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Joint ancestry and association test indicate two distinct pathogenic pathways involved in classical dengue fever and dengue shock syndrome

Marisa Oliveira 1 Worachart Lert-Itthiporn 2 Bruno Cavadas 1 Verónica Fernandes 1 Ampaiwan Chuansumrit 2 Orlando Anunciação 3 Isabelle Casademont 4, 5 Fanny Koeth 4, 5 Marina Penova 4, 5 Kanchana Tangnararatchakit 6 Chiea Chuen Khor 7 Richard Paul 4, 5 Prida Malasit 8 Fumihiko Matsuda 5 Etienne Simon-Loriere 4, 5 Prapat Suriyaphol 8 Luisa Pereira 3 Anavaj Sakuntabhai 4, 5, *
* Corresponding author
1 I3S - Instituto de Investigação e Inovação em Saúde
2 Siriraj Hospital, Mahidol University
3 Universidade do Porto
4 Génétique fonctionnelle des Maladies infectieuses - Functional Genetics of Infectious Diseases
5 Pasteur Kyoto International Joint Research Unit for Integrative Vaccinomics [Kyoto, Japan]
6 Department of Pediatrics, Faculty of Medicine
7 NUS - National University of Singapore
8 Mahidol University [Bangkok]
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 hap-lotypes 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
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Marisa Oliveira, Worachart Lert-Itthiporn, Bruno Cavadas, Verónica Fernandes, Ampaiwan Chuansumrit, et al.. Joint ancestry and association test indicate two distinct pathogenic pathways involved in classical dengue fever and dengue shock syndrome. PLoS Neglected Tropical Diseases, Public Library of Science, 2018, 12 (2), pp.e0006202. ⟨10.1371/journal.pntd.0006202⟩. ⟨pasteur-02003869⟩

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