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Ethnic differences in susceptibility to Dengue
#1
Dengue virus (DENV) is the most common mosquito-borne viral infection, infecting approximately 390 million people per year worldwide with one quarter developing dengue disease (MIM: 614371) . Symptoms range from undifferentiated fever, classical dengue fever (DF) to shock syndrome (DSS; hemorrhage, plasma leakage and vital organ impairment) 

Since the beginning of 2023, ongoing transmission, combined with an unexpected spike in dengue cases have resulted in close to a historic high of over five million cases and more than 5000 dengue-related deaths reported in over 80 countries/territories and five WHO regions: Africa, Americas, South-East Asia, Western Pacific and Eastern Mediterranean Regions globally (Figure 1). Close to 80% of these cases, or 4.1 million, have been reported in the Region of the Americas. Dengue is the most widespread arbovirus and causes the highest number of arboviral disease cases in the Region of the Americas, with cyclic epidemics recurring every 3 to 5 years. In addition, clusters of autochthonous dengue have been reported in the WHO European Region. However, these numbers are likely an underestimate of the true burden as most of the primary infections are asymptomatic and dengue reporting is not mandatory in many countries.     

Epidemiologic reports have shown the existence of ethnic differences in susceptibility to dengue fever not only in Cuba but also in Malaysia where the incidence rate by ethnic group was 3.7:1:1.3 for Chinese, Malays and Indians, respectively, in the years 1970’s and 1980’s.

In Dengue Fever, phosphatase control is crucial, including through binding to viral proteins, as we showed for PPP2R5E protein co-localization with DENV1 and DENV2-NS5 proteins within liver cells and differential cellular localizations along time. In Dengue Shock Syndrome, cytokine dynamics, inflammation and activation of vascular endothelium cells are dominant features. The particular genetic risk conferred by these genes indicates that Southeast and Northeast Asians are highly susceptible to both phenotypes, while Africans are best protected against DSS, and Europeans best protected against DF but the most susceptible against DSS.


BMIX analysis on Vietnamese cohort indicates also the association of DSS with MICB and PLCE1 genes. The identified region surrounding MICB encompasses seven significant SNPs, placed along 165,080 bp, from the downstream MICA to the upstream LTB gene, a region highly rich in genes. Three linked (S2 Fig) SNPs in MICB have the most significant p-values, forming the protective haplotype GTT (OR = 0.77; p-value<0.0001), which is the most frequent haplotype in worldwide populations (Fig 3C). The susceptible MICB haplotype ACC (OR = 1.39; p-value<0.0001) is more frequent in Europeans and South Asians (0.18 to 0.34). The two SNPs found for PLCE1 reached significant p-values and are almost in complete linkage (S5 Fig). The DSS protective PLCE1 haplotype (CG; OR = 0.75; p-value<0.0001) is more frequent (Fig 3B) in Northeast Asia (0.12–0.28) and Southeast Asia (0.19), followed by Europe (0.04–0.14) and absent in Africa.
[/url][url=https://www.ncbi.nlm.nih.gov/core/lw/2.0/html/tileshop_pmc/tileshop_pmc_inline.html?title=Click%20on%20image%20to%20zoom&p=PMC3&id=5813895_pntd.0006202.g002.jpg]
[Image: pntd.0006202.g002.jpg]

figure: Manhattan plots of BMIX analysis in Vietnamese DSS vs Control (A), Thai DSS vs Control (B) and Thai DF vs Control © for Northeast and Southeast Asian ancestries. The red line represents the significance threshold. The protein coding genes with significantly associated SNPs are identified.

[Image: pntd.0006202.g003.jpg]
figure:  Worldwide (from the 1000 Genomes database) and Thai dengue cohorts (control, DF and DSS) frequencies for significantly associated haplotypes in the various genes.
A- PLCB4; B- PLCE1; C- MICB; D- CHST10; E- AHRR; F- GRIP1; G- PPP2R5E. The protective and causative haplotypes are highlighted.


[Image: pntd.0006202.g004.jpg]
figure:Genetic risk for the various worldwide regions by considering an additive model of protective and causative haplotypes/SNPs for DSS (A) and DF (B). Median (middle line), mean (little square), 95% confidence interval (whiskers) and extreme values (crosses) are indicated.

For both DF and DSS phenotypes, Northeast and Southeast Asian populations have a higher ancestral prone risk when compared with other geographical regions, considering the particular genes identified in this work. Specifically, Southeast Asian ancestry has a slightly higher risk for DF than Northeast Asian ancestry (Fig 4B). These genetic predictions agree with observations that almost 75% of the global population exposed to dengue live in Asia-Pacific, with rates of severe dengue being 18 times higher in this region compared with the Americas [36]. African and its descendant populations are the most protected ones against DSS, and displaying an intermediate protection against DF, adding genetic evidence to previous claims that this ancestry is protected against worse dengue phenotypes [37, 38]. Our inferred genetic risk for DF in Africa, slightly higher that the risk in America, agrees quite well with the risk predictions inferred by Bhatt et al. [1] of 16% and 14%, respectively, of the global burden. Climatic change and globalization are enlarging the spread of dengue vector and virus to northern latitudes, putting Europe and North America at risk of autochthonous infections [39]. The considerable number of autochthonous infections that occurred in Madeira Island, Portugal, in 2012/2013 [40] is the first example of a reality that can take place in a near future in continental Europe. The genetic risk calculated here, for the newly and confirmed susceptible/resistant haplotypes, shows that European populations (as well as South Asian and USA) present an even higher risk than Southeast Asian populations to DSS, while they are the best protected ones against DF.



from 
Joint ancestry and association test indicate two distinct pathogenic pathways involved in classical dengue fever and dengue shock syndrome - PMC (nih.gov)

and

Dengue- Global situation (who.int)
Mulay 'Abdullah, Albruic, ronin92 like this post
Salkhit 625 SNP, Otzi 803 SNP, Mik15 798 SNP, RISE493 1335 SNP, I11456 1024 SNP, I7718 980 SNP, I9041 512S
Target: tipirneni:dante
Chebyshev distance: 0.64%
79.0 IRN_SIS_BA2
12.4 ITA_Daunian
8.6 Poland_Viking.SG
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