Polymorphism in the Human FAS Gene Promoter Associated with Severe Childhood Malaria

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Human genetics and immune responses are considered to critically influence the outcome of malaria infections including life-threatening syndromes caused by Plasmodium falciparum. An important role in immune regulation is assigned to the apoptosis-signaling cell surface receptor CD95 (Fas, APO-1), encoded by the gene FAS.

Here, a candidate-gene association study including variant discovery at the FAS gene locus was carried out in a case-control group comprising 1,195 pediatric cases of severe falciparum malaria and 769 unaffected controls from a region highly endemic for malaria in Ghana, West Africa. We found the A allele of c.−436C>A (rs9658676) located in the promoter region of FAS to be significantly associated with protection from severe childhood malaria (odds ratio 0.71, 95% confidence interval 0.58–0.88, pempirical = 0.02) and confirmed this finding in a replication group of 1,412 additional severe malaria cases and 2,659 community controls from the same geographic area.

The combined analysis resulted in an odds ratio of 0.71 (95% confidence interval 0.62–0.80, p = 1.8×10−7, n = 6035). The association applied to c.−436AA homozygotes (odds ratio 0.47, 95% confidence interval 0.36–0.60) and to a lesser extent to c.−436AC heterozygotes (odds ratio 0.73, 95% confidence interval 0.63–0.84), and also to all phenotypic subgroups studied, including severe malaria anemia, cerebral malaria, and other malaria complications. Quantitative FACS analyses assessing CD95 surface expression of peripheral blood mononuclear cells of naïve donors showed a significantly higher proportion of CD69+CD95+ cells among persons homozygous for the protective A allele compared to AC heterozygotes and CC homozygotes, indicating a functional role of the associated CD95 variant, possibly in supporting lymphocyte apoptosis.

Author Summary

Severe malaria caused by infection with the protozoan parasite Plasmodium falciparum is a major health burden, causing approximately one million fatalities annually, predominantly among young children in Sub-Saharan Africa. The occurrence of severe malaria may depend on a complex interplay of transmission dynamics and the development of a protective immune response but also on heritable differences in the susceptibility to the disease.

In two large studies including a total of 2,607 affected children and 3,428 apparently healthy individuals from Ghana, West Africa, we investigated genetic variants of the FAS gene, which encodes CD95, a molecule critically involved in the programmed cell death of lymphocytes. We found that a single nucleotide variant in the FAS promoter was associated with a 29%–reduced risk of developing severe malaria. In individuals carrying two copies of the protective allele, a higher proportion of activated lymphocytes was found to express CD95. These findings indicate that a predisposition to an increased expression of CD95 may help to protect from severe malaria, possibly by rendering activated T-lymphocytes more susceptible to programmed cell death.

Citation: Schuldt K, Kretz CC, Timmann C, Sievertsen J, Ehmen C, et al. (2011) A −436C>A Polymorphism in the Human FAS Gene Promoter Associated with Severe Childhood Malaria. PLoS Genet 7(5): e1002066. doi:10.1371/journal.pgen.1002066

Editor: Daniel C. Jeffares, University College London, United Kingdom

Received: November 3, 2010; Accepted: March 18, 2011; Published: May 19, 2011

Copyright: © 2011 Schuldt et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Funding: The work was supported by the German National Genome Research Network (NGFN). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing interests: The authors have declared that no competing interests exist.

Authors: Kathrin Schuldt1,2*, Cosima C. Kretz3, Christian Timmann1,2, Jürgen Sievertsen1, Christa Ehmen1, Claudia Esser1, Wibke Loag4, Daniel Ansong5, Carmen Dering2, Jennifer Evans1, Andreas Ziegler2, Jürgen May4, Peter H. Krammer3, Tsiri Agbenyega5, Rolf D. Horstmann1

1 Department of Molecular Medicine, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany, 2 Institute of Medical Biometry and Statistics, University at Lübeck, University Hospital Schleswig-Holstein, Lübeck, Germany, 3 Division of Immunogenetics, German Cancer Research Centre, Heidelberg, Germany, 4 Infectious Disease Epidemiology Group, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany, 5 School of Medical Sciences, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana

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Researchers Find Gene That Fights Severe Malaria in Children

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Scientists have discovered a genetic variant in children that significantly reduces their risk of developing a life-threatening form of malaria.

Children with the unusual, or variant, gene have a 30 percent lower risk of developing cerebral malaria than those without the gene. Cerebral malaria is the most serious form of the parasitic illness that causes very high fever and coma, and leads rapidly to death in the 20 to 50 percent of people whose brains become infected.
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The mosquito-borne illness affects almost 300 million people every year. But most of the one million deaths occur in children under the age of five.

Researchers at Germany’s Bernhard Nocht Institute for Tropical Medicine and Kumasi University in Ghana identified the protective gene in a study involving more than 6,000 children. Called FAS, the gene is responsible for a molecule involved in the programmed cell death of some white blood cells, which are immune system cells that attack and destroy microbes that invade the body.

Researchers think that children who develop a life-threatening form of malaria have a hyper-immune response to the parasite. But youngsters with the FAS variant have increased expression of the molecule, called CD95, which appears to promote a greater number of immune system cell suicides—thus a less intense and ultimately survivable immune reaction to malaria.

At least that’s the theory, according to Kathrin Schuldt, a biologist and co-author of the study. Schuldt says children who are vulnerable to cerebral malaria are constantly bitten by mosquitoes that carry the parasite.

“So the immune response is constantly on a very high level trying to eliminate the pathogen from the body. And so what we found with this naturally occurring variant, these children probably have a regulation in their immune response which down-regulates the immune response to a certain level and therefore is kind of protective,” Schuldt said.

Humans never develop full immunity against malaria, but they can gain a partial immunity to the parasite, which is why the disease is less severe in adults. But children can become quite sick because they have had less exposure to the disease.

Schuldt says her goal now is to figure out the underlying mechanism for the protective effect of the genetic variant. Then, Schuldt says, it may be possible to develop drugs to protect children from this fatal form of malaria.

An article on the protective malaria gene is published in the on-line journal PLoS Genetics.

Source: VOA News