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Dengue Disease Risk Linked to Gene Variants Among World Populations

NEW YORK (GenomeWeb) – Gene variants with different prevalence among world populations affect susceptibility to classic dengue fever or dengue shock syndrome, a new study has found.

Dengue virus is the most common mosquito-borne viral disease and infects about 390 million people each year. About a quarter of those infected develop dengue disease, which could come in the form of classical dengue fever or dengue shock syndrome. The severe form of the disease is more common in some parts of the world than others.

Researchers led by the Institut Pasteur-Paris' Anavaj Sakuntabhai conducted a coupled association-admixture analysis of a cohort of patients admitted to three hospitals in Thailand with either dengue fever (DF) or dengue shock syndrome (DSS), along with controls, and a previously published Vietnamese cohort. As they reported today in PLOS Neglected Tropical Diseases, they identified new candidate genes for DF risk and confirmed the link between the phospholipase C gene family and DSS risk. They also found that prevalence of these risk variants varies by ethnicity.

"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 to DSS," the researchers wrote in their paper.

Their Thai sample included 252 people who developed DF, 159 with DSS, and 290 controls, while the Vietnamese dataset included 2,008 DSS patients and 2,018 controls. Both datasets underwent genotyping and subsequent joint ancestry and association testing, or BMIX.

In the Vietnamese dataset, the researchers noted an association between DSS and the genes MICB and PLCE1, a member of the phospholipase C family. The region around MICB houses seven significant SNPs, three of which form a protective haplotype, GTT. Sakuntabhai and his colleagues said that this haplotype is the most frequent among most world populations, though the susceptible ACC haplotype is common among European and South Asian populations.

Additionally, they traced two SNPs to near PLCE1, and found that the protective haplotype CG there is more common among Northeast and Southeast Asian populations, followed by European populations, but it isn't found among African populations.

Meanwhile, in the Thai cohort, the researchers identified six SNPs associated with DSS linked to PLCB4, which also belongs to the phospholipase C family. This, they said, underscores the connection between that gene family and dengue disease. The protective PLCB4 haplotype is rare among world populations, though has the highest frequency in African populations

By calculating genetic risk based on these haplotypes, the researchers estimated that African and African-descent Caribbean populations are best protected against dengue shock syndrome, while Asian, European, and Latin American populations are the most susceptible to it.

Sakuntabhai and his colleagues likewise compared the Thai individuals with DF to controls to link a handful of genes with at least two SNPs to disease susceptibility: CHST10, AHRR, PPP2R5E, and GRIP1.

The protective CHST10 haplotype is frequent among South Asian populations, while the susceptible haplotype is common among Northeast Asian populations and is rare among African populations, they found. The protective AHRR haplotype is more frequent among South Asian and African populations, while its opposite is more common in Northeast Asian populations. Meanwhile, the protective PPP2R5E haplotype is found among South Asian populations at a high frequency, but is only found at low levels among African populations. Lastly, the protective GRIP1 allele is frequent among South Asians, but absent among Africans.

The researchers estimated that European and South Asian populations are the most protected against dengue fever, while Northeast and Southeast Asians are the most susceptible, and African, Caribbean, and Latin American populations have intermediate risk.

These genes — CHST10, AHRR, PPP2R5E, and GRIP1 — linked to dengue fever susceptibility are involved in the xenobiotic metabolism signaling pathway, implicating the pathway in disease pathogenesis.