title: Persistence of full-length caspase-12 and its relation to malaria in West and Central African populations.
abstract: BACKGROUND
  The full-length (L-) variant of caspase-12 is believed to predispose to sepsis. It has been replaced in the genome of most human populations by the (S-) variant, which leads to premature termination of translation. Strikingly, the L-allele is still widely prevalent in African populations, presumably due to a counterbalancing selective force specific to this continent, for which malaria is a prime candidate.
  
  
  METHODS
  We investigated associations between caspase-12 genotype and malarial parameters in three West-African populations, in studies encompassing immunological, clinical and obstetric data.
  
  
  RESULTS
  The caspase-12 L-allele was found at frequencies of 11-34%. Plasmodium falciparum-stimulated mononuclear cells from S/L heterozygote donors produced stronger interferon-gamma and interleukin-10 responses than S/S homozygotes (p = 0.011 and p = 0.023 in uninfected and infected donors respectively). Nevertheless, we found no association between caspase-12 genotype and either the presentation of severe malaria or individual clinical parameters in sick children. Amongst pregnant women, the caspase-12 genotype did not influence peripheral or placental malaria infection, or basic obstetric parameters. Interestingly, perinatal mortality was more frequent in children of both S/S and L/L than S/L mothers, independent of placental P. falciparum-infection.
  
  
  CONCLUSIONS
  We find little clinical or epidemiological evidence that malaria has contributed to the persistence of functional caspase-12 in Africa, suggesting either that alternative selective forces are at work or that genetic drift underlies its current global distribution.
authors.affiliation: Department of Medical Microbiology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: Matthew B B
authors.initials: MB
authors.lastname: McCall
authors.forename: Bart
authors.initials: B
authors.lastname: Ferwerda
authors.forename: Joost
authors.initials: J
authors.lastname: Hopman
authors.forename: Ivo
authors.initials: I
authors.lastname: Ploemen
authors.forename: Boubacar
authors.initials: B
authors.lastname: Maiga
authors.forename: Modibo
authors.initials: M
authors.lastname: Daou
authors.forename: Amagana
authors.initials: A
authors.lastname: Dolo
authors.forename: Cornelus C
authors.initials: CC
authors.lastname: Hermsen
authors.forename: Ogobara K
authors.initials: OK
authors.lastname: Doumbo
authors.forename: George
authors.initials: G
authors.lastname: Bedu-Addo
authors.forename: Jos W
authors.initials: JW
authors.lastname: van der Meer
authors.forename: Marita
authors.initials: M
authors.lastname: Troye-Blomberg
authors.forename: André J A M
authors.initials: AJ
authors.lastname: van der Ven
authors.forename: Ralf R
authors.initials: RR
authors.lastname: Schumann
authors.forename: Robert W
authors.initials: RW
authors.lastname: Sauerwein
authors.forename: Frank P
authors.initials: FP
authors.lastname: Mockenhaupt
authors.forename: Mihai G
authors.initials: MG
authors.lastname: Netea
mesh_terms: D000350:Africa, Central / Q000453:epidemiology; D000354:Africa, Western / Q000453:epidemiology; D000483:Alleles; D053454:Caspase 12 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005838:Genotype; D006801:Humans; D016778:Malaria, Falciparum / Q000150:complications / Q000201:enzymology / Q000453:epidemiology*; D008297:Male; D011247:Pregnancy; D015597:Pregnancy Complications, Parasitic / Q000201:enzymology / Q000453:epidemiology
chemical_list: D053454:Caspase 12