Open Access

ARTICLE

Persistence of full-length caspase-12 and its relation to malaria in West and Central African populations

Matthew B. B. McCall^1,*, Bart Ferwerda^2,*, Joost Hopman¹, Ivo Ploemen¹, Boubacar Maiga³, Modibo Daou³, Amagana Dolo³, Cornelus C. Hermsen¹, Ogobara K. Doumbo³, George Bedu-Addo⁴, Jos W. van der Meer², Marita Troye-Blomberg⁵, André J. A. M. van der Ven², Ralf R. Schumann⁶, Robert W. Sauerwein¹, Frank P. Mockenhaupt⁷, Mihai G. Netea²

1 Department of Medical Microbiology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
2 Department of General Internal Medicine, 463, Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands
3 Malaria Research and Training Centre, Faculty of Medicine, University of Bamako, Bamako, Mali
4 School of Medical Sciences, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana
5 Wenner-Grenn Institute of Immunology, Stockholm University, Stockholm, Sweden
6 Institute of Microbiology and Hygiene, Charité – University Medical Center, Berlin, Germany
7 Institute of Tropical Medicine and International Health, Charité – University Medical Center, Berlin, Germany

* Corresponding Author: M. Netea,

European Cytokine Network 2010, 21(2), 77-83. https://doi.org/10.1684/ecn.2010.0187

Accepted 31 March 2010;

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-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.

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