Browsing by Author "Peshu, N."
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Item Association of the GNAS locus with severe malaria. Human Genetics,(2008) Auburn, S.; Diakite, M.; Fry, A.E.; Ghansah, A.; Campino, S.; Richardson, A.; Jallow, M.; Sisay-Joof, F.; Pinder, M.; Griffiths, M.J.; Peshu, N.; William, T.N.; Marsh, K.; Molyneux, M.E.; Taylor, T.E.; Koram, K.A.; Oduro, A.R.; Rogers, W.O.; Rockett, K.A.; Halder, K.; Kwiatkowski, D.P.Functional studies have demonstrated an interaction between the stimulatory G protein alpha subunit (G-alpha-s) and the malaria parasite at a cellular level. Obstruction of signal transduction via the erythrocyte G-alpha-s subunit reduced invasion by Plasmodium falciparum parasites. We sought to determine whether this signal pathway had an impact at the disease level by testing polymorphisms in the gene encoding G-alpha-s (GNAS) for association with severe malaria in a large multi-centre study encompassing family and case - control studies from The Gambia, Kenya and Malawi, and a case - control study from Ghana. We gained power to detect association using meta-analysis across the seven studies, with an overall sample size approximating 4,000 cases and 4,000 controls. Out of 12 SNPs investigated in the 19 kb GNAS region, four presented signals of association (P < 0.05) with severe malaria. The strongest single-locus association demonstrated an odds ratio of 1.13 (1.05-1.21), P = 0.001. Three of the loci presenting significant associations were clustered at the 5-prime end of the GNAS gene. Accordingly, haplotypes constructed from these loci demonstrated significant associations with severe malaria [OR = 0.88 (0.81-0.96), P = 0.005 and OR = 1.12 (1.03-1.20), P = 0.005]. The evidence presented here indicates that the influence of G-alpha-s on erythrocyte invasion efficacy may, indeed, alter individual susceptibility to disease. © Springer-Verlag 2008.Item Ethics: Fair benefits for research in developing countries: Participants in the 2001 conference on ethical aspects of research in developing countries.(2002-12-13) El Setouhy, M.; Agbenyega, T.; Anto, F.; Clerk, C.A.; Koram, K.A.; English, M.; Molyneux, C.; Peshu, N.; Juma, R.; Kumwend, N.; Mfutso-Bengu, J.; Molyneux, M.; Taylor, T.; Diarra, D.A.; Maiga, S.; Sylla, M.; Youssouf, D.; Falade, C.O.; Gbadegesin, S.; Lie, R.; Mugusi, F.; Ngassapa, D.; Ecuru, J.; Talisuna, A.; Emanuel, E.; Grady, C.; Wendler, D.; Higgs, E.; Plowe, C.; Sugarman, J.Item The Malaria Genomic Epidemiology Network. A global network for investigating the genomic epidemiology of malaria(Nature 456(7223): 732-7, 2008) Achidi, E.A.; Agbenyega, T.; Allen, S.; Amodu, O.; Bojang, K.; Conway, D.; Corran, P.; Deloukas, P.; Djimde, A.; Dolo, A.; Doumbo, O.; Drakeley, C.; Duffy, P.; Dunstan, S.; Evans, J.; Farrar, J.; Fernando, D.; Tran, T.H.; Horstmann, R.; Ibrahim, M.; Karunaweera, N.; Kokwaro, G.; Koram, K.; Kwiatkowski, D.; Lemnge, M.; Makani, J.; Marsh, K.; Michon, P.; Modiano, D.; Molyneux, M.E.; Mueller, I.; Mutabingwa, T.; Parker, M.; Peshu, N.; Plowe, C.; Puijalon, O.; Ragoussis, J.; Reeder, J.; Reyburn, H.; Riley, E.; Rogers, J.; Wilson, M.; Ghansah, A.Large-scale studies of genomic variation could assist efforts to eliminate malaria. But there are scientific, ethical and practical challenges to carrying out such studies in developing countries, where the burden of disease is greatest. The Malaria Genomic Epidemiology Network (MalariaGEN) is now working to overcome these obstacles, using a consortial approach that brings together researchers from 21 countries.Item An open dataset of Plasmodium falciparum genome variation in 7,000 worldwide samples(2021) MalariaGEN; Ahouidi, A.; Ali, M.; Almagro-Garcia, J.; Amambua-Ngwa, A.; Amaratunga, C.; Amato, R.; Amenga-Etego, L.; Andagalu, B.; Anderson, T.J.C.; Andrianaranjaka, V.; Apinjoh, T.; Ariani, C.; Ashley, E.A.; Auburn, S.; Awandare, G.A.; Ba, H.; Baraka, V.; Barry, A.E.; Bejon, P.; Bertin, G.I.; Boni, M.F.; Borrmann, S.; Bousema, T.; Branch, O.; Bull, P.C.; Busby, G.B.J.; Chookajorn, T.; Chotivanich, K.; Claessens, A.; Conway, D.; Craig, A.; D'Alessandro, U.; Dama, S.; Day, N.P.J.; Denis, B.; Diakite, M.; Djimdé, A.; Dolecek, C.; Dondorp, A.M.; Drakeley, C.; Drury, E.; Duffy, P.; Echeverry, D.F.; Egwang, T.G.; Erko, B.; Fairhurst, R.M.; Faiz, A.; Fanello, C.A.; Fukuda, M.M.; Gamboa, D.; Ghansah, A.; Golassa, L.; Goncalves, S.; Hamilton, W.L.; Harrison, G.L.A.; Hart, L.; Henrichs, C.; Hien, T.T.; Hill, C.A.; Hodgson, A.; Hubbart, C.; Imwong, M.; Ishengoma, D.S.; Jackson, S.A.; Jacob, C.G.; Jeffery, B.; Jeffreys, A.E.; Johnson, K.J.; Jyothi, D.; Kamaliddin, C.; Kamau, E.; Kekre, M.; Kluczynski, K.; Kochakarn, T.; Konaté, A.; Kwiatkowski, D.P.; Kyaw, M.P.; Lim, P.; Lon, C.; Loua, K.M.; Maïga-Ascofaré, O.; Malangone, C.; Manske, M.; Marfurt, J.; Marsh, K.; Mayxay, M.; Miles, A.; Miotto, O.; Mobegi, V.; Mokuolu, O.A.; Montgomery, J.; Mueller, I.; Newton, P.N.; Nguyen, T.; Nguyen, T.; Noedl, H.; Nosten, F.; Noviyanti, R.; Nzila, A.; Ochola-Oyier, L.I.; Ocholla, H.; Oduro, A.; Omedo, I.; Onyamboko, M.A.; Ouedraogo, J.; Oyebola, K.; Pearson, R.D.; Peshu, N.; Phyo, A.P.; Plowe, C.V.; Price, R.N.; Pukrittayakamee, S.; Randrianarivelojosia, M.; Rayner, J.C.; Ringwald, P.; Rockett, K.A.; Rowlands, K.; Ruiz, L.; Saunders, D.; Shayo, A.; Siba, P.; Simpson, V.J.; Stalker, J.; Su, X.; Sutherland, C.; Takala-Harrison, S.; Tavul, L.; Thathy, V.; Tshefu, A.; Verra, F.; Vinetz, J.; Wellems, T.E.; Wendler, J.; White, N.J.; Wright, I.; Yavo, W.; Ye, H.MalariaGEN is a data-sharing network that enables groups around the world to work together on the genomic epidemiology of malaria. Here we describe a new release of curated genome variation data on 7,000 Plasmodium falciparum samples from MalariaGEN partner studies in 28 malaria-endemic countries. High-quality genotype calls on 3 million single nucleotide polymorphisms (SNPs) and short indels were produced using a standardised analysis pipeline. Copy number variants associated with drug resistance and structural variants that cause failure of rapid diagnostic tests were also analysed. Almost all samples showed genetic evidence of resistance to at least one antimalarial drug, and some samples from Southeast Asia carried markers of resistance to six commonly-used drugs. Genes expressed during the mosquito stage of the parasite life-cycle are prominent among loci that show strong geographic differentiation. By continuing to enlarge this open data resource we aim to facilitate research into the evolutionary processes affecting malaria control and to accelerate development of the surveillance toolkit required for malaria elimination.Item Positive selection of a CD36 nonsense variant in sub-saharan Africa, but no association with severe malaria phenotypes(2009) Fry, A.E.; Ghansa, A.; Small, K. S.; Palma, A.; Auburn, S.; Diakite, M.; Green, A.; Campino, S.; Teo, Y.Y.; Clarke, T.G.; Jeffreys, A.E.; Wilson, J.; Jallow, M.; Sisay-Joof, F.; Pinder, M.; Griffiths, M.J.; Peshu, N.; William, T.N.; Newton, C.R.; Marsh, K.; Molyneux, M.E.; Taylor, T.E.; Koram, K.A.; Oduro, A.R.; Roger, W.O.; Rockett, K.A.; Sabeti, P.C.; Kwiatkowski, D.P.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. © 2009 The Author(s).