| 摘要: | Dengue fever is one of infectious disease that caused by the co-circulation of four serotypes of DENV (DENV-1~4). Globally, dengue is becoming more common, especially in tropical and sub-tropical areas like Indonesia. Despite the fact that this disease is a self-limited acute febrile illness, but early identification of high-risk patients might help to lower the mortality and avoid from progression to severe dengue (SD). Risk factors for SD could be from viral factors or host factors. This thesis will focus on determining host risk factors for SD concerning on epidemiological and genomic study, also utilizing the drug repurposing approach to identify the candidate drug for SD. The primary goal of epidemiological study is to understand the trends of dengue sign and symptoms and basic laboratory abnormalities for SD. While the genomic study will focus on single nucleotide polymorphisms (SNPs) that are essential to the pathway of SD and responsible for its pathogenesis.
In the first study, we conducted a retrospective study in Indonesia, with the objectives: a) exploring factors that contributed to dengue hemorrhagic fever (DHF) according to the data from the first day of hospitalization, b) understanding the dynamic pattern of some laboratory parameters in dengue patients. This study involved febrile patients who were hospitalized and diagnosed with dengue between 2018 and 2020. Identification variables related to DHF were analyzed using logistic regression models. A total of 1087 patients fulfilled the criteria as suspected dengue patients, and according to the WHO 1997 classification, 468 patients were diagnosed with dengue fever (DF) and 619 had DHF. Male patients, with a mean age of 17.92 years old, and secondary dengue infection are common characteristics of DHF patients. Results from multivariate analysis confirmed that DHF was related with thrombocytopenia and hemoglobin level on admission day. Furthermore, DHF patients require a longer stay at hospital than DF patients. In conclusion, the two laboratory parameters, platelet value and level of hemoglobin, can be utilized as essential factors of DHF, more importantly with the limits of diagnostic testing for suspected dengue patients. Fluctuation of platelet values was reported to emphasize the importance of daily measurement of platelets as one rapid strategy to predict severe disease.
The second study is genomic approach studies that are divided into candidate gene association study and bioinformatic analysis to investigate the gene-mediated DHF development. In the genetic association study, we investigated the relationships between genotypes of MICB (rs3132468) or PLCE1 (rs3740360, rs3765524) and dengue severity also thrombocytopenia in two populations from Indonesia and Taiwan. These two genes are known to be strongly related to DSS based on the results from a genome-wide association study (GWAS). In this study, we included 160 Indonesian dengue patients and 273 Taiwanese dengue patients. There were no DSS among the Taiwanese population. According to the age, our findings indicate that younger Indonesians are more susceptible to dengue fever, while it affects adults more frequently in the Taiwanese population. Our findings demonstrated the association between DSS and a variant of MICB (rs3132468). Furthermore, another association was identified between DHF and a variant of PLCE1 (rs3740360) particularly in secondary dengue patients. Though, neither MICB nor PLCE1 variants are linked to thrombocytopenia.
Another part of the genomic study is a bioinformatic analysis using public microarray data, which aims to observe the mechanisms of some genes that interact to drive DHF development and identify potential repositioned candidates for DHF treatment. Two eligible datasets from the database of Gene Expression Omnibus (GEO) were examined to discover the differentially expressed genes (DEGs). Identified DEGs were further analyzed for exploring the functional annotation by pathway enrichment analysis, constructing a protein-protein interaction (PPI) network, and finding the genes correlated to DHF, also utilizing two platforms to identify candidate drugs that can reverse the disease by drug repurposing approach. In this study, we found some genes or proteins that possibly interact to drive severe dengue development. CD38, and SDC1, might act as biomarkers for severe dengue. Furthermore, based on a literature review about the efficacy and safety of each drug, lipid-modifying agents (simvastatin, fenofibrate, and gemfibrozil) may have a higher possibility of being repurposed as antiviral for DHF. These results could be used for further research to determine the pathway and mechanism of biomarkers involved in the development of severe types of dengue and to observe the efficacy and safety of the drugs for DHF patients. |
