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Genetic Variants Boost Risk of Severe Malaria in Children

Polymorphisms in toll-like receptor genes increase the risk of severe disease

THURSDAY, Dec. 22 (HealthDay News) -- Children with severe malaria are more likely to have certain genetic variants in an immune system-signaling molecule, according to a study published online Dec. 21 in the Proceedings of the National Academy of Sciences Early Edition. The polymorphisms in the toll-like receptor (TLR) genes seem to increase the risk of developing severe disease.

Ralf R. Schumann, M.D., of Charite-Universitatsmedizin in Berlin, Germany, and colleagues sequenced the gene for TLR-2, TLR-4, and TLR-9 in 290 Plasmodium falciparum-infected Ghanaian children with severe symptoms and 290 age- and sex-matched controls who were healthy or had asymptomatic infection. TLRs are involved in the innate immune response against microbes and trigger the release of proinflammatory cytokines. The three TLRs have previously been shown to be involved in the immune response to malaria.

Two mutations in TLR-4 were more common in children with severe malaria. The Asp299Gly mutation was found in 17.6% of controls and 24.1% of patients, increasing the risk of severe malaria by 1.5-fold, while the Thr399Ile mutation was found in 2.4% of controls and 6.2% of patients, increasing the risk of severe malaria by 2.6-fold. The researchers did not find any associations with TLR-2 or TLR-9 mutations and severe malaria, although one rare TLR-2 mutation was found that impaired signaling.

"Irrespective of the pending elucidation of the mechanisms involved, TLR-4 polymorphisms, particularly the 399 single-nucleotide polymorphism, predispose to severe malaria," the authors conclude. "This suggests that TLR-4 contributes to parasite recognition and host responses in vivo."

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