A −436C>A Polymorphism in the Human FAS Gene Promoter Associated with Severe Childhood Malaria
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Auteurs : Kathrin Schuldt [Allemagne] ; Cosima C. Kretz [Allemagne] ; Christian Timmann [Allemagne] ; Jürgen Sievertsen [Allemagne] ; Christa Ehmen [Allemagne] ; Claudia Esser [Allemagne] ; Wibke Loag [Allemagne] ; Daniel Ansong [Ghana] ; Carmen Dering [Allemagne] ; Jennifer Evans [Allemagne] ; Andreas Ziegler [Allemagne] ; Jürgen May [Allemagne] ; Peter H. Krammer [Allemagne] ; Tsiri Agbenyega [Ghana] ; Rolf D. Horstmann [Allemagne]Source :
- PLoS Genetics [ 1553-7390 ] ; 2011.
Abstract
Human genetics and immune responses are considered to critically influence the outcome of malaria infections including life-threatening syndromes caused by
Url:
DOI: 10.1371/journal.pgen.1002066
PubMed: 21625619
PubMed Central: 3098189
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Kretz</name><affiliation wicri:level="1"><nlm:aff id="aff3"><addr-line>Division of Immunogenetics, German Cancer Research Centre, Heidelberg, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Division of Immunogenetics, German Cancer Research Centre, Heidelberg</wicri:regionArea></affiliation></author><author><name sortKey="Timmann, Christian" sort="Timmann, Christian" uniqKey="Timmann C" first="Christian" last="Timmann">Christian Timmann</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Department of Molecular Medicine, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Molecular Medicine, Bernhard Nocht Institute for Tropical Medicine, Hamburg</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2"><addr-line>Institute of Medical Biometry and Statistics, University at Lübeck, University Hospital Schleswig-Holstein, Lübeck, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Medical Biometry and Statistics, University at Lübeck, University Hospital Schleswig-Holstein, Lübeck</wicri:regionArea></affiliation></author><author><name sortKey="Sievertsen, Jurgen" sort="Sievertsen, Jurgen" uniqKey="Sievertsen J" first="Jürgen" last="Sievertsen">Jürgen Sievertsen</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Department of Molecular Medicine, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Molecular Medicine, Bernhard Nocht Institute for Tropical Medicine, Hamburg</wicri:regionArea></affiliation></author><author><name sortKey="Ehmen, Christa" sort="Ehmen, Christa" uniqKey="Ehmen C" first="Christa" last="Ehmen">Christa Ehmen</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Department of Molecular Medicine, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Molecular Medicine, Bernhard Nocht Institute for Tropical Medicine, Hamburg</wicri:regionArea></affiliation></author><author><name sortKey="Esser, Claudia" sort="Esser, Claudia" uniqKey="Esser C" first="Claudia" last="Esser">Claudia Esser</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Department of Molecular Medicine, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Molecular Medicine, Bernhard Nocht Institute for Tropical Medicine, Hamburg</wicri:regionArea></affiliation></author><author><name sortKey="Loag, Wibke" sort="Loag, Wibke" uniqKey="Loag W" first="Wibke" last="Loag">Wibke Loag</name><affiliation wicri:level="1"><nlm:aff id="aff4"><addr-line>Infectious Disease Epidemiology Group, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Infectious Disease Epidemiology Group, Bernhard Nocht Institute for Tropical Medicine, Hamburg</wicri:regionArea></affiliation></author><author><name sortKey="Ansong, Daniel" sort="Ansong, Daniel" uniqKey="Ansong D" first="Daniel" last="Ansong">Daniel Ansong</name><affiliation wicri:level="1"><nlm:aff id="aff5"><addr-line>School of Medical Sciences, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana</addr-line></nlm:aff><country xml:lang="fr">Ghana</country><wicri:regionArea>School of Medical Sciences, Kwame Nkrumah University of Science and Technology, Kumasi</wicri:regionArea></affiliation></author><author><name sortKey="Dering, Carmen" sort="Dering, Carmen" uniqKey="Dering C" first="Carmen" last="Dering">Carmen Dering</name><affiliation wicri:level="1"><nlm:aff id="aff2"><addr-line>Institute of Medical Biometry and Statistics, University at Lübeck, University Hospital Schleswig-Holstein, Lübeck, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Medical Biometry and Statistics, University at Lübeck, University Hospital Schleswig-Holstein, Lübeck</wicri:regionArea></affiliation></author><author><name sortKey="Evans, Jennifer" sort="Evans, Jennifer" uniqKey="Evans J" first="Jennifer" last="Evans">Jennifer Evans</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Department of Molecular Medicine, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Molecular Medicine, Bernhard Nocht Institute for Tropical Medicine, Hamburg</wicri:regionArea></affiliation></author><author><name sortKey="Ziegler, Andreas" sort="Ziegler, Andreas" uniqKey="Ziegler A" first="Andreas" last="Ziegler">Andreas Ziegler</name><affiliation wicri:level="1"><nlm:aff id="aff2"><addr-line>Institute of Medical Biometry and Statistics, University at Lübeck, University Hospital Schleswig-Holstein, Lübeck, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Medical Biometry and Statistics, University at Lübeck, University Hospital Schleswig-Holstein, Lübeck</wicri:regionArea></affiliation></author><author><name sortKey="May, Jurgen" sort="May, Jurgen" uniqKey="May J" first="Jürgen" last="May">Jürgen May</name><affiliation wicri:level="1"><nlm:aff id="aff4"><addr-line>Infectious Disease Epidemiology Group, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Infectious Disease Epidemiology Group, Bernhard Nocht Institute for Tropical Medicine, Hamburg</wicri:regionArea></affiliation></author><author><name sortKey="Krammer, Peter H" sort="Krammer, Peter H" uniqKey="Krammer P" first="Peter H." last="Krammer">Peter H. Krammer</name><affiliation wicri:level="1"><nlm:aff id="aff3"><addr-line>Division of Immunogenetics, German Cancer Research Centre, Heidelberg, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Division of Immunogenetics, German Cancer Research Centre, Heidelberg</wicri:regionArea></affiliation></author><author><name sortKey="Agbenyega, Tsiri" sort="Agbenyega, Tsiri" uniqKey="Agbenyega T" first="Tsiri" last="Agbenyega">Tsiri Agbenyega</name><affiliation wicri:level="1"><nlm:aff id="aff5"><addr-line>School of Medical Sciences, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana</addr-line></nlm:aff><country xml:lang="fr">Ghana</country><wicri:regionArea>School of Medical Sciences, Kwame Nkrumah University of Science and Technology, Kumasi</wicri:regionArea></affiliation></author><author><name sortKey="Horstmann, Rolf D" sort="Horstmann, Rolf D" uniqKey="Horstmann R" first="Rolf D." last="Horstmann">Rolf D. Horstmann</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Department of Molecular Medicine, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Molecular Medicine, Bernhard Nocht Institute for Tropical Medicine, Hamburg</wicri:regionArea></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">21625619</idno><idno type="pmc">3098189</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3098189</idno><idno type="RBID">PMC:3098189</idno><idno type="doi">10.1371/journal.pgen.1002066</idno><date when="2011">2011</date><idno type="wicri:Area/Pmc/Corpus">000471</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000471</idno><idno type="wicri:Area/Pmc/Curation">000470</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000470</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">A −436C>A Polymorphism in the Human <italic>FAS</italic> Gene Promoter Associated with Severe Childhood Malaria</title><author><name sortKey="Schuldt, Kathrin" sort="Schuldt, Kathrin" uniqKey="Schuldt K" first="Kathrin" last="Schuldt">Kathrin Schuldt</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Department of Molecular Medicine, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Molecular Medicine, Bernhard Nocht Institute for Tropical Medicine, Hamburg</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2"><addr-line>Institute of Medical Biometry and Statistics, University at Lübeck, University Hospital Schleswig-Holstein, Lübeck, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Medical Biometry and Statistics, University at Lübeck, University Hospital Schleswig-Holstein, Lübeck</wicri:regionArea></affiliation></author><author><name sortKey="Kretz, Cosima C" sort="Kretz, Cosima C" uniqKey="Kretz C" first="Cosima C." last="Kretz">Cosima C. Kretz</name><affiliation wicri:level="1"><nlm:aff id="aff3"><addr-line>Division of Immunogenetics, German Cancer Research Centre, Heidelberg, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Division of Immunogenetics, German Cancer Research Centre, Heidelberg</wicri:regionArea></affiliation></author><author><name sortKey="Timmann, Christian" sort="Timmann, Christian" uniqKey="Timmann C" first="Christian" last="Timmann">Christian Timmann</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Department of Molecular Medicine, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Molecular Medicine, Bernhard Nocht Institute for Tropical Medicine, Hamburg</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff2"><addr-line>Institute of Medical Biometry and Statistics, University at Lübeck, University Hospital Schleswig-Holstein, Lübeck, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Medical Biometry and Statistics, University at Lübeck, University Hospital Schleswig-Holstein, Lübeck</wicri:regionArea></affiliation></author><author><name sortKey="Sievertsen, Jurgen" sort="Sievertsen, Jurgen" uniqKey="Sievertsen J" first="Jürgen" last="Sievertsen">Jürgen Sievertsen</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Department of Molecular Medicine, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Molecular Medicine, Bernhard Nocht Institute for Tropical Medicine, Hamburg</wicri:regionArea></affiliation></author><author><name sortKey="Ehmen, Christa" sort="Ehmen, Christa" uniqKey="Ehmen C" first="Christa" last="Ehmen">Christa Ehmen</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Department of Molecular Medicine, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Molecular Medicine, Bernhard Nocht Institute for Tropical Medicine, Hamburg</wicri:regionArea></affiliation></author><author><name sortKey="Esser, Claudia" sort="Esser, Claudia" uniqKey="Esser C" first="Claudia" last="Esser">Claudia Esser</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Department of Molecular Medicine, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Molecular Medicine, Bernhard Nocht Institute for Tropical Medicine, Hamburg</wicri:regionArea></affiliation></author><author><name sortKey="Loag, Wibke" sort="Loag, Wibke" uniqKey="Loag W" first="Wibke" last="Loag">Wibke Loag</name><affiliation wicri:level="1"><nlm:aff id="aff4"><addr-line>Infectious Disease Epidemiology Group, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Infectious Disease Epidemiology Group, Bernhard Nocht Institute for Tropical Medicine, Hamburg</wicri:regionArea></affiliation></author><author><name sortKey="Ansong, Daniel" sort="Ansong, Daniel" uniqKey="Ansong D" first="Daniel" last="Ansong">Daniel Ansong</name><affiliation wicri:level="1"><nlm:aff id="aff5"><addr-line>School of Medical Sciences, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana</addr-line></nlm:aff><country xml:lang="fr">Ghana</country><wicri:regionArea>School of Medical Sciences, Kwame Nkrumah University of Science and Technology, Kumasi</wicri:regionArea></affiliation></author><author><name sortKey="Dering, Carmen" sort="Dering, Carmen" uniqKey="Dering C" first="Carmen" last="Dering">Carmen Dering</name><affiliation wicri:level="1"><nlm:aff id="aff2"><addr-line>Institute of Medical Biometry and Statistics, University at Lübeck, University Hospital Schleswig-Holstein, Lübeck, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Medical Biometry and Statistics, University at Lübeck, University Hospital Schleswig-Holstein, Lübeck</wicri:regionArea></affiliation></author><author><name sortKey="Evans, Jennifer" sort="Evans, Jennifer" uniqKey="Evans J" first="Jennifer" last="Evans">Jennifer Evans</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Department of Molecular Medicine, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Molecular Medicine, Bernhard Nocht Institute for Tropical Medicine, Hamburg</wicri:regionArea></affiliation></author><author><name sortKey="Ziegler, Andreas" sort="Ziegler, Andreas" uniqKey="Ziegler A" first="Andreas" last="Ziegler">Andreas Ziegler</name><affiliation wicri:level="1"><nlm:aff id="aff2"><addr-line>Institute of Medical Biometry and Statistics, University at Lübeck, University Hospital Schleswig-Holstein, Lübeck, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Medical Biometry and Statistics, University at Lübeck, University Hospital Schleswig-Holstein, Lübeck</wicri:regionArea></affiliation></author><author><name sortKey="May, Jurgen" sort="May, Jurgen" uniqKey="May J" first="Jürgen" last="May">Jürgen May</name><affiliation wicri:level="1"><nlm:aff id="aff4"><addr-line>Infectious Disease Epidemiology Group, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Infectious Disease Epidemiology Group, Bernhard Nocht Institute for Tropical Medicine, Hamburg</wicri:regionArea></affiliation></author><author><name sortKey="Krammer, Peter H" sort="Krammer, Peter H" uniqKey="Krammer P" first="Peter H." last="Krammer">Peter H. Krammer</name><affiliation wicri:level="1"><nlm:aff id="aff3"><addr-line>Division of Immunogenetics, German Cancer Research Centre, Heidelberg, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Division of Immunogenetics, German Cancer Research Centre, Heidelberg</wicri:regionArea></affiliation></author><author><name sortKey="Agbenyega, Tsiri" sort="Agbenyega, Tsiri" uniqKey="Agbenyega T" first="Tsiri" last="Agbenyega">Tsiri Agbenyega</name><affiliation wicri:level="1"><nlm:aff id="aff5"><addr-line>School of Medical Sciences, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana</addr-line></nlm:aff><country xml:lang="fr">Ghana</country><wicri:regionArea>School of Medical Sciences, Kwame Nkrumah University of Science and Technology, Kumasi</wicri:regionArea></affiliation></author><author><name sortKey="Horstmann, Rolf D" sort="Horstmann, Rolf D" uniqKey="Horstmann R" first="Rolf D." last="Horstmann">Rolf D. Horstmann</name><affiliation wicri:level="1"><nlm:aff id="aff1"><addr-line>Department of Molecular Medicine, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany</addr-line></nlm:aff><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Molecular Medicine, Bernhard Nocht Institute for Tropical Medicine, Hamburg</wicri:regionArea></affiliation></author></analytic><series><title level="j">PLoS Genetics</title><idno type="ISSN">1553-7390</idno><idno type="eISSN">1553-7404</idno><imprint><date when="2011">2011</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Human genetics and immune responses are considered to critically influence the outcome of malaria infections including life-threatening syndromes caused by <italic>Plasmodium falciparum</italic>. An important role in immune regulation is assigned to the apoptosis-signaling cell surface receptor CD95 (Fas, APO-1), encoded by the gene <italic>FAS</italic>. Here, a candidate-gene association study including variant discovery at the <italic>FAS</italic> 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 <italic>FAS</italic> to be significantly associated with protection from severe childhood malaria (odds ratio 0.71, 95% confidence interval 0.58–0.88, p<sub>empirical</sub> = 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<sup>−7</sup>, 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<sup>+</sup>CD95<sup>+</sup> 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.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct></biblStruct><biblStruct><analytic><author><name sortKey="Marsh, K" uniqKey="Marsh K">K Marsh</name></author><author><name sortKey="Forster, D" uniqKey="Forster D">D Forster</name></author><author><name sortKey="Waruiru, C" uniqKey="Waruiru C">C Waruiru</name></author><author><name sortKey="Mwangi, I" uniqKey="Mwangi I">I Mwangi</name></author><author><name sortKey="Winstanley, M" uniqKey="Winstanley M">M Winstanley</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kwiatkowski, Dp" uniqKey="Kwiatkowski D">DP Kwiatkowski</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Behrmann, I" uniqKey="Behrmann I">I Behrmann</name></author><author><name sortKey="Walczak, H" uniqKey="Walczak H">H Walczak</name></author><author><name sortKey="Krammer, Ph" uniqKey="Krammer P">PH Krammer</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Lichter, P" uniqKey="Lichter P">P Lichter</name></author><author><name sortKey="Walczak, H" uniqKey="Walczak H">H Walczak</name></author><author><name sortKey="Weitz, S" uniqKey="Weitz S">S Weitz</name></author><author><name sortKey="Behrmann, I" uniqKey="Behrmann I">I Behrmann</name></author><author><name sortKey="Krammer, Ph" uniqKey="Krammer P">PH Krammer</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Krammer, Ph" uniqKey="Krammer P">PH Krammer</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Suda, T" uniqKey="Suda T">T Suda</name></author><author><name sortKey="Takahashi, T" uniqKey="Takahashi T">T Takahashi</name></author><author><name sortKey="Golstein, P" uniqKey="Golstein P">P Golstein</name></author><author><name sortKey="Nagata, S" uniqKey="Nagata S">S Nagata</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Tanaka, M" uniqKey="Tanaka M">M Tanaka</name></author><author><name sortKey="Suda, T" uniqKey="Suda T">T Suda</name></author><author><name sortKey="Takahashi, T" uniqKey="Takahashi T">T Takahashi</name></author><author><name sortKey="Nagata, S" uniqKey="Nagata S">S Nagata</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Bidere, N" uniqKey="Bidere N">N Bidere</name></author><author><name sortKey="Su, Hc" uniqKey="Su H">HC Su</name></author><author><name sortKey="Lenardo, Mj" uniqKey="Lenardo M">MJ Lenardo</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Sprent, J" 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<front><journal-meta><journal-id journal-id-type="nlm-ta">PLoS Genet</journal-id><journal-id journal-id-type="iso-abbrev">PLoS Genet</journal-id><journal-id journal-id-type="publisher-id">plos</journal-id><journal-id journal-id-type="pmc">plosgen</journal-id><journal-title-group><journal-title>PLoS Genetics</journal-title></journal-title-group><issn pub-type="ppub">1553-7390</issn><issn pub-type="epub">1553-7404</issn><publisher><publisher-name>Public Library of Science</publisher-name><publisher-loc>San Francisco, USA</publisher-loc></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">21625619</article-id><article-id pub-id-type="pmc">3098189</article-id><article-id pub-id-type="publisher-id">PGENETICS-D-10-00254</article-id><article-id pub-id-type="doi">10.1371/journal.pgen.1002066</article-id><article-categories><subj-group subj-group-type="heading"><subject>Research Article</subject></subj-group><subj-group subj-group-type="Discipline-v2"><subject>Biology</subject><subj-group><subject>Genetics</subject><subj-group><subject>Human Genetics</subject><subj-group><subject>Genetic Association Studies</subject></subj-group></subj-group></subj-group><subj-group><subject>Microbiology</subject><subj-group><subject>Protozoology</subject><subj-group><subject>Parastic Protozoans</subject><subj-group><subject>Plasmodium Falciparum</subject></subj-group></subj-group></subj-group></subj-group></subj-group></article-categories><title-group><article-title>A −436C>A Polymorphism in the Human <italic>FAS</italic> Gene Promoter Associated with Severe Childhood Malaria</article-title><alt-title alt-title-type="running-head"><italic>FAS</italic> Variant Associated with Severe Malaria</alt-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Schuldt</surname><given-names>Kathrin</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref><xref ref-type="aff" rid="aff2"><sup>2</sup></xref><xref ref-type="corresp" rid="cor1"><sup>*</sup></xref></contrib><contrib contrib-type="author"><name><surname>Kretz</surname><given-names>Cosima C.</given-names></name><xref ref-type="aff" rid="aff3"><sup>3</sup></xref></contrib><contrib contrib-type="author"><name><surname>Timmann</surname><given-names>Christian</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref><xref ref-type="aff" rid="aff2"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Sievertsen</surname><given-names>Jürgen</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Ehmen</surname><given-names>Christa</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Esser</surname><given-names>Claudia</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Loag</surname><given-names>Wibke</given-names></name><xref ref-type="aff" rid="aff4"><sup>4</sup></xref></contrib><contrib contrib-type="author"><name><surname>Ansong</surname><given-names>Daniel</given-names></name><xref ref-type="aff" rid="aff5"><sup>5</sup></xref></contrib><contrib contrib-type="author"><name><surname>Dering</surname><given-names>Carmen</given-names></name><xref ref-type="aff" rid="aff2"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>Evans</surname><given-names>Jennifer</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Ziegler</surname><given-names>Andreas</given-names></name><xref ref-type="aff" rid="aff2"><sup>2</sup></xref></contrib><contrib contrib-type="author"><name><surname>May</surname><given-names>Jürgen</given-names></name><xref ref-type="aff" rid="aff4"><sup>4</sup></xref></contrib><contrib contrib-type="author"><name><surname>Krammer</surname><given-names>Peter H.</given-names></name><xref ref-type="aff" rid="aff3"><sup>3</sup></xref></contrib><contrib contrib-type="author"><name><surname>Agbenyega</surname><given-names>Tsiri</given-names></name><xref ref-type="aff" rid="aff5"><sup>5</sup></xref></contrib><contrib contrib-type="author"><name><surname>Horstmann</surname><given-names>Rolf D.</given-names></name><xref ref-type="aff" rid="aff1"><sup>1</sup></xref></contrib></contrib-group><aff id="aff1"><label>1</label><addr-line>Department of Molecular Medicine, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany</addr-line></aff><aff id="aff2"><label>2</label><addr-line>Institute of Medical Biometry and Statistics, University at Lübeck, University Hospital Schleswig-Holstein, Lübeck, Germany</addr-line></aff><aff id="aff3"><label>3</label><addr-line>Division of Immunogenetics, German Cancer Research Centre, Heidelberg, Germany</addr-line></aff><aff id="aff4"><label>4</label><addr-line>Infectious Disease Epidemiology Group, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany</addr-line></aff><aff id="aff5"><label>5</label><addr-line>School of Medical Sciences, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana</addr-line></aff><contrib-group><contrib contrib-type="editor"><name><surname>Jeffares</surname><given-names>Daniel C.</given-names></name><role>Editor</role><xref ref-type="aff" rid="edit1"></xref></contrib></contrib-group><aff id="edit1">University College London, United Kingdom</aff><author-notes><corresp id="cor1">* E-mail: <email>schuldt@bnitm.de</email></corresp><fn fn-type="con"><p>Conceived and designed the experiments: K Schuldt, CC Kretz, C Timman, J Evans, J May, PH Krammer, T Agbenyega, RD Horstmann. Performed the experiments: K Schuldt, CC Kretz, C Ehmen, J Evans, D Ansong, J Sievertsen. Analyzed the data: K Schuldt, CC Kretz, C Timman, C Esser, W Loag, C Dering, A Ziegler, RD Horstmann. Contributed reagents/materials/analysis tools: PH Krammer. Wrote the manuscript: K Schuldt, A Ziegler, J May, RD Horstmann.</p></fn></author-notes><pub-date pub-type="collection"><month>5</month><year>2011</year></pub-date><pub-date pub-type="epub"><day>19</day><month>5</month><year>2011</year></pub-date><volume>7</volume><issue>5</issue><elocation-id>e1002066</elocation-id><history><date date-type="received"><day>3</day><month>11</month><year>2010</year></date><date date-type="accepted"><day>18</day><month>3</month><year>2011</year></date></history><permissions><copyright-statement>Schuldt et al.</copyright-statement><copyright-year>2011</copyright-year><license xlink:href="http://creativecommons.org/licenses/by/4.0/"><license-p>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 properly credited.</license-p></license></permissions><abstract><p>Human genetics and immune responses are considered to critically influence the outcome of malaria infections including life-threatening syndromes caused by <italic>Plasmodium falciparum</italic>. An important role in immune regulation is assigned to the apoptosis-signaling cell surface receptor CD95 (Fas, APO-1), encoded by the gene <italic>FAS</italic>. Here, a candidate-gene association study including variant discovery at the <italic>FAS</italic> 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 <italic>FAS</italic> to be significantly associated with protection from severe childhood malaria (odds ratio 0.71, 95% confidence interval 0.58–0.88, p<sub>empirical</sub> = 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<sup>−7</sup>, 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<sup>+</sup>CD95<sup>+</sup> 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.</p></abstract><abstract abstract-type="summary"><title>Author Summary</title><p>Severe malaria caused by infection with the protozoan parasite <italic>Plasmodium falciparum</italic> 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 <italic>FAS</italic> gene, which encodes CD95, a molecule critically involved in the programmed cell death of lymphocytes. We found that a single nucleotide variant in the <italic>FAS</italic> 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.</p></abstract><counts><page-count count="10"></page-count></counts></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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