Population genetics-informed meta-analysis in seven genes associated with risk to dengue fever disease

Abstract

Population genetics theory predicted that rare frequent markers would be the main contributors for heritability of complex diseases, but meta-analyses of genome-wide association studies are revealing otherwise common markers, present in all population groups, as the identified candidate genes. In this work, we applied a population-genetics informed meta-analysis to 10 markers located in seven genes said to be associated with dengue fever disease. Seven markers (in PLCE1, CD32, CD209, OAS1 and OAS3 genes) have high-frequency and the other three (in MICB and TNFA genes) have intermediate frequency. Most of these markers have high discriminatory power between population groups, but their frequencies follow the rules of genetic drift, and seem to have not been under strong selective pressure. There was a good agreement in directional consistency across trans-ethnic association signals, in East Asian and Latin American cohorts, with heterogeneity generated by randomness between studies and especially by low sample sizes. This led to confirm the following significant associations: with DF, odds ratio of 0.67 for TNFA-rs1800629-A; with DHF, 0.82 for CD32-rs1801274-G; with DSS, 0.55 for OAS3-rs2285933-G, 0.80 for PLCE1-rs2274223-G and 1.32 for MICB-rs3132468-C. The overall genetic risks confirmed sub-Saharan African populations and descendants as the best protected against the severer forms of the disease, while Southeast and Northeast Asians are the least protected ones. European and close neighbours are the best protected against dengue fever, while, again, Southeast and Northeast Asians are the least protected ones. These risk scores provide important predictive information for the largely naïve European and North American regions, as well as for Africa where misdiagnosis with other hemorrhagic diseases is of concern.

Different Associations between DC-SIGN Promoter-336G/A (rs4804803) Polymorphism with Severe Dengue in Asians and South-Central Americans: a Meta-Analysis

“…Studies conducted in Brazil indicated that the G carrier was a protective factor for the symptoms of headache and arthralgia in dengue fever [26]. Besides dengue, the polymorphism of rs4804803 was also associated with the severity of tuberculosis, severe acute respiratory syndromes and tick-borne encephalitis [37,38,47]. The opposite effect of rs4804803 on the development of severe dengue is not inexplicable in consideration the role of DC- SIGN in ADE and DENV-dependent platelet activation: the expression of DC-SIGN was inversely correlated with ADE, but positively correlated with DENV-dependent platelet activation [21,22,46].…”

Uncovering the Burden of Dengue in Africa: Considerations on Magnitude, Misdiagnosis, and Ancestry

“…A genetics meta-analysis on seven genes associated with dengue severity risk found that sub-Saharan African populations and descendants of these populations are most protected against DHF/DSS compared to other ancestral groups and that Southeast/Northeast Asians are the least protected [214]. Similarly, the "Host genetics and dengue fever" review discussed above also found that African ancestry is associated with protection from severe dengue [203].…”

Multi-Tissue Transcriptomic-Informed In Silico Investigation of Drugs for the Treatment of Dengue Fever Disease

“…The CMap tool results for the drug discovery in the blood cohort indicated a total of 203 known compounds that were inferred (CMap score inferior to −90) as having a potential impact in Dengue hemorrhagic fever treatment (Supplementary Table S6). These drugs were spread across seven main different mechanisms of action: antineoplastic (120), antibiotic (11), antiparasitic (2), immunosuppressant (6), cardiovascular (11), antiinflammatory (9) and antiviral drugs (7). Among these, some compounds have already been shown to have some action against DENV or the mechanism of action taken by flavivirus.…”

“…Host genetic factors are also associated with susceptibility to DENV, including immune system factors such as HLA-I and HLA-II, TNF-α, Fc receptor, TAP and DC-SIGN (reviewed in [ 7 ]); immune system and endothelial homeostasis genes MICB and PLCE1 [ 8 ]; genes controlling lipid ( OSBPL10 and RXRA [ 9 ]) and xenobiotic metabolism ( PLCB4 , CHST10 , AHRR , PPP2R5E and GRIP1 [ 10 ]). A metanalysis of several of these genes across worldwide populations [ 11 ] made it possible to infer a preliminary worldwide map of host susceptibility to Dengue disease: sub-Saharan Africans and descendants are best protected against severe forms; Europeans and close neighbours are best protected against DF but not against severe forms; Northeast and Southeast Asians are less protected against mild and severe forms.…”