An integrative genomics approach identifies novel pathways that influence candidaemia susceptibility.
Candidaemia is a bloodstream infection caused by Candida species that primarily affects specific groups of at-risk patients. Because only small candidaemia patient cohorts are available, classical genome wide association cannot be used to identify Candida susceptibility genes. Therefore, we have app...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2017-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC5519064?pdf=render |
| _version_ | 1818478364371976192 |
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| author | Vasiliki Matzaraki Mark S Gresnigt Martin Jaeger Isis Ricaño-Ponce Melissa D Johnson Marije Oosting Lude Franke Sebo Withoff John R Perfect Leo A B Joosten Bart Jan Kullberg Frank L van de Veerdonk Iris Jonkers Yang Li Cisca Wijmenga Mihai G Netea Vinod Kumar |
| author_facet | Vasiliki Matzaraki Mark S Gresnigt Martin Jaeger Isis Ricaño-Ponce Melissa D Johnson Marije Oosting Lude Franke Sebo Withoff John R Perfect Leo A B Joosten Bart Jan Kullberg Frank L van de Veerdonk Iris Jonkers Yang Li Cisca Wijmenga Mihai G Netea Vinod Kumar |
| author_sort | Vasiliki Matzaraki |
| collection | DOAJ |
| description | Candidaemia is a bloodstream infection caused by Candida species that primarily affects specific groups of at-risk patients. Because only small candidaemia patient cohorts are available, classical genome wide association cannot be used to identify Candida susceptibility genes. Therefore, we have applied an integrative genomics approach to identify novel susceptibility genes and pathways for candidaemia. Candida-induced transcriptome changes in human primary leukocytes were assessed by RNA sequencing. Genetic susceptibility to candidaemia was assessed using the Illumina immunochip platform for genotyping of a cohort of 217 patients. We then integrated genetics data with gene-expression profiles, Candida-induced cytokine production capacity, and circulating concentrations of cytokines. Based on the intersection of transcriptome pathways and genomic data, we prioritized 31 candidate genes for candidaemia susceptibility. This group of genes was enriched with genes involved in inflammation, innate immunity, complement, and hemostasis. We then validated the role of MAP3K8 in cytokine regulation in response to Candida stimulation. Here, we present a new framework for the identification of susceptibility genes for infectious diseases that uses an unbiased, hypothesis-free, systems genetics approach. By applying this approach to candidaemia, we identified novel susceptibility genes and pathways for candidaemia, and future studies should assess their potential as therapeutic targets. |
| first_indexed | 2024-12-10T09:47:09Z |
| format | Article |
| id | doaj.art-f6256566380a42a59a899b29b2e9aa2d |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-10T09:47:09Z |
| publishDate | 2017-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-f6256566380a42a59a899b29b2e9aa2d2022-12-22T01:53:47ZengPublic Library of Science (PLoS)PLoS ONE1932-62032017-01-01127e018082410.1371/journal.pone.0180824An integrative genomics approach identifies novel pathways that influence candidaemia susceptibility.Vasiliki MatzarakiMark S GresnigtMartin JaegerIsis Ricaño-PonceMelissa D JohnsonMarije OostingLude FrankeSebo WithoffJohn R PerfectLeo A B JoostenBart Jan KullbergFrank L van de VeerdonkIris JonkersYang LiCisca WijmengaMihai G NeteaVinod KumarCandidaemia is a bloodstream infection caused by Candida species that primarily affects specific groups of at-risk patients. Because only small candidaemia patient cohorts are available, classical genome wide association cannot be used to identify Candida susceptibility genes. Therefore, we have applied an integrative genomics approach to identify novel susceptibility genes and pathways for candidaemia. Candida-induced transcriptome changes in human primary leukocytes were assessed by RNA sequencing. Genetic susceptibility to candidaemia was assessed using the Illumina immunochip platform for genotyping of a cohort of 217 patients. We then integrated genetics data with gene-expression profiles, Candida-induced cytokine production capacity, and circulating concentrations of cytokines. Based on the intersection of transcriptome pathways and genomic data, we prioritized 31 candidate genes for candidaemia susceptibility. This group of genes was enriched with genes involved in inflammation, innate immunity, complement, and hemostasis. We then validated the role of MAP3K8 in cytokine regulation in response to Candida stimulation. Here, we present a new framework for the identification of susceptibility genes for infectious diseases that uses an unbiased, hypothesis-free, systems genetics approach. By applying this approach to candidaemia, we identified novel susceptibility genes and pathways for candidaemia, and future studies should assess their potential as therapeutic targets.http://europepmc.org/articles/PMC5519064?pdf=render |
| spellingShingle | Vasiliki Matzaraki Mark S Gresnigt Martin Jaeger Isis Ricaño-Ponce Melissa D Johnson Marije Oosting Lude Franke Sebo Withoff John R Perfect Leo A B Joosten Bart Jan Kullberg Frank L van de Veerdonk Iris Jonkers Yang Li Cisca Wijmenga Mihai G Netea Vinod Kumar An integrative genomics approach identifies novel pathways that influence candidaemia susceptibility. PLoS ONE |
| title | An integrative genomics approach identifies novel pathways that influence candidaemia susceptibility. |
| title_full | An integrative genomics approach identifies novel pathways that influence candidaemia susceptibility. |
| title_fullStr | An integrative genomics approach identifies novel pathways that influence candidaemia susceptibility. |
| title_full_unstemmed | An integrative genomics approach identifies novel pathways that influence candidaemia susceptibility. |
| title_short | An integrative genomics approach identifies novel pathways that influence candidaemia susceptibility. |
| title_sort | integrative genomics approach identifies novel pathways that influence candidaemia susceptibility |
| url | http://europepmc.org/articles/PMC5519064?pdf=render |
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