucleotide polymorphisms (SNPs: −568G/C, −408C/T, −3C/T) and one variable number tandem repeat [VNTR: −77(GT)n] within the IFNAR1 promoter sequence in 49 HCC patients. RNAseq data from 10 genotyped HCC samples were grouped according to their −77VNTR or −3SNP genotype to evaluate the impact of these polymorphisms on the differential expression on the HCC transcriptome.ResultsThere is a fourfold higher impact of the −77VNTR on the HCC transcriptome compared to the −3SNP (q < 0.1, p < 0.001). The expression of the primary IFNAR1 transcript is not affected by these polymorphisms but a secondary, HCC-specific transcript is expressed only in homozygous −77VNTR ≤8/≤8(GT)n samples (p < 0.05). At the same time, patients carrying at least one −77VNTR >8(GT) allele, presented a strong upregulation of the fibronectin-1 (FN-1) gene, which has been associated with the development of HCC. Gene Ontology and pathway enrichment analysis of the differentially expressed genes revealed a strong disruption of the PI3K–AKT signaling pathway, which can be partially triggered by the extracellular matrix FN-1.ConclusionThe IFNAR-1 promoter polymorphisms are not involved in the expression levels of the main IFNAR-1 transcript. The −77VNTR has a regulatory role on the expression of a secondary, truncated, HCC-specific transcript, which in turn coincides with disruptions in cancer-associated pathways and in FN-1 expression modifications. |
| first_indexed | 2024-12-13T21:52:34Z |
| format | Article |
| id | doaj.art-e8f9e702f8604c09afeeaa3335d2dec8 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-13T21:52:34Z |
| publishDate | 2018-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-e8f9e702f8604c09afeeaa3335d2dec82022-12-21T23:30:13ZengFrontiers Media S.A.Frontiers in Immunology1664-32242018-04-01910.3389/fimmu.2018.00777314391Impact of Interferon-α Receptor-1 Promoter Polymorphisms on the Transcriptome of the Hepatitis B Virus-Associated Hepatocellular CarcinomaTimokratis Karamitros0Timokratis Karamitros1George Papatheodoridis2Dimitrios Paraskevis3Angelos Hatzakis4Jean L. Mbisa5Urania Georgopoulou6Paul Klenerman7Gkikas Magiorkinis8Gkikas Magiorkinis9Department of Zoology, University of Oxford, Oxford, United KingdomDepartment of Microbiology, Public Health Laboratories, Hellenic Pasteur Institute, Athens, GreeceAcademic Department of Gastroenterology, Laiko General Hospital, Medical School of National and Kapodistrian University of Athens, Athens, GreeceDepartment of Hygiene and Epidemiology and Medical Statistics, Medical School of National and Kapodistrian University of Athens, Athens, GreeceDepartment of Hygiene and Epidemiology and Medical Statistics, Medical School of National and Kapodistrian University of Athens, Athens, GreeceVirus Reference Department, Public Health England, London, United KingdomDepartment of Microbiology, Molecular Virology Laboratory, Hellenic Pasteur Institute, Athens, GreecePeter Medawar Building for Pathogen Research and Translational Gastroenterology Unit, University of Oxford, Oxford, United KingdomDepartment of Zoology, University of Oxford, Oxford, United KingdomDepartment of Hygiene and Epidemiology and Medical Statistics, Medical School of National and Kapodistrian University of Athens, Athens, GreeceBackground and aimsGenetic polymorphisms within the promoter of interferon-α receptor type-1 (IFNAR1) have been associated with the susceptibility to and the outcome of chronic hepatitis B virus (HBV) infection. However, the impact of these polymorphisms in the transcriptome of the HBV-associated hepatocellular carcinoma (HCC) remains largely unexplored.MethodsUsing whole-genome and exome sequencing data from The Cancer Genome Atlas project, we characterized three single-nucleotide polymorphisms (SNPs: −568G/C, −408C/T, −3C/T) and one variable number tandem repeat [VNTR: −77(GT)n] within the IFNAR1 promoter sequence in 49 HCC patients. RNAseq data from 10 genotyped HCC samples were grouped according to their −77VNTR or −3SNP genotype to evaluate the impact of these polymorphisms on the differential expression on the HCC transcriptome.ResultsThere is a fourfold higher impact of the −77VNTR on the HCC transcriptome compared to the −3SNP (q < 0.1, p < 0.001). The expression of the primary IFNAR1 transcript is not affected by these polymorphisms but a secondary, HCC-specific transcript is expressed only in homozygous −77VNTR ≤8/≤8(GT)n samples (p < 0.05). At the same time, patients carrying at least one −77VNTR >8(GT) allele, presented a strong upregulation of the fibronectin-1 (FN-1) gene, which has been associated with the development of HCC. Gene Ontology and pathway enrichment analysis of the differentially expressed genes revealed a strong disruption of the PI3K–AKT signaling pathway, which can be partially triggered by the extracellular matrix FN-1.ConclusionThe IFNAR-1 promoter polymorphisms are not involved in the expression levels of the main IFNAR-1 transcript. The −77VNTR has a regulatory role on the expression of a secondary, truncated, HCC-specific transcript, which in turn coincides with disruptions in cancer-associated pathways and in FN-1 expression modifications.http://journal.frontiersin.org/article/10.3389/fimmu.2018.00777/fullhepatitis virus Binterferon-α receptor type-1 promoterhepatocellular carcinomainterferon-α receptorpolymorphismtranscriptome |
| spellingShingle | Timokratis Karamitros Timokratis Karamitros George Papatheodoridis Dimitrios Paraskevis Angelos Hatzakis Jean L. Mbisa Urania Georgopoulou Paul Klenerman Gkikas Magiorkinis Gkikas Magiorkinis Impact of Interferon-α Receptor-1 Promoter Polymorphisms on the Transcriptome of the Hepatitis B Virus-Associated Hepatocellular Carcinoma Frontiers in Immunology hepatitis virus B interferon-α receptor type-1 promoter hepatocellular carcinoma interferon-α receptor polymorphism transcriptome |
| title | Impact of Interferon-α Receptor-1 Promoter Polymorphisms on the Transcriptome of the Hepatitis B Virus-Associated Hepatocellular Carcinoma |
| title_full | Impact of Interferon-α Receptor-1 Promoter Polymorphisms on the Transcriptome of the Hepatitis B Virus-Associated Hepatocellular Carcinoma |
| title_fullStr | Impact of Interferon-α Receptor-1 Promoter Polymorphisms on the Transcriptome of the Hepatitis B Virus-Associated Hepatocellular Carcinoma |
| title_full_unstemmed | Impact of Interferon-α Receptor-1 Promoter Polymorphisms on the Transcriptome of the Hepatitis B Virus-Associated Hepatocellular Carcinoma |
| title_short | Impact of Interferon-α Receptor-1 Promoter Polymorphisms on the Transcriptome of the Hepatitis B Virus-Associated Hepatocellular Carcinoma |
| title_sort | impact of interferon α receptor 1 promoter polymorphisms on the transcriptome of the hepatitis b virus associated hepatocellular carcinoma |
| topic | hepatitis virus B interferon-α receptor type-1 promoter hepatocellular carcinoma interferon-α receptor polymorphism transcriptome |
| url | http://journal.frontiersin.org/article/10.3389/fimmu.2018.00777/full |
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