Abstract
Original language | English |
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Article number | 3307 |
Journal | Nature communications |
Volume | 13 |
Issue number | 1 |
DOIs | |
Publication status | Published - 1 Dec 2022 |
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In: Nature communications, Vol. 13, No. 1, 3307, 01.12.2022.
Research output: Contribution to journal › Article › Academic › peer-review
TY - JOUR
T1 - The impact of malaria-protective red blood cell polymorphisms on parasite biomass in children with severe Plasmodium falciparum malaria
AU - Uyoga, S.
AU - Watson, J. A.
AU - Wanjiku, P.
AU - Rop, J. C.
AU - Makale, J.
AU - Macharia, A. W.
AU - Kariuki, S. N.
AU - Nyutu, G. M.
AU - Shebe, M.
AU - Mosobo, M.
AU - Mturi, N.
AU - Rockett, K. A.
AU - Woodrow, C. J.
AU - Dondorp, A. M.
AU - Maitland, K.
AU - White, N. J.
AU - Williams, T. N.
N1 - Funding Information: This research was funded, in whole or in part, by The Wellcome Trust, Grant 093956/Z/10/C. A CC-BY or equivalent license is applied to author accepted manuscript arising from this submission, in accordance with the grant’s open access conditions. This work was conducted as part of SMAART (Severe Malaria Africa – A consortium for Research and Trials) funded by a Wellcome Collaborative Award in Science grant (209265/Z/17/Z) held in part by K.M. and A.M.D. Sample genotyping was conducted in part by the Malaria Genomic Epidemiology Network, supported by Wellcome (WT077383/Z/05/Z) and the Bill & Melinda Gates Foundation through the Foundations of the National Institutes of Health (566) as part of the Grand Challenges in Global Health Initiative. The Resource Centre for Genomic Epidemiology of Malaria is supported by Wellcome (090770/Z/09/Z; 204911/Z/16/Z). This research was supported by the Medical Research Council (G0600718; G0600230; MR/M006212/1). Wellcome also provides core awards to the Wellcome Centre for Human Genetics (203141/Z/16/Z) and the Wellcome Sanger Institute (206194). Sample collection and processing was further supported through a Programme Grant (092654) to the Kilifi Programme from Wellcome. T.N.W. and N.J.W. are senior and principal research fellows respectively, funded by the Wellcome Trust (202800/Z/16/Z and 093956/Z/10/C, respectively). J.A.W. is a Sir Henry Dale Fellow funded by the Wellcome Trust (223253/Z/21/Z). This paper is published with permission from the Director of the Kenya Medical Research Institute (KEMRI). Funding Information: This research was funded, in whole or in part, by The Wellcome Trust, Grant 093956/Z/10/C. A CC-BY or equivalent license is applied to author accepted manuscript arising from this submission, in accordance with the grant’s open access conditions. This work was conducted as part of SMAART (Severe Malaria Africa – A consortium for Research and Trials) funded by a Wellcome Collaborative Award in Science grant (209265/Z/17/Z) held in part by K.M. and A.M.D. Sample genotyping was conducted in part by the Malaria Genomic Epidemiology Network, supported by Wellcome (WT077383/Z/05/Z) and the Bill & Melinda Gates Foundation through the Foundations of the National Institutes of Health (566) as part of the Grand Challenges in Global Health Initiative. The Resource Centre for Genomic Epidemiology of Malaria is supported by Wellcome (090770/Z/09/Z; 204911/Z/16/Z). This research was supported by the Medical Research Council (G0600718; G0600230; MR/M006212/1). Wellcome also provides core awards to the Wellcome Centre for Human Genetics (203141/Z/16/Z) and the Wellcome Sanger Institute (206194). Sample collection and processing was further supported through a Programme Grant (092654) to the Kilifi Programme from Wellcome. T.N.W. and N.J.W. are senior and principal research fellows respectively, funded by the Wellcome Trust (202800/Z/16/Z and 093956/Z/10/C, respectively). J.A.W. is a Sir Henry Dale Fellow funded by the Wellcome Trust (223253/Z/21/Z). This paper is published with permission from the Director of the Kenya Medical Research Institute (KEMRI). Publisher Copyright: © 2022, The Author(s).
PY - 2022/12/1
Y1 - 2022/12/1
N2 - Severe falciparum malaria is a major cause of preventable child mortality in sub-Saharan Africa. Plasma concentrations of P. falciparum Histidine-Rich Protein 2 (PfHRP2) have diagnostic and prognostic value in severe malaria. We investigate the potential use of plasma PfHRP2 and the sequestration index (the ratio of PfHRP2 to parasite density) as quantitative traits for case-only genetic association studies of severe malaria. Data from 2198 Kenyan children diagnosed with severe malaria, genotyped for 14 major candidate genes, show that polymorphisms in four major red cell genes that lead to hemoglobin S, O blood group, α-thalassemia, and the Dantu blood group, are associated with substantially lower admission plasma PfHRP2 concentrations, consistent with protective effects against extensive parasitized erythrocyte sequestration. In contrast the known protective ATP2B4 polymorphism is associated with higher plasma PfHRP2 concentrations, lower parasite densities and a higher sequestration index. We provide testable hypotheses for the mechanism of protection of ATP2B4.
AB - Severe falciparum malaria is a major cause of preventable child mortality in sub-Saharan Africa. Plasma concentrations of P. falciparum Histidine-Rich Protein 2 (PfHRP2) have diagnostic and prognostic value in severe malaria. We investigate the potential use of plasma PfHRP2 and the sequestration index (the ratio of PfHRP2 to parasite density) as quantitative traits for case-only genetic association studies of severe malaria. Data from 2198 Kenyan children diagnosed with severe malaria, genotyped for 14 major candidate genes, show that polymorphisms in four major red cell genes that lead to hemoglobin S, O blood group, α-thalassemia, and the Dantu blood group, are associated with substantially lower admission plasma PfHRP2 concentrations, consistent with protective effects against extensive parasitized erythrocyte sequestration. In contrast the known protective ATP2B4 polymorphism is associated with higher plasma PfHRP2 concentrations, lower parasite densities and a higher sequestration index. We provide testable hypotheses for the mechanism of protection of ATP2B4.
UR - http://www.scopus.com/inward/record.url?scp=85131647062&partnerID=8YFLogxK
U2 - https://doi.org/10.1038/s41467-022-30990-5
DO - https://doi.org/10.1038/s41467-022-30990-5
M3 - Article
C2 - 35676275
SN - 2041-1723
VL - 13
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 3307
ER -