ABSTRACT
BACKGROUND: Cerebral malaria (CM) represents a severe outcome of the Plasmodium falciparum infection. Recent genetic studies have correlated human genes with severe malaria susceptibility, but there is little data on genetic variants that increase the risk of developing specific malaria clinical complications. Nevertheless, susceptibility to experimental CM in the mouse has been linked to host genes including Transforming Growth Factor Beta 2 (TGFB2) and Heme oxygenase-1 (HMOX1). Here, we tested whether those genes were governing the risk of progressing to CM in patients with severe malaria syndromes. METHODOLOGY/PRINCIPAL FINDINGS: We report that the clinical outcome of P. falciparum infection in a cohort of Angolan children (n = 430) correlated with nine TGFB2 SNPs that modify the risk of progression to CM as compared to other severe forms of malaria. This genetic effect was explained by two haplotypes harboring the CM-associated SNPs (Pcorrec. = 0.035 and 0.036). In addition, one HMOX1 haplotype composed of five CM-associated SNPs increased the risk of developing the CM syndrome (Pcorrec. = 0.002) and was under-transmitted to children with uncomplicated malaria (P = 0.036). Notably, the HMOX1-associated haplotype conferred increased HMOX1 mRNA expression in peripheral blood cells of CM patients (P = 0.012). CONCLUSIONS/SIGNIFICANCE: These results represent the first report on CM genetic risk factors in Angolan children and suggest the novel hypothesis that genetic variants of the TGFB2 and HMOX1 genes may contribute to confer a specific risk of developing the CM syndrome in patients with severe P. falciparum malaria. This work may provide motivation for future studies aiming to replicate our findings in larger populations and to confirm a role for these genes in determining the clinical course of malaria.
Subject(s)
Genetic Predisposition to Disease , Heme Oxygenase (Decyclizing)/genetics , Malaria, Cerebral/genetics , Malaria, Falciparum/genetics , Transforming Growth Factor beta2/genetics , Angola , Child , Cohort Studies , Genetic Markers , Haplotypes , Humans , Linkage Disequilibrium , Polymorphism, Single Nucleotide , RNA, Messenger/geneticsABSTRACT
Allele and haplotype frequencies of 16 chromosome STR loci, 15 of them included in the Kit PowerPlex16 System from Promega were determined in a sample of unrelated males from the Açores Archipelago. All subjects were subjected to an interview in order to make sure that their ancestors belonged to the same island at least back to three generations. This way we intended to look for possible inter-islands differences. PowerPlex16 includes STRs not studied before in the Açores population. The Kit includes two new allele markers (Penta D and Penta E), which proved to be extremely useful for paternity testing (PD=0.921 and 0.971, respectively). The study revealed that the Açores population is considerable different from the previous studied Madeira population, but does not differ from that of the north Portugal. Nevertheless, some loci presented alleles not previously reported for Portugal.
