TY - JOUR
T1 - Persistence of full-length caspase-12 and its relation to malaria in West and Central African populations
AU - McCall, Matthew B.B.
AU - Ferwerda, Bart
AU - Hopman, Joost
AU - Ploemen, Ivo
AU - Maiga, Boubacar
AU - Daou, Modibo
AU - Dolo, Amagana
AU - Hermsen, Cornelus C.
AU - Doumbo, Ogobara K.
AU - Bedu-Addo, George
AU - Van Der Meer, Jos W.
AU - Troye-Blomberg, Marita
AU - Van Der Ven, André J.A.M.
AU - Schumann, Ralf R.
AU - Sauerwein, Robert W.
AU - Mockenhaupt, Frank P.
AU - Netea, Mihai G.
PY - 2010/6
Y1 - 2010/6
N2 - 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-γ 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. Conclusion. 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.
AB - 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-γ 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. Conclusion. 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.
KW - Caspase-12
KW - Cytokines
KW - Genetic selection
KW - P. falciparum malaria
KW - Pregnancy
UR - http://www.scopus.com/inward/record.url?scp=77953883725&partnerID=8YFLogxK
U2 - https://doi.org/10.1684/ecn.2010.0187
DO - https://doi.org/10.1684/ecn.2010.0187
M3 - Article
C2 - 20423816
SN - 1148-5493
VL - 21
SP - 77
EP - 83
JO - European Cytokine Network
JF - European Cytokine Network
IS - 2
ER -