Transforming Growth Factor Beta 2 and Heme Oxygenase 1 Genes Are Risk Factors for the Cerebral Malaria Syndrome in Angolan Children

Maria Rosário Sambo, Maria Jesus Trovoada, Carla Benchimol, Vatúsia Quinhentos, Lígia Gonçalves, Rute Velosa, Maria Isabel Marques, Nuno Sepúlveda, Taane G Clark, Stefan Mustafa, Oswald Wagner, António Coutinho, Carlos Penha-Gonçalves

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Article numbere11141
JournalPloS ONE
Volume5
Issue number6
DOIs
Publication statusPublished - 16 Jun 2010

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heme oxygenase (biliverdin-producing)
transforming growth factor beta 2
Cerebral Malaria
Heme Oxygenase-1
Transforming Growth Factor beta
risk factors
Genes
Malaria
malaria
genes
Plasmodium falciparum
Haplotypes
Single Nucleotide Polymorphism
haplotypes
cerebral malaria
Blood
Cells
Falciparum Malaria
blood cells
Messenger RNA

Keywords

  • Angola
  • Child
  • Cohort Studies
  • Genetic Markers
  • Genetic Predisposition to Disease
  • Haplotypes
  • Heme Oxygenase (Decyclizing)
  • Humans
  • Linkage Disequilibrium
  • Malaria, Cerebral
  • Malaria, Falciparum
  • Polymorphism, Single Nucleotide
  • RNA, Messenger
  • Transforming Growth Factor beta2
  • Journal Article
  • Research Support, Non-U.S. Gov't

Cite this

Sambo, M. R., Trovoada, M. J., Benchimol, C., Quinhentos, V., Gonçalves, L., Velosa, R., ... Penha-Gonçalves, C. (2010). Transforming Growth Factor Beta 2 and Heme Oxygenase 1 Genes Are Risk Factors for the Cerebral Malaria Syndrome in Angolan Children. PloS ONE, 5(6), [e11141]. https://doi.org/10.1371/journal.pone.0011141

Transforming Growth Factor Beta 2 and Heme Oxygenase 1 Genes Are Risk Factors for the Cerebral Malaria Syndrome in Angolan Children. / Sambo, Maria Rosário; Trovoada, Maria Jesus; Benchimol, Carla; Quinhentos, Vatúsia; Gonçalves, Lígia; Velosa, Rute; Marques, Maria Isabel; Sepúlveda, Nuno; Clark, Taane G; Mustafa, Stefan; Wagner, Oswald; Coutinho, António; Penha-Gonçalves, Carlos.

In: PloS ONE, Vol. 5, No. 6, e11141, 16.06.2010.

Research output: Contribution to journalArticle

Sambo, MR, Trovoada, MJ, Benchimol, C, Quinhentos, V, Gonçalves, L, Velosa, R, Marques, MI, Sepúlveda, N, Clark, TG, Mustafa, S, Wagner, O, Coutinho, A & Penha-Gonçalves, C 2010, 'Transforming Growth Factor Beta 2 and Heme Oxygenase 1 Genes Are Risk Factors for the Cerebral Malaria Syndrome in Angolan Children', PloS ONE, vol. 5, no. 6, e11141. https://doi.org/10.1371/journal.pone.0011141
Sambo, Maria Rosário ; Trovoada, Maria Jesus ; Benchimol, Carla ; Quinhentos, Vatúsia ; Gonçalves, Lígia ; Velosa, Rute ; Marques, Maria Isabel ; Sepúlveda, Nuno ; Clark, Taane G ; Mustafa, Stefan ; Wagner, Oswald ; Coutinho, António ; Penha-Gonçalves, Carlos. / Transforming Growth Factor Beta 2 and Heme Oxygenase 1 Genes Are Risk Factors for the Cerebral Malaria Syndrome in Angolan Children. In: PloS ONE. 2010 ; Vol. 5, No. 6.
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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.",
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T1 - Transforming Growth Factor Beta 2 and Heme Oxygenase 1 Genes Are Risk Factors for the Cerebral Malaria Syndrome in Angolan Children

AU - Sambo, Maria Rosário

AU - Trovoada, Maria Jesus

AU - Benchimol, Carla

AU - Quinhentos, Vatúsia

AU - Gonçalves, Lígia

AU - Velosa, Rute

AU - Marques, Maria Isabel

AU - Sepúlveda, Nuno

AU - Clark, Taane G

AU - Mustafa, Stefan

AU - Wagner, Oswald

AU - Coutinho, António

AU - Penha-Gonçalves, Carlos

N1 - Funding: This project was supported by the Instituto Gulbenkian de Ciência. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

PY - 2010/6/16

Y1 - 2010/6/16

N2 - 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.

AB - 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.

KW - Angola

KW - Child

KW - Cohort Studies

KW - Genetic Markers

KW - Genetic Predisposition to Disease

KW - Haplotypes

KW - Heme Oxygenase (Decyclizing)

KW - Humans

KW - Linkage Disequilibrium

KW - Malaria, Cerebral

KW - Malaria, Falciparum

KW - Polymorphism, Single Nucleotide

KW - RNA, Messenger

KW - Transforming Growth Factor beta2

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1371/journal.pone.0011141

DO - 10.1371/journal.pone.0011141

M3 - Article

VL - 5

JO - PloS ONE

JF - PloS ONE

SN - 1932-6203

IS - 6

M1 - e11141

ER -