Human Molecular Genetics Advance Access published online on April 29, 2009
Human Molecular Genetics, doi:10.1093/hmg/ddp192
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Positive selection of a CD36 nonsense variant in sub-Saharan Africa, but no association with severe malaria phenotypes
,11 The Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford, OX3 7BN, UK 2 Noguchi Memorial Institute for Medical Research, P. O. Box LG581, Legon-Accra, Ghana 3 Broad Institute, Cambridge, Massachusetts, 02142, USA 4 Wellcome Trust Genome Campus, Hinxton, Cambridge, CB10 1SA, UK 5 Medical Research Council, PO Box 273, Banjul, he Gambia. 6 Kenya Medical Research Institute Centre for Geographical Medicine Research (Coast), P.O. Box 230, Kilifi, Kenya 7 Nuffield Department of Medicine, John Radcliffe Hospital, Oxford OX3 9DS, UK 8 Institute of Child Health, University College of London, London WC1 N 1EH 9 Malawi–Liverpool–Wellcome Trust Programme of Clinical Tropical Research, PO Box 30096, Blantyre, Malawi 10 Liverpool School of Tropical Medicine, Pembroke Place, Liverpool, L3 5QA, UK 11 Blantyre Malaria Project, College of Medicine, PO Box 30096, Blantyre, Malawi 12 Department of Internal Medicine, College of Osteopathic Medicine, Michigan State University, East Lansing, Michigan, 48824, USA 13 Navrongo Health Research Centre, P.O. Box 114, Navrongo, Ghana 14 Naval Medical Research Unit #2, Jakarta, Indonesia 15 Center for Systems Biology, Department of Organismic and Evolutionary Biology, Harvard University, Cambridge, Massachusetts, 02138, USA
* To whom correspondence should be addressed at: The Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford, OX3 7BN, UK. Tel: +441865287536, Fax: +441865287533, Email: afry{at}well.ox.ac.uk
Received December 15, 2008; Revised April 18, 2009; Accepted April 27, 2009
The prevalence of CD36 deficiency in East Asian and African populations suggests that the causal variants are under selection by severe malaria. Previous analysis of data from the International HapMap Project indicated that a CD36 haplotype bearing a nonsense mutation (T1264G; rs3211938) had undergone recent positive selection in the Yoruba of Nigeria. To investigate the global distribution of this putative selection event we genotyped T1264G in 3420 individuals from 66 populations. We confirmed the high frequency of 1264G in the Yoruba (26%). However, the 1264G allele is less common in other African populations and absent from all non-African populations without recent African admixture. Using long-range linkage disequilibrium we studied two West African groups in depth. Evidence for recent positive selection at the locus was demonstrable in the Yoruba, although not Gambians. We screened 70 variants from across CD36 for an association with severe malaria phenotypes, employing a case-control study of 1350 subjects, and a family study of 1288 parent-offspring trios. No marker was significantly associated with severe malaria. We focused on T1264G, genotyping 10,922 samples from 4 African populations. The nonsense allele was not associated with severe malaria (pooled allelic odds ratio, 1.0; 95% confidence interval, 0.89 – 1.12; P=0.98). These results suggest a range of possible explanations including the existence of alternative selection pressures on CD36, co-evolution between host and parasite, or confounding caused by allelic heterogeneity of CD36 deficiency.
Deceased