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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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  • معلومة اضافية
    • Contributors:
      Instituto de Investigação e Inovação em Saúde
    • بيانات النشر:
      Public Library of Science
    • الموضوع:
      2018
    • Collection:
      Repositório Aberto da Universidade do Porto
    • نبذة مختصرة :
      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. ; The research leading to these results has received funding from the European Commission Seventh Framework Programme [FP7/2007-2013] for the DENFREE project under Grant Agreement no. 282378. MO has a PhD grant from FCT (The Portuguese Foundation for Science and Technology - SFRH/BD/95626/2013). I3S is financed by FEDER - Fundo Europeu de Desenvolvimento Regional funds through the COMPETE 2020 - Competitiveness and Internationalization Operational Programme (POCI), Portugal 2020, and by Portuguese funds through FCT/Ministério da Ciência, Tecnologia e Inovação in the ...
    • File Description:
      application/pdf
    • ISSN:
      1935-2727
    • Relation:
      info:eu-repo/grantAgreement/EC/FP7/282378/EU; PLoS Neglected Tropical Diseases, vol.12(2):e0006202; https://journals.plos.org/plosntds/article?id=10.1371/journal.pntd.0006202; https://hdl.handle.net/10216/127390
    • الرقم المعرف:
      10.1371/journal.pntd.0006202
    • Rights:
      info:eu-repo/semantics/openAccess
    • الرقم المعرف:
      edsbas.D34E3E46