Transforming growth factor beta 2 and heme oxygenase 1 genes are risk factors for the cerebral malaria syndrome in Angolan children

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.

Figure 1. Association tests and LD analysis in the TGFB2 gene single-nucleotide polymorphisms (SNPs).

The diagram represents in the vertical axis, the log10 of the P value of association tests of SNPs listed in the y-axis, obtained from logistic regression analysis. The points in red, blue and green represent the results of the association with the SNPs between cases of cerebral malaria (CM) and controls with severe no cerebral malaria (SnC), uncomplicated malaria (UM) and uninfected (UIF), respectively. The upper diagram shows a scale representation of the structure of the TGFB2 gene: exons are represented by boxes and marked with its number. The bottom of the diagram represents the LD between a pair of SNPs measured by r². The image, below and to the left, corresponds to the color scale representing the values of LD, from yellow (r² = 0) to red (r² = 1). This diagram is an adaptation of the figure produced by the snp. plotter R package.

Figure 2. Association tests and LD analysis in the HMOX1 gene single-nucleotide polymorphisms (SNPs).

The diagram represents in the vertical axis, the log10 of the P value of association tests of SNPs listed in the y-axis, obtained from logistic regression analysis. The points in red, blue and green represent the results of the association with the SNPs between cases of cerebral malaria (CM) and controls with severe no cerebral malaria (SnC), uncomplicated malaria (UM) and uninfected (UIF), respectively. The upper diagram shows a scale representation of the structure of the HMOX1 gene: exons are represented by boxes and marked with its number. The bottom of the diagram represents the LD between a pair of SNPs measured by r². The image, below and to the left, corresponds to the color scale representing the values of LD, from yellow (r² = 0) to red (r² = 1). This diagram is an adaptation of the figure produced by the snp. plotter R package.