title: A -436C>A polymorphism in the human FAS gene promoter associated with severe childhood malaria.
abstract: 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.
authors.affiliation: Department of Molecular Medicine, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany. schuldt@bnitm.de
authors.forename: Kathrin
authors.initials: K
authors.lastname: Schuldt
authors.forename: Cosima C
authors.initials: CC
authors.lastname: Kretz
authors.forename: Christian
authors.initials: C
authors.lastname: Timmann
authors.forename: Jürgen
authors.initials: J
authors.lastname: Sievertsen
authors.forename: Christa
authors.initials: C
authors.lastname: Ehmen
authors.forename: Claudia
authors.initials: C
authors.lastname: Esser
authors.forename: Wibke
authors.initials: W
authors.lastname: Loag
authors.forename: Daniel
authors.initials: D
authors.lastname: Ansong
authors.forename: Carmen
authors.initials: C
authors.lastname: Dering
authors.forename: Jennifer
authors.initials: J
authors.lastname: Evans
authors.forename: Andreas
authors.initials: A
authors.lastname: Ziegler
authors.forename: Jürgen
authors.initials: J
authors.lastname: May
authors.forename: Peter H
authors.initials: PH
authors.lastname: Krammer
authors.forename: Tsiri
authors.initials: T
authors.lastname: Agbenyega
authors.forename: Rolf D
authors.initials: RD
authors.lastname: Horstmann
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D008040:Genetic Linkage; D006239:Haplotypes; D006801:Humans; D007223:Infant; D016778:Malaria, Falciparum / Q000235:genetics* / Q000473:pathology; D008875:Middle Aged; D010963:Plasmodium falciparum / Q000502:physiology*; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D055815:Young Adult; D019014:fas Receptor / Q000235:genetics*
chemical_list: C491901:FAS protein, human; D019014:fas Receptor