A -436C>A polymorphism in the human FAS gene promoter associated with severe childhood malaria.
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), en...
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2011-05-01
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doaj-abb074d2235a42f384577f00bcbbcbe72020-11-24T21:19:24ZengPublic Library of Science (PLoS)PLoS Genetics1553-73901553-74042011-05-0175e100206610.1371/journal.pgen.1002066A -436C>A polymorphism in the human FAS gene promoter associated with severe childhood malaria.Kathrin SchuldtCosima C KretzChristian TimmannJürgen SievertsenChrista EhmenClaudia EsserWibke LoagDaniel AnsongCarmen DeringJennifer EvansAndreas ZieglerJürgen MayPeter H KrammerTsiri AgbenyegaRolf D HorstmannHuman 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, p(empirical) = 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.http://europepmc.org/articles/PMC3098189?pdf=render |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Kathrin Schuldt Cosima C Kretz Christian Timmann Jürgen Sievertsen Christa Ehmen Claudia Esser Wibke Loag Daniel Ansong Carmen Dering Jennifer Evans Andreas Ziegler Jürgen May Peter H Krammer Tsiri Agbenyega Rolf D Horstmann |
spellingShingle |
Kathrin Schuldt Cosima C Kretz Christian Timmann Jürgen Sievertsen Christa Ehmen Claudia Esser Wibke Loag Daniel Ansong Carmen Dering Jennifer Evans Andreas Ziegler Jürgen May Peter H Krammer Tsiri Agbenyega Rolf D Horstmann A -436C>A polymorphism in the human FAS gene promoter associated with severe childhood malaria. PLoS Genetics |
author_facet |
Kathrin Schuldt Cosima C Kretz Christian Timmann Jürgen Sievertsen Christa Ehmen Claudia Esser Wibke Loag Daniel Ansong Carmen Dering Jennifer Evans Andreas Ziegler Jürgen May Peter H Krammer Tsiri Agbenyega Rolf D Horstmann |
author_sort |
Kathrin Schuldt |
title |
A -436C>A polymorphism in the human FAS gene promoter associated with severe childhood malaria. |
title_short |
A -436C>A polymorphism in the human FAS gene promoter associated with severe childhood malaria. |
title_full |
A -436C>A polymorphism in the human FAS gene promoter associated with severe childhood malaria. |
title_fullStr |
A -436C>A polymorphism in the human FAS gene promoter associated with severe childhood malaria. |
title_full_unstemmed |
A -436C>A polymorphism in the human FAS gene promoter associated with severe childhood malaria. |
title_sort |
-436c>a polymorphism in the human fas gene promoter associated with severe childhood malaria. |
publisher |
Public Library of Science (PLoS) |
series |
PLoS Genetics |
issn |
1553-7390 1553-7404 |
publishDate |
2011-05-01 |
description |
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, p(empirical) = 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. |
url |
http://europepmc.org/articles/PMC3098189?pdf=render |
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