Host Gene Expression and Genetic Susceptibility to Dengue Virus Infection in Vietnamese Children

Hoang Truongo Long (2011). Host Gene Expression and Genetic Susceptibility to Dengue Virus Infection in Vietnamese Children. PhD thesis The Open University.



Dengue has been a public health problem in over 120 tropical and subtropical countries. It is estimated that there are approximately 3.6 billion of the world’s population at risk of dengue virus (DENV) infection, and about 70-500 million DENV infections annually. Every year, about 36 million cases of dengue fever, of which about 2.1 million cases are dengue haemorrhagic fever and dengue shock syndrome (DHF/DSS) resulting in 21,000 deaths among children and young adults, are reported. The disease pathogenesis is still poorly understood. Effective antiviral drug, vaccine and animal model for the disease are not available. We conducted two global gene expression microarray studies and a genome-wide association study in order to identify prognostic markers of severe dengue in Vietnamese patients and to identify genetic markers that confer susceptibility to dengue and DSS. The results show that acute DENV infection is associated with over-presentation of transcripts that are related to interferon-inducible transcripts and canonical gene ontology terms that included response to virus, immune response, innate immune response and inflammatory response. Pathway and network analysis identified STAT1, STAT2, STAT3, IRF7, IRF9, IRF1, CEBPB and SP1 as key transcriptional factors mediating the early response. Interestingly, the only differences in the transcriptional signatures of early DSS and uncomplicated dengue cases were the greater abundance of several neutrophil-associated transcripts in patients who progressed to DSS. Host genetic study identified several single nucleotide polymorphisms (SNPs) that show strong evidence for association with dengue or DSS. None of the SNPs was significant at suggestive genome-wide level but ontology analysis of genes implicated by associated SNPs suggests biologically plausible functional relationships between the genes. This thesis provides insights into host gene response in DENV infection and also host genetic susceptibility to dengue which in turn could be useful hint for future studies in the field.

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