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


RESULTS
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
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.
Sambo
Maria Rosário
MR
Instituto Gulbenkian de Ciência, Oeiras, Portugal.
Trovoada
Maria Jesus
MJ
Benchimol
Carla
C
Quinhentos
Vatúsia
V
Gonçalves
Lígia
L
Velosa
Rute
R
Marques
Maria Isabel
MI
Sepúlveda
Nuno
N
Clark
Taane G
TG
Mustafa
Stefan
S
Wagner
Oswald
O
Coutinho
António
A
Penha-Gonçalves
Carlos
C
D000810:Angola; D002648:Child; D015331:Cohort Studies; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006419:Heme Oxygenase (Decyclizing) / Q000235:genetics*; D006801:Humans; D015810:Linkage Disequilibrium; D016779:Malaria, Cerebral / Q000235:genetics*; D016778:Malaria, Falciparum / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000235:genetics; D053781:Transforming Growth Factor beta2 / Q000235:genetics*
D005819:Genetic Markers; D012333:RNA, Messenger; D053781:Transforming Growth Factor beta2; D006419:Heme Oxygenase (Decyclizing)