FCGR2A functional genetic variant associated with susceptibility to severe malarial anaemia in Ghanaian children
- Kathrin Schuldt1,2,3,
- Claudia Esser1,
- Jennifer Evans1,
- Jürgen May4,
- Christian Timmann1,2,
- Christa Ehmen1,
- Wibke Loag3,
- Daniel Ansong5,
- Andreas Ziegler2,
- Tsiri Agbenyega5,
- Christian G Meyer1,
- Rolf D Horstmann1
- 1Department of Molecular Medicine, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany
- 2Institute of Medical Biometry and Statistics, University at Lübeck, University Hospital Schleswig-Holstein, Campus Lübeck, Lübeck, Germany
- 3Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
- 4Infectious Disease Epidemiology Group, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany
- 5School of Medical Sciences, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana
- Correspondence to Dr Rolf Horstmann, Bernhard Nocht Institute for Tropical Medicine, Bernhard-Nocht-Str. 74, 20359 Hamburg, Germany;
Contributors Study concept and design: JE, JM, CT, TA, and RDH. Acquisition of data: JE, C Ehmen, DA, and TA. Analyses and interpretation of the data: KS, C Esser, JM, WL, AZ, and RDH. Manuscript: KS, C Esser, CGM, and RDH.
- Received 28 September 2009
- Revised 17 November 2009
- Accepted 23 November 2009
- Published Online First 3 December 2009
Background Severe malarial anaemia is a major cause of mortality from malaria. Although of enormous relevance, its pathogenesis is largely unknown. Interestingly, the extent of anaemia greatly exceeds the loss of erythrocytes due to direct destruction by the pathogen Plasmodium falciparum. Immune response against the parasite is partially mediated through the Fc receptor for immunoglobulin (Ig) G IIa (FcγRIIa, CD32). The presence of an arginine instead of a histidine residue at amino acid position 131 (H131R) in the extracellular domain of FcγRIIa reduces the affinity of the receptor for IgG2 and IgG3 isotypes but increases the binding activity for C reactive protein (CRP).
Methods In Ghana, West Africa, 2504 children with severe malaria and 2027 matched healthy controls were studied for the FcγRIIaH131R polymorphism in order to ascertain its influence on major manifestations of the disease. The study group included patients with partly overlapping symptoms of severe malaria, among them 1591 cases with severe anaemia, 562 cases with cerebral malaria, and 497 cases with other malaria complications.
Results Analyses of the genotype distributions indicated that, under a recessive model, FcγRIIa131RR was positively associated with severe malaria collectively (OR 1.20, 95% CI 1.05 to 1.38; p=0.007, pcorrected=0.021) and, after stratification for phenotypes, with severe anaemia (OR 1.33, 95% CI 1.13 to 1.57; p=0.001, pcorrected=0.009), but not with cerebral malaria (OR 1.04, 95% CI 0.82 to 1.33; p=0.733) or other malaria complications (OR 1.03, 95% CI 0.78 to 1.37; p=0.827). No association was found with levels of parasitaemia.
Conclusion The positive association with a CRP binding variant of FcγRIIa supports evidence for a role of CRP mediated defence mechanisms in the pathogenesis of severe malarial anaemia.
- Falciparum malaria
- malarial anaemia
- genetic variation
- molecular genetics
- genetic epidemiology
Funding The study was supported by the German National Genome Research Network (NGFN). The NGFN was not involved in any of the following: study design; collection, analysis and interpretation of the data; writing the report; and in the decision to submit the paper for publication.
Competing interests None.
Ethics approval This study was conducted with the approval of the Committee for Research, Publications and Ethics of the School of Medical Sciences, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana.