Abstract
Malaria causes approximately one million fatalities per year, mostly among African children1. Although highlighted by the strong protective effect of the sickle-cell trait2,3, the full impact of human genetics on resistance to the disease remains largely unexplored4. Genome-wide association (GWA) studies are designed to unravel relevant genetic variants comprehensively; however, in malaria, as in other infectious diseases, these studies have been only partly successful5. Here we identify two previously unknown loci associated with severe falciparum malaria in patients and controls from Ghana, West Africa. We applied the GWA approach to the diverse clinical syndromes of severe falciparum malaria, thereby targeting human genetic variants influencing any step in the complex pathogenesis of the disease. One of the loci was identified on chromosome 1q32 within the ATP2B4 gene, which encodes the main calcium pump of erythrocytes6, the host cells of the pathogenic stage of malaria parasites. The second was indicated by an intergenic single nucleotide polymorphism on chromosome 16q22.2, possibly linked to a neighbouring gene encoding the tight-junction protein MARVELD3. The protein is expressed on endothelial cells7 and might therefore have a role in microvascular damage caused by endothelial adherence of parasitized erythrocytes. We also confirmed previous reports on protective effects of the sickle-cell trait and blood group O5,8,9. Our findings underline the potential of the GWA approach to provide candidates for the development of control measures against infectious diseases in humans.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 51 print issues and online access
$199.00 per year
only $3.90 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Murray, C. J. L. et al. Global malaria mortality between 1980 and 2010: a systematic analysis. Lancet 379, 413–431 (2012)
Miller, L. H., Baruch, D. I., Marsh, K. & Doumbo, O. K. The pathogenic basis of malaria. Nature 415, 673–679 (2002)
Idro, R., Marsh, K., John, C. C. & Newton, C. R. Cerebral malaria: mechanisms of brain injury and strategies for improved neurocognitive outcome. Pediatr. Res. 68, 267–274 (2010)
Mackinnon, M. J., Mwangi, T. W., Snow, R. W., Marsh, K. & Williams, T. N. Heritability of malaria in Africa. PLoS Med. 12, e340 (2005)
Jallow, M. et al. Genome-wide and fine-resolution association analysis of malaria in West Africa. Nature Genet. 41, 657–665 (2009)
Stauffer, T. P., Guerini, D. & Carafoli, E. Tissue distribution of the four gene products of the plasma membrane Ca2+ pump. A study using specific antibodies. J. Biol. Chem. 270, 12184–12190 (1995)
Steed, E., Rodrigues, N. T., Balda, M. S. & Matter, K. Identification of MarvelD3 as a tight junction-associated transmembrane protein of the occludin family. BMC Cell Biol. 10, 95 (2009)
Kwiatkowski, D. P. How malaria has affected the human genome and what human genetics can teach us about malaria. Am. J. Hum. Genet. 77, 171–192 (2005)
May, J. et al. Hemoglobin variants and disease manifestations in severe falciparum malaria. J. Am. Med. Assoc. 297, 2220–2226 (2007)
World Health Organization. Communicable diseases cluster: severe falciparum malaria. Trans. R. Soc. Trop. Med. Hyg. 94 (suppl. 1). S1–S90 (2000)
Marsh, K. et al. Indicators of life-threatening malaria in African children. N. Engl. J. Med. 332, 1399–1404 (1995)
Pe’er, I., Yelensky, R., Altshuler, D. & Daly, M. J. Estimation of the multiple testing burden for genomewide association studies of nearly all common variants. Genet. Epidemiol. 32, 381–385 (2008)
Hindorff, L. A. et al. Potential etiologic and functional implications of genome-wide association loci for human diseases and traits. Proc. Natl Acad. Sci. USA 106, 9362–9367 (2009)
Brini, M. & Carafoli, E. Calcium pumps in health and disease. Physiol. Rev. 89, 1341–1378 (2009)
Gazarini, M. L., Thomas, A. P., Pozzan, T. & Garcia, C. R. Calcium signaling in a low calcium environment: how the intracellular malaria parasite solves the problem. J. Cell Biol. 161, 103–110 (2003)
Szewczyk, M. M. et al. Ca2+-pumps and Na2+–Ca2+-exchangers in coronary artery endothelium versus smooth muscle. J. Cell. Mol. Med. 11, 129–138 (2007)
Varga-Szabo, D., Braun, A. & Nieswandt, B. Calcium signaling in platelets. J. Thromb. Haemost. 7, 1057–1066 (2009)
McMorran, B. J. et al. Platelets kill intraerythrocytic malarial parasites and mediate survival to infection. Science 323, 797–800 (2009)
Bridges, D. J. et al. Rapid activation of endothelial cells enables Plasmodium falciparum adhesion to platelet-decorated von Willebrand factor strings. Blood 115, 1472–1474 (2010)
Wassmer, S. C., Cianciolo, G. J., Combes, V. & Grau, G. E. Inhibition of endothelial activation: a new way to treat cerebral malaria? PLoS Med. 2, e245 (2005)
Cinel, I. & Dellinger, R. P. Advances in pathogenesis and management of sepsis. Curr. Opin. Infect. Dis. 20, 345–352 (2007)
Loscertales, M. et al. ABO blood group phenotypes and Plasmodium falciparum malaria: unlocking a pivotal mechanism. Adv. Parasitol. 65, 2–41 (2007)
Fry, A. E. et al. Common variation in the ABO glycosyltransferase is associated with susceptibility to severe Plasmodium falciparum malaria. Hum. Mol. Genet. 17, 567–576 (2008)
Editorial Are genome-wide association studies of infection any value? Lancet Infect. Dis. 10, 577 (2010)
de Bakker, P. I. & Telenti, A. Infectious diseases not immune to genome-wide association. Nature Genet. 42, 731–732 (2010)
Molyneux, M. E., Taylor, T. E., Wirima, J. J. & Borgstein, A. Clinical features and prognostic indicators in paediatric cerebral malaria: a study of 131 comatose Malawian children. Q. J. Med. 71, 441–459 (1989)
Purcell, S. et al. PLINK: a toolset for whole-genome association and population-based linkage analysis. Am. J. Hum. Genet. 81, 559–575 (2007)
Acknowledgements
We thank the participating children, their parents and guardians; L. N. Badu, S. Opoku, M. Attan-Ayibo and D. Sambian for technical assistance. Ethical approval was obtained from the Committee for Research, Publications and Ethics of the School of Medical Sciences, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana. Informed consent was obtained from the parents or guardians of the children and documented by signature, or thumbprint in cases of illiteracy. The study complied with the Ethical Principles for Medical Research Involving Human Subjects as laid out in the Declaration of Helsinki. The study was supported by the National Genome Research Network (NGFN1, NGFN2) of the German Ministry for Education and Research (BMBF). In addition, this study makes use of data generated by MalariaGEN5. A full list of the investigators who contributed to the generation of the data is available from http://www.malariagen.net. The MalariaGEN Project is supported by the Wellcome Trust (WT077383/Z/05/Z) and by the Foundation for the National Institutes of Health (566) as part of the Bill & Melinda Gates’ Grand Challenges in Global Health Initiative.
Author information
Authors and Affiliations
Contributions
R.D.H., C.T. and A.Z. designed the study. C.T., R.D.H., C.G.M., A.Z. and T.T. drafted the manuscript. D.A., S.A., E.A.A., S.B.N., K.O.K., A.O.Y.A., J.Sy., W.L., J.E. and J.M. recruited cases and controls and acquired materials. C.E., J.Si., B.M. and G.R. performed resequencing and SNP genotyping. T.T., C.T., M.B., M.V., K.S., C.L., A.Z., J.M. and R.D.H. calculated the statistical analysis and/or interpreted data. R.D.H. and A.Z. obtained funding. J.E., T.A., J.M. and A.F. provided administrative, technical or material support. R.D.H., A.Z. and T.A. supervised the study.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Additional information
Genetic variants identified by Sanger-based resequencing at the ATP2B4 and MARVELD3 loci are deposited in dbSNP (see Supplementary Table 5).
Supplementary information
Supplementary Information
This file contains Supplementary Text, Supplementary Figures 1-4, Supplementary Tables 1-5 and Supplementary References. (PDF 1013 kb)
PowerPoint slides
Rights and permissions
About this article
Cite this article
Timmann, C., Thye, T., Vens, M. et al. Genome-wide association study indicates two novel resistance loci for severe malaria. Nature 489, 443–446 (2012). https://doi.org/10.1038/nature11334
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/nature11334
This article is cited by
-
ATP2B4 regulatory genetic variants are associated with mild malaria
Malaria Journal (2023)
-
Genetic variations in human ATP2B4 gene alter Plasmodium falciparum in vitro growth in RBCs from Gambian adults
Malaria Journal (2023)
-
Identifying signatures of positive selection in human populations from North Africa
Scientific Reports (2023)
-
A robust fluorescence-based assay for human erythrocyte Ca++ efflux suitable for high-throughput inhibitor screens
European Biophysics Journal (2023)
-
Treatment with specific and pan-plasma membrane calcium ATPase (PMCA) inhibitors reduces malaria parasite growth in vitro and in vivo
Malaria Journal (2022)
Comments
By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.
