Reappraisal of known malaria resistance loci in a large multicenter study


Rockett, KA; Clarke, GM; Fitzpatrick, K; Hubbart, C; Jeffreys, AE; Rowlands, K; Craik, R; Jallow, M; Conway, DJ; Bojang, KA; Pinder, M; Usen, S; Sisay-Joof, F; Sirugo, G; Toure, O; Thera, MA; Konate, S; Sissoko, S; Niangaly, A; Poudiougou, B; Mangano, VD; Bougouma, EC; Sirima, SB; Modiano, D; Amenga-Etego, LN; Ghansah, A; Koram, KA; Wilson, MD; Enimil, A; Evans, J; Amodu, O; Olaniyan, S; Apinjoh, T; Mugri, R; Ndi, A; Ndila, CM; Uyoga, S; Macharia, A; Peshu, N; Williams, TN; Manjurano, A; Riley, E; Drakeley, C; Reyburn, H; Nyirongo, V; Kachala, D; Molyneux, M; Dunstan, SJ; Nguyen Hoan, P; Nguyen Thi Ngoc, Q; Cao Quang, T; Tran Tinh, H; Manning, L; Laman, M; Siba, P; Karunajeewa, H; Allen, S; Allen, A; Davis, TME; Michon, P; Mueller, I; Green, A; Molloy, S; Johnson, KJ; Kerasidou, A; Cornelius, V; Hart, L; Vanderwal, A; Sanjoaquin, M; Band, G; le, SQ; Pirinen, M; Sepulveda, N; Spencer, CCA; Clark, TG; Agbenyega, T; Achidi, E; Doumbo, O; Farrar, J; Marsh, K; Taylor, T; Kwiatkowski, DP; Malaria Genomic Epidemiology, N; (2014) Reappraisal of known malaria resistance loci in a large multicenter study. Nature genetics, 46 (11). pp. 1197-1204. ISSN 1061-4036 DOI: 10.1038/ng.3107

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Abstract

Many human genetic associations with resistance to malaria have been reported, but few have been reliably replicated. We collected data on 11,890 cases of severe malaria due to Plasmodium falciparum and 17,441 controls from 12 locations in Africa, Asia and Oceania. We tested 55 SNPs in 27 loci previously reported to associate with severe malaria. There was evidence of association at P < 1 x 10(-4) with the HBB, ABO, ATP2B4, G6PD and CD40LG loci, but previously reported associations at 22 other loci did not replicate in the multicenter analysis. The large sample size made it possible to identify authentic genetic effects that are heterogeneous across populations or phenotypes, with a striking example being the main African form of G6PD deficiency, which reduced the risk of cerebral malaria but increased the risk of severe malarial anemia. The finding that G6PD deficiency has opposing effects on different fatal complications of P. falciparum infection indicates that the evolutionary origins of this common human genetic disorder are more complex than previously supposed.

Item Type: Article
Faculty and Department: Faculty of Infectious and Tropical Diseases > Dept of Pathogen Molecular Biology
Faculty of Infectious and Tropical Diseases > Dept of Immunology and Infection
Faculty of Infectious and Tropical Diseases > Dept of Disease Control
Faculty of Epidemiology and Population Health > Dept of Non-Communicable Disease Epidemiology
Faculty of Epidemiology and Population Health > Dept of Infectious Disease Epidemiology
Faculty of Epidemiology and Population Health > Dept of Population Health (2012- ) > Dept of Nutrition and Public Health Interventions Research (2003-2012)
Faculty of Epidemiology and Population Health > Dept of Population Health (2012- )
Faculty of Public Health and Policy > Dept of Health Services Research and Policy
Research Centre: Malaria Centre
Antimicrobial Resistance Centre (AMR)
PubMed ID: 25261933
Web of Science ID: 344131900010
URI: http://researchonline.lshtm.ac.uk/id/eprint/2026651

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