Fry, AE and Ghansa, A and Small, KS and Palma, A and Auburn, S and Diakite, M and Green, A and Campino, S and Teo, YY and Clark, TG and Jeffreys, AE and Wilson, J and Jallow, M and Sisay-Joof, F and Pinder, M and Griffiths, MJ and Peshu, N and Williams, TN and Newton, CR and Marsh, K and Molyneux, ME and Taylor, TE and Koram, KA and Oduro, AR and Rogers, WO and Rockett, KA and Sabeti, PC and Kwiatkowski, DP (2009) Positive selection of a CD36 nonsense variant in sub-Saharan Africa, but no association with severe malaria phenotypes. HUM MOL GENET , 18 (14) 2683 - 2692. 10.1093/hmg/ddp192.
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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 in 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 four 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.
|Title:||Positive selection of a CD36 nonsense variant in sub-Saharan Africa, but no association with severe malaria phenotypes|
|Keywords:||PLASMODIUM-FALCIPARUM MALARIA, INTERCELLULAR-ADHESION MOLECULE-1, CELL-LINE PANEL, HUMAN GENOME, CYTOADHERENCE CHARACTERISTICS, HAPLOTYPE RECONSTRUCTION, INFECTED ERYTHROCYTES, ENDOTHELIAL-CELLS, NATURAL-SELECTION, GENOTYPE DATA|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Child Health|
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