title: Positive selection of a CD36 nonsense variant in sub-Saharan Africa, but no association with severe malaria phenotypes.
abstract: 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.
authors.affiliation: Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford OX3 7BN, UK. afry@well.ox.ac.uk
authors.forename: Andrew E
authors.initials: AE
authors.lastname: Fry
authors.forename: Anita
authors.initials: A
authors.lastname: Ghansa
authors.forename: Kerrin S
authors.initials: KS
authors.lastname: Small
authors.forename: Alejandro
authors.initials: A
authors.lastname: Palma
authors.forename: Sarah
authors.initials: S
authors.lastname: Auburn
authors.forename: Mahamadou
authors.initials: M
authors.lastname: Diakite
authors.forename: Angela
authors.initials: A
authors.lastname: Green
authors.forename: Susana
authors.initials: S
authors.lastname: Campino
authors.forename: Yik Y
authors.initials: YY
authors.lastname: Teo
authors.forename: Taane G
authors.initials: TG
authors.lastname: Clark
authors.forename: Anna E
authors.initials: AE
authors.lastname: Jeffreys
authors.forename: Jonathan
authors.initials: J
authors.lastname: Wilson
authors.forename: Muminatou
authors.initials: M
authors.lastname: Jallow
authors.forename: Fatou
authors.initials: F
authors.lastname: Sisay-Joof
authors.forename: Margaret
authors.initials: M
authors.lastname: Pinder
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Griffiths
authors.forename: Norbert
authors.initials: N
authors.lastname: Peshu
authors.forename: Thomas N
authors.initials: TN
authors.lastname: Williams
authors.forename: Charles R
authors.initials: CR
authors.lastname: Newton
authors.forename: Kevin
authors.initials: K
authors.lastname: Marsh
authors.forename: Malcolm E
authors.initials: ME
authors.lastname: Molyneux
authors.forename: Terrie E
authors.initials: TE
authors.lastname: Taylor
authors.forename: Kwadwo A
authors.initials: KA
authors.lastname: Koram
authors.forename: Abraham R
authors.initials: AR
authors.lastname: Oduro
authors.forename: William O
authors.initials: WO
authors.lastname: Rogers
authors.forename: Kirk A
authors.initials: KA
authors.lastname: Rockett
authors.forename: Pardis C
authors.initials: PC
authors.lastname: Sabeti
authors.forename: Dominic P
authors.initials: DP
authors.lastname: Kwiatkowski
mesh_terms: D017954:Africa South of the Sahara / Q000453:epidemiology / Q000208:ethnology; D044383:Black People / Q000208:ethnology / Q000235:genetics*; D018955:CD36 Antigens / Q000235:genetics*; D016022:Case-Control Studies; D018389:Codon, Nonsense; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008288:Malaria / Q000453:epidemiology / Q000208:ethnology / Q000235:genetics* / Q000473:pathology; D008297:Male; D010375:Pedigree; D012641:Selection, Genetic; D012720:Severity of Illness Index
chemical_list: D018955:CD36 Antigens; D018389:Codon, Nonsense