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PLoS Neglected Tropical DiseasesVolume 12, Issue 2, 15 February 2018, Article number e0006202

Joint ancestry and association test indicate two distinct pathogenic pathways involved in classical dengue fever and dengue shock syndrome(Article)(Open Access)

  • 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.
  • View Correspondence (jump link)
  • ai3S—Instituto de Investigação e Inovação emSaúde, Universidade do Porto, Porto, Portugal
  • bInstituto de Patologia e Imunologia Molecular da Universidade do Porto (IPATIMUP), Porto, Portugal
  • cInstituto de Ciências Biomédicas Abel Salazar (ICBAS), Universidade do Porto, Porto, Portugal
  • dFunctional Genetics of Infectious Diseases Unit, Institut Pasteur, Paris, France
  • eBioinformatics and Data Management for Research, Office for Research and Development, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand
  • fDepartment of Pediatrics, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
  • gPasteur Kyoto International Joint Research Unit for Integrative Vaccinomics, Kyoto, Japan
  • hCenter for Genomic Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan
  • iGenome Institute of Singapore, A-STAR, Singapore
  • jDepartment of Biochemistry, National University of Singapore, Singapore
  • kCNRS, Unité de Recherche Associée 3012, Paris, France
  • lDengue Hemorrhagic Fever Research Unit, Office for Research and Development, Siriraj Hospital, Faculty of Medicine, Mahidol University, Bangkok, Thailand
  • mMedical Biotechnology Unit, National Center for Genetic Engineering and Biotechnology, National Science and Technology Development Agency, Pathumthani, Thailand
  • nDepartment of Pathology, Faculty of Medicine, University of Porto, Porto, Portugal

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.

Indexed keywords

EMTREE drug terms:alpha interferonaromatic hydrocarbon receptorglutamate receptorimmunoglobulin Mnonstructural protein 5nuclear receptor coactivator 2phospholipase CsulfotransferaseAHRR protein, humanbasic helix loop helix transcription factorcarrier proteinCHST10 protein, humanGRIP1 protein, humannerve proteinNS5 protein, dengue virusphospholipase Cphosphoprotein phosphatase 2PPP2R5E protein, humanrepressor proteinsulfotransferaseviral protein
EMTREE medical terms:adaptive immunityadolescentadultalgorithmArticleB lymphocytebiodiversitycell maturationcell nucleus transplantationchildclimate changeclinical evaluationcohort analysisconsanguinitycontrolled studydemographydenguedengue shock syndromeDengue virus 1Dengue virus 2disease associationdisease predispositiondynamicsenzyme linked immunosorbent assayfemalefrequency analysisgene frequencygenotype phenotype correlationgenotyping techniquehaplotypehumanimmunofluorescenceinfantinflammationmajor clinical studymalemiddle agedpathogenicitypreschool childretrospective studyschool childserotypesignal transductionsingle nucleotide polymorphismvascular endothelial cellxenobiotic metabolismyoung adultAsian continental ancestry groupcell linecell nucleusdengueDengue virusethnologygene expressiongenetic predispositiongeneticsgenome-wide association studygenotypeodds ratiosevere dengueSoutheast AsiaThailandvirologyvirus genome
MeSH:AdolescentAdultAsia, SoutheasternAsian Continental Ancestry GroupBasic Helix-Loop-Helix Transcription FactorsCarrier ProteinsCell LineCell NucleusChild, PreschoolCohort StudiesDengueDengue VirusFemaleGene ExpressionGenetic Predisposition to DiseaseGenome, ViralGenome-Wide Association StudyGenotypeHumansInfantMaleNerve Tissue ProteinsOdds RatioProtein Phosphatase 2Repressor ProteinsSerogroupSevere DengueSulfotransferasesThailandType C PhospholipasesViral Nonstructural ProteinsViral ProteinsYoung Adult

Chemicals and CAS Registry Numbers:

immunoglobulin M, 9007-85-6; phospholipase C, 9001-86-9; sulfotransferase, 9023-09-0; carrier protein, 80700-39-6;

AHRR protein, human; Basic Helix-Loop-Helix Transcription Factors; Carrier Proteins; CHST10 protein, human; GRIP1 protein, human; Nerve Tissue Proteins; NS5 protein, dengue virus; PPP2R5E protein, human; Protein Phosphatase 2; Repressor Proteins; Sulfotransferases; Type C Phospholipases; Viral Nonstructural Proteins; Viral Proteins

  • ISSN: 19352727
  • Source Type: Journal
  • Original language: English
  • DOI: 10.1371/journal.pntd.0006202
  • PubMed ID: 29447178
  • Document Type: Article
  • Publisher: Public Library of Science

  Pereira, L.; i3S—Instituto de Investigação e Inovação emSaúde, Universidade do Porto, Porto, Portugal;
© Copyright 2018 Elsevier B.V., All rights reserved.

Cited by 4 documents

Halstead, S.
Recent advances in understanding dengue [version 1; peer review: 2 approved]
(2019) F1000Research
Oliveira, M. , Saraiva, D.P. , Cavadas, B.
Population genetics-informed meta-analysis in seven genes associated with risk to dengue fever disease
(2018) Infection, Genetics and Evolution
Manet, C. , Roth, C. , Tawfik, A.
Host genetic control of mosquito-borne Flavivirus infections
(2018) Mammalian Genome
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