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Joint ancestry and association test indicate two distinct pathogenic pathways involved in classical dengue fever and dengue shock syndrome
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Document Title
Joint ancestry and association test indicate two distinct pathogenic pathways involved in classical dengue fever and dengue shock syndrome
Author
Oliveira M.,Lert-itthiporn W.,Cavadas B.,Fernandes V.,Chuansumrit A.,Anunciação O.,Casademont I.,Koeth F.,Penova M.,Tangnararatchakit K.,Khor C.C.,Paul R.,Malasit P.,Matsuda F.,Simon-Lorière E.,Suriyaphol P.,Pereira L.,Sakuntabhai A.
Name from Authors Collection
Affiliations
i3S—Instituto de Investigação e Inovação emSaúde, Universidade do Porto, Porto, Portugal; Instituto de Patologia e Imunologia Molecular da Universidade do Porto (IPATIMUP), Porto, Portugal; Instituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto, Porto, Portugal; Functional Genetics of Infectious Diseases Unit, Institut Pasteur, Paris, France; Bioinformatics and Data Management for Research, Office for Research and Development, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand; Department of Pediatrics, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand; Pasteur Kyoto International Joint Research Unit for Integrative Vaccinomics, Kyoto, Japan; Center for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan; Genome Institute of Singapore, A-STAR, Singapore; Department of Biochemistry, National University of Singapore, Singapore; CNRS, Unité de Recherche Associée 3012, Paris, France; Dengue Hemorrhagic Fever Research Unit, Office for Research and Development, Siriraj Hospital, Faculty of Medicine, Mahidol University, Bangkok, Thailand; Medical Biotechnology Unit, National Center for Genetic Engineering and Biotechnology, National Science and Technology Development Agency, Pathumthani, Thailand; Department of Pathology, Faculty of Medicine, University of Porto, Porto, Portugal
Type
Article
Source Title
PLoS Neglected Tropical Diseases
ISSN
19352727
Year
2018
Volume
12
Issue
2
Open Access
All Open Access, Gold, Green
Publisher
Public Library of Science
DOI
10.1371/journal.pntd.0006202
Abstract
Ethnic diversity has been long considered as one of the factors explaining why the severe forms of dengue are more prevalent in Southeast Asia than anywhere else. Here we take advantage of the admixed profile of Southeast Asians to perform coupled association-admixture analyses in Thai cohorts. For dengue shock syndrome (DSS), the significant haplotypes are located in genes coding for phospholipase C members (PLCB4 added to previously reported PLCE1), related to inflammation of blood vessels. For dengue fever (DF), we found evidence of significant association with CHST10, AHRR, PPP2R5E and GRIP1 genes, which participate in the xenobiotic metabolism signaling pathway. We conducted functional analyses for PPP2R5E, revealing by immunofluorescence imaging that the coded protein co-localizes with both DENV1 and DENV2 NS5 proteins. Interestingly, only DENV2-NS5 migrated to the nucleus, and a deletion of the predicted top-linking motif in NS5 abolished the nuclear transfer. These observations support the existence of differences between serotypes in their cellular dynamics, which may contribute to differential infection outcome risk. The contribution of the identified genes to the genetic risk render Southeast and Northeast Asian populations more susceptible to both phenotypes, while African populations are best protected against DSS and intermediately protected against DF, and Europeans the best protected against DF but the most susceptible against DSS. © 2018 Oliveira et al.
Industrial Classification
Knowledge Taxonomy Level 1
Knowledge Taxonomy Level 2
Knowledge Taxonomy Level 3
License
CC BY
Rights
Author
Publication Source
Scopus