Ethnic differences in susceptibility to Dengue

[tipirneni]

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]

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.


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.


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)

[okarinaofsteiner]

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.

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)

If the "SE Asia" ancestry component/genotype is at greater disease risk than the "NE Asia" ancestry component/genotype, that calls into question why the incidence rate for Malaysian Chinese was much higher than for Malaysian Malays. Perhaps there could've been different rates of reporting or disease vector exposure between those two populations during the 1970s and 1980s?

[CLTVTE]

Etymologia: dengue
PMCID: PMC3373045
[den′gē]

An acute, self-limited disease characterized by fever, headache, myalgia, and rash caused by any of 4 related but distinct viruses of the genus Flavivirus and spread by Aedes mosquitos. Dengue (a Spanish homonym for the Swahili ki denga pepo, which describes a sudden, cramplike seizure caused by an evil spirit) is believed to have been first recorded in a Chinese medical encyclopedia from the Chin Dynasty (265–420 AD). The Chinese called dengue “water poison” and knew that it was somehow associated with flying insects.

Sources: Dorland’s illustrated medical dictionary. 30th ed. Philadelphia: Saunders; 2003; Gubler DJ. Dengue and dengue hemorrhagic fever. Clin Microbiol Rev. 1998;11:480–96; and Halstead SB. Dengue hemorrhagic fever—a public health problem and a field for research. Bull World Health Organ. 1980;58:1–21.

Dengue “early 19th century: from West Indian Spanish, from Kiswahili dinga (in full kidingapopo ), influenced by Spanish dengue ‘fastidiousness’ (with reference to the dislike of movement by affected patients)”

The latter popular available etymology for /dengue/, which should have been created later than the first variant, already swaps the general Swahili for Kiswahili. Kiswahili (a Bantu language, originally spoken by the Swahili people, who are found primarily in Tanzania, Kenya and Mozambique (along the East African coast and adjacent littoral islands)) was classified as one of Africa’s languages with polysynthetic features (“A Morphological Classification of Kiswahili”) in addition to the Afroasiatic Somali language (https://www.researchgate.net/publication...c_Language)

One should caution that both Swahili /ki denga pepo/ (or Kiswahili /kidingapopo/) and Spanish /dengue/ are no similar to the way of the formation of the ethnonym /Deng/ from China in accordance with the data of the IVPP (the Institute of Vertebrate Paleontology and Paleoanthropology), because the formation of the ethnonym /Deng/ should have been more complicated due to the involvement of different languages from East Asia.

Consequently, one can say that any Early Upper Paleolithic migration of the ancient East Asia-related population, bypassing the remote ancestors of the Deng in the direction of the northern individual Kostenki14, who was not surrounded by the mosquitos, could not probably cause the distribution of the dengue disease along with such a migration. The ancient Kostenki14 individual had his own interaction with the African-related population in accordance with the data of "40,000-Year-Old Individual from Asia Provides Insight into Early Population Structure in Eurasia".

Consequently, the association that the dengue disease spread along with the polysynthetic languages, which the second popular available etymology for /dengue/ may cause, should not be a correct association.

Regarding the relationship of the population, responsible for the origin of the polysynthetic features of the polysynthetic African languages (a Bantu one and an Afroasiatic one), the IVPP data point to the indigenous African origin. The IVPP data highlighted the very ancient divergent ancestral component, which should have been obviously present in the mtDNA L3-related population of Sudan, and the existence of this component is accompanied by the existence of certain mtDNA L3 mutations, which are quite rare (populations, speaking polysynthetic languages, were also rare). One such mutation appeared in an mtDNA L3 lineage in Spain, though this lineage is not related to the Basques. Another more widely distributed mutation appeared in mtDNA L3 of Sudan, and it also appeared in an mtDNA lineage, whose comparable relative was reported from the ancient DNA of China, and researchers from Japan have recently shown that this mtDNA lineage, when observed in some mainstream non-Ainu individuals of Japan, can be characterized by such relationships that it can be shown to separate from the broadly understood mtDNA L3 of the specific location, such as Sudan, despite the fact that some mutations of this lineage cannot belong to the initial Sudanese mtDNA L3 populations. It has been long unclear: since the speakers of the polysynthetic Ainu language predominantly belong to yDNA D-M174>D-M64 and the rare Ainu outside Japan also belonged to yDNA D-M174, should it be understood that the polysynthetic features were initially characteristic of languages, spoken by bearers of yDNA D-M174 lineages, belonging to the Eurasian populations? However, it would cast shadow on populations of other Eurasian lineages. Fortunately, the above mentioned researchers from Japan have shown that they have a special component from the population of Sudan, belonging to mtDNA L3 of Sudan, and the IVPP data added other populations, speaking polysynthetic languages, in which such mutations also appeared as the mutation in an mtDNA lineage, whose comparable relative was reported from the ancient DNA of China, and researchers from Japan have recently shown that this mtDNA lineage, when observed in some mainstream non-Ainu individuals of Japan, can be characterized by such relationships that it can be shown to separate from the broadly understood mtDNA L3 of the specific location, such as Sudan, despite the fact that some mutations of this lineage could not belong to the initial Sudanese mtDNA L3 populations. Consequently, the arrival of the population, carrying the special component, related to the specific Sudanese mtDNA L3 population, which settled on the Japanese Archipelago and inadvertently contributed to ancestors of yDNA D-M64 Ainu as well, may be responsible for the appearance of polysynthetic features in pre-Yayoi-/Jomon-related languages of the Japanese Archipelago, influencing the yDNA D-M64 Ainu ancestors, since polysynthetic features were also reported from languages, the speakers of which were located on the way of such specific Sudanese mtDNA L3 population to the Japanese Archipelago, as the IVPP data pointed. The IVPP data highlighted a similar mutation, which had been mentioned before, in a Kostenki14-related mtDNA lineage, and another such a rare mtDNA L3 lineage, a mutation of which was observed in speakers of the polysynthetic languages, had reached Spain.