Abstract
The Brazilian Amazon is a hypo-endemic malaria region with nearly 300,000 cases each year. A variety of genetic polymorphisms, particularly in erythrocyte receptors and immune response related genes, have been described to be associated with susceptibility and resistance to malaria. In order to identify polymorphisms that might be associated with malaria clinical outcomes in a Brazilian Amazonian population, sixty-four human single nucleotide polymorphisms in 37 genes were analyzed using a Sequenom massARRAY iPLEX platform. A total of 648 individuals from two malaria endemic areas were studied, including 535 malaria cases (113 individuals with clinical mild malaria, 122 individuals with asymptomatic infection and 300 individuals with history of previous mild malaria) and 113 health controls with no history of malaria. The data revealed significant associations (p<0.003) between one SNP in the IL10 gene (rs1800896) and one SNP in the TLR4 gene (rs4986790) with reduced risk for clinical malaria, one SNP in the IRF1 gene (rs2706384) with increased risk for clinical malaria, one SNP in the LTA gene (rs909253) with protection from clinical malaria and one SNP in the TNF gene (RS1800750) associated with susceptibility to clinical malaria. Also, a new association was found between a SNP in the CTL4 gene (rs2242665), located at the major histocompatibility complex III region, and reduced risk for clinical malaria. This study represents the first association study from an Amazonian population involving a large number of host genetic polymorphisms with susceptibility or resistance to Plasmodium infection and malaria outcomes. Further studies should include a larger number of individuals, refined parameters and a fine-scale map obtained through DNA sequencing to increase the knowledge of the Amazonian population genetic diversity.
Highlights
Malaria is a life-threatening parasitic disease transmitted by mosquitoes
There were five significant results for those with any_malaria versus never_malaria group: rs1800896– IL10-1082 (OR: 0.528, CI: 0.360–0.774; P = 0.0014), rs2706384 - Interferon Regulatory Factor 1 gene (IRF1) (OR: 1.881, 95% CI: 1.298–2.724; P = 0.0005), rs2242665 - CTL4 (OR: 0.595, 95% CI: 0.434–0.816; P = 0.0012), rs4986790 - TLR4 (OR: 0.274, 95% CI: 0.124–0.604; P = 0.0014) and rs909253 - LTA+252 (OR: 0.343, 95% CI: 0.182–0.647; P = 0.0009)
Four of these single nucleotide polymorphisms (SNPs) were significant when analyzing clinical_malaria versus never_malaria group: rs2706384 - IRF1 (OR: 2.023, 95% CI: 1.371–2.987; P = 0.0002), rs2242665 - CTL4 (OR: 0.564, 95% CI: 0.406–0.784; P = 0.0006), rs4986790 - TLR4 (OR: 0.271, 95% CI: 0.116–0.633; P = 0.002) and rs909253 - LTA+252 (OR: 0.366, 95% CI: 0.192–0.699; P = 0.001)
Summary
Malaria is a life-threatening parasitic disease transmitted by mosquitoes. Despite major efforts aimed at controlling the spread and impact of the disease, it still persists as a major health burden, being responsible for over a million deaths each year, mainly children in Sub-Saharan Africa. Malaria is a complex disease with many genetic and environmental determinants influencing the observed variation in response to infection, progression and severity. Several factors important for these different phenotypes include the parasite genetic make-up and host age, state of immunity and genetic background [2]. Resistance involves genetically-based and cellmediated immunological mechanisms, including the production of specific antibodies that are main actors in the acquired immune response [3], thereby reducing the severity of symptoms and mortality. Resistance mechanisms have been described for both the liver and blood stages of the parasite in the host [4]
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