Persistence of full-length caspase-12 and its relation to malaria in West and Central African populations.
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.
McCall
Matthew B B
MB
Department of Medical Microbiology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Ferwerda
Bart
B
Hopman
Joost
J
Ploemen
Ivo
I
Maiga
Boubacar
B
Daou
Modibo
M
Dolo
Amagana
A
Hermsen
Cornelus C
CC
Doumbo
Ogobara K
OK
Bedu-Addo
George
G
van der Meer
Jos W
JW
Troye-Blomberg
Marita
M
van der Ven
André J A M
AJ
Schumann
Ralf R
RR
Sauerwein
Robert W
RW
Mockenhaupt
Frank P
FP
Netea
Mihai G
MG
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
D053454:Caspase 12