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1. Plasmodium malariae structure and genetic diversity in sub-Saharan Africa determined from microsatellite variants and linked SNPs in orthologues of antimalarial resistance genes

Author

Eniyou C. Oriero, Martha A. Demba, Mouhamadou F. Diop, Deus S. Ishengoma, Lucas N. Amenga-Etego, Anita Ghansah, Tobias Apinjoh, Soulama Issiaka, Abdoulaye Djimde, Umberto D’Alessandro, Martin Meremikwu, and Alfred Amambua-Ngwa

Subjects
Medicine, Science
Abstract

Abstract Plasmodium malariae, a neglected human malaria parasite, contributes up to 10% of malaria infections in sub-Saharan Africa (sSA). Though P. malariae infection is considered clinically benign, it presents mostly as coinfections with the dominant P. falciparum. Completion of its reference genome has paved the way to further understand its biology and interactions with the human host, including responses to antimalarial interventions. We characterized 75 P. malariae isolates from seven endemic countries in sSA using highly divergent microsatellites. The P. malariae infections were highly diverse and five subpopulations from three ancestries (independent of origin of isolates) were determined. Sequences of 11 orthologous antimalarial resistance genes, identified low frequency single nucleotide polymorphisms (SNPs), strong linkage disequilibrium between loci that may be due to antimalarial drug selection. At least three sub-populations were detectable from a subset of denoised SNP data from mostly the mitochondrial cytochrome b coding region. This evidence of diversity and selection calls for including P. malariae in malaria genomic surveillance towards improved tools and strategies for malaria elimination.

Published
2022
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2. Pf7: an open dataset of Plasmodium falciparum genome variation in 20,000 worldwide samples [version 1; peer review: 2 approved]

Author

Mohamed Hassan Abdelraheem, Sonia Goncalves, Lemu Golassa, Tim Anderson, Desmond Omane Acheampong, Enoch Aninagyei, Ifeyinwa Aniebo, Patrick O Ansah, Felix Ansah, Gordon A Awandare, Paulo Arnaldo, Maciej F Boni, Gwladys I Bertin, Peter C Bull, Marielle Bouyou-Akotet, Keobouphaphone Chindavongsa, Edwin Kamau, Huch Cheah, Claire Kamaliddin, Vladimir Corredor, David J Conway, Nicholas Day, Abibatou Konaté, Erin Courtier, Theerarat Kochakarn, Arjen Dondorp, Abdoulaye Djimde, Diego F Echeverry, Seydou Doumbia, Mara Lawniczak, Pharath Lim, Sonia Maria Mauricio Enosse, Oumou Maïga-Ascofaré, Thomas G Egwang, Aung Myint Thu, Mark Fleharty, Jutta Marfurt, Caterina A Fanello, Mark Fukuda, Victor Mobegi, Matthew Forbes, Sara Anne Healy, G L Abby Harrison, Anastasia Hernandez-Koutoucheva, Jason A Hendry, Ivo Mueller, Francis Hombhanje, Harald Noedl, Catherine A Hill, Thuy-Nhien Nguyen, Mazza Hussein, Amanda Hott, Rintis Noviyanti, Scott A Jackson, Abraham Oduro, Deus Ishengoma, Harold Ocholla, Julia Jeans, Jean-Bosco Ouedraogo, Chris G Jacob, Drissa S Konate, Jon Keatley, Francois Nosten, Kolapo Oyebola, Myat P Kyaw, Aminatou Kone, Norbert Peshu, Samuel K Lee, Dennis Kyle, Kovana M Loua, Milijaona Randrianarivelojosia, Martha Lemnge, Sasithon Pukrittayakamee, Richard James Maude, Pascal Ringwald, Celine I Mandara, Abdelrahim Osman Mohamed, Toshihiro Mita, Jaqui Montgomery, Julian C Rayner, David Saunders, Olugbenga A Mokuolu, Lastenia Ruiz, Kathryn Murie, Peter Siba, Collins Misita Morang’a, Alex Shayo, Tuyen Nguyen Thi Kim, Thang Ngo Duc, Vincent Ntui-Njock Ntui, Colin Sutherland, Hong Nguyen Van, Xin-zhuan Su, Marie A Onyamboko, Livingstone Tavul, Irene Omedo, Richard Pearson, Antoinette Tshefu, Wellington Aghoghovwia Oyibo, Vandana Thathy, Chris Drakeley, Huynh Hong Quang, Joseph Vinetz, Christopher V Plowe, Federica Verra, Eduard Rovira-Vallbona, Jason Wendler, Anna Rosanas-Urgell, Teun Bousema, Thuy Nguyen, Mahamadou S. Sissoko, Valentin Ruano-Rubio, Alexis Nzila, Shannon Takala-Harrison, Christen Smith, William Yavo, Ngo Viet Thanh, Arthur Talman, Georgia Whitton, Mahamoudou Toure, Rob W van der Pluijm, Sarah Auburn, Antoine Claessens, Mahamadou Diakite, Kesinee Chotivanich, Mehul Dhorda, Olivo Miotto, Mallika Imwong, Mayfong Mayxay, Alfred Amambua-Ngwa, Philip Bejon, Elizabeth Ashley, Alyssa Barry, Rick M. Fairhurst, Ye Htut, Tran Tinh Hien, Kimberly J Johnson, Dominic P Kwiatkowski, Umberto D'Alessandro, Chanthap Lon, Paul N Newton, Aung P Phyo, Ric N Price, Victoria J Simpson, Kevin Marsh, Nicholas J White, Thomas E Wellems, Lynette Isabella Ochola-Oyier, Mozam Ali, Ambroise Ahouidi, Jacob Almagro-Garcia, Ben Andagalu, Lucas Amenga-Etego, Voahangy Andrianaranjaka, Tobias Apinjoh, Vito Baraka, Hampate Ba, Steffen Borrmann, Oralee Branch, Thanat Chookajorn, Souleymane Dama, Chanaki Amaratunga, Alister Craig, Brigitte Denis, Eleanor Drury, Christiane Dolecek, Patrick Duffy, Berhanu Erko, Abdul Faiz, Muzamil Mahdi Abdel Hamid, Anita Ghansah, and Dionicia Gamboa

Subjects
malaria, plasmodium falciparum, genomics, data resource, genomic epidemiology, eng, Medicine, Science
Abstract

We describe the MalariaGEN Pf7 data resource, the seventh release of Plasmodium falciparum genome variation data from the MalariaGEN network. It comprises over 20,000 samples from 82 partner studies in 33 countries, including several malaria endemic regions that were previously underrepresented. For the first time we include dried blood spot samples that were sequenced after selective whole genome amplification, necessitating new methods to genotype copy number variations. We identify a large number of newly emerging crt mutations in parts of Southeast Asia, and show examples of heterogeneities in patterns of drug resistance within Africa and within the Indian subcontinent. We describe the profile of variations in the C-terminal of the csp gene and relate this to the sequence used in the RTS,S and R21 malaria vaccines. Pf7 provides high-quality data on genotype calls for 6 million SNPs and short indels, analysis of large deletions that cause failure of rapid diagnostic tests, and systematic characterisation of six major drug resistance loci, all of which can be freely downloaded from the MalariaGEN website.

Published
2023
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3. An open dataset of Plasmodium falciparum genome variation in 7,000 worldwide samples [version 2; peer review: 2 approved]

Author

MalariaGEN, Ambroise Ahouidi, Mozam Ali, Jacob Almagro-Garcia, Alfred Amambua-Ngwa, Chanaki Amaratunga, Roberto Amato, Lucas Amenga-Etego, Ben Andagalu, Tim J. C. Anderson, Voahangy Andrianaranjaka, Tobias Apinjoh, Cristina Ariani, Elizabeth A Ashley, Sarah Auburn, Gordon A. Awandare, Hampate Ba, Vito Baraka, Alyssa E. Barry, Philip Bejon, Gwladys I. Bertin, Maciej F. Boni, Steffen Borrmann, Teun Bousema, Oralee Branch, Peter C. Bull, George B. J. Busby, Thanat Chookajorn, Kesinee Chotivanich, Antoine Claessens, David Conway, Alister Craig, Umberto D'Alessandro, Souleymane Dama, Nicholas PJ Day, Brigitte Denis, Mahamadou Diakite, Abdoulaye Djimdé, Christiane Dolecek, Arjen M Dondorp, Chris Drakeley, Eleanor Drury, Patrick Duffy, Diego F. Echeverry, Thomas G. Egwang, Berhanu Erko, Rick M. Fairhurst, Abdul Faiz, Caterina A. Fanello, Mark M. Fukuda, Dionicia Gamboa, Anita Ghansah, Lemu Golassa, Sonia Goncalves, William L. Hamilton, G. L. Abby Harrison, Lee Hart, Christa Henrichs, Tran Tinh Hien, Catherine A. Hill, Abraham Hodgson, Christina Hubbart, Mallika Imwong, Deus S. Ishengoma, Scott A. Jackson, Chris G. Jacob, Ben Jeffery, Anna E. Jeffreys, Kimberly J. Johnson, Dushyanth Jyothi, Claire Kamaliddin, Edwin Kamau, Mihir Kekre, Krzysztof Kluczynski, Theerarat Kochakarn, Abibatou Konaté, Dominic P. Kwiatkowski, Myat Phone Kyaw, Pharath Lim, Chanthap Lon, Kovana M. Loua, Oumou Maïga-Ascofaré, Cinzia Malangone, Magnus Manske, Jutta Marfurt, Kevin Marsh, Mayfong Mayxay, Alistair Miles, Olivo Miotto, Victor Mobegi, Olugbenga A. Mokuolu, Jacqui Montgomery, Ivo Mueller, Paul N. Newton, Thuy Nguyen, Thuy-Nhien Nguyen, Harald Noedl, Francois Nosten, Rintis Noviyanti, Alexis Nzila, Lynette I. Ochola-Oyier, Harold Ocholla, Abraham Oduro, Irene Omedo, Marie A. Onyamboko, Jean-Bosco Ouedraogo, Kolapo Oyebola, Richard D. Pearson, Norbert Peshu, Aung Pyae Phyo, Chris V. Plowe, Ric N. Price, Sasithon Pukrittayakamee, Milijaona Randrianarivelojosia, Julian C. Rayner, Pascal Ringwald, Kirk A. Rockett, Katherine Rowlands, Lastenia Ruiz, David Saunders, Alex Shayo, Peter Siba, Victoria J. Simpson, Jim Stalker, Xin-zhuan Su, Colin Sutherland, Shannon Takala-Harrison, Livingstone Tavul, Vandana Thathy, Antoinette Tshefu, Federica Verra, Joseph Vinetz, Thomas E. Wellems, Jason Wendler, Nicholas J. White, Ian Wright, William Yavo, and Htut Ye

Subjects
Medicine, Science
Abstract

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.

Published
2021
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4. An open dataset of Plasmodium falciparum genome variation in 7,000 worldwide samples [version 1; peer review: 2 approved]

Author

MalariaGEN, Ambroise Ahouidi, Mozam Ali, Jacob Almagro-Garcia, Alfred Amambua-Ngwa, Chanaki Amaratunga, Roberto Amato, Lucas Amenga-Etego, Ben Andagalu, Tim J. C. Anderson, Voahangy Andrianaranjaka, Tobias Apinjoh, Cristina Ariani, Elizabeth A. Ashley, Sarah Auburn, Gordon Awandare, Hampate Ba, Vito Baraka, Alyssa E. Barry, Philip Bejon, Gwladys I. Bertin, Maciej F. Boni, Steffen Borrmann, Teun Bousema, Oralee Branch, Peter C. Bull, George B. J. Busby, Thanat Chookajorn, Kesinee Chotivanich, Antoine Claessens, David Conway, Alister Craig, Umberto D'Alessandro, Souleymane Dama, Nicholas PJ Day, Brigitte Denis, Mahamadou Diakite, Abdoulaye Djimdé, Christiane Dolecek, Arjen M Dondorp, Chris Drakeley, Eleanor Drury, Patrick Duffy, Diego F. Echeverry, Thomas G. Egwang, Berhanu Erko, Rick M. Fairhurst, Abdul Faiz, Caterina A. Fanello, Mark M. Fukuda, Dionicia Gamboa, Anita Ghansah, Lemu Golassa, Sonia Goncalves, William L. Hamilton, G. L. Abby Harrison, Lee Hart, Christa Henrichs, Tran Tinh Hien, Catherine A. Hill, Abraham Hodgson, Christina Hubbart, Mallika Imwong, Deus S. Ishengoma, Scott A. Jackson, Chris G. Jacob, Ben Jeffery, Anna E. Jeffreys, Kimberly J. Johnson, Dushyanth Jyothi, Claire Kamaliddin, Edwin Kamau, Mihir Kekre, Krzysztof Kluczynski, Theerarat Kochakarn, Abibatou Konaté, Dominic P. Kwiatkowski, Myat Phone Kyaw, Pharath Lim, Chanthap Lon, Kovana M. Loua, Oumou Maïga-Ascofaré, Cinzia Malangone, Magnus Manske, Jutta Marfurt, Kevin Marsh, Mayfong Mayxay, Alistair Miles, Olivo Miotto, Victor Mobegi, Olugbenga A. Mokuolu, Jacqui Montgomery, Ivo Mueller, Paul N. Newton, Thuy Nguyen, Thuy-Nhien Nguyen, Harald Noedl, Francois Nosten, Rintis Noviyanti, Alexis Nzila, Lynette I. Ochola-Oyier, Harold Ocholla, Abraham Oduro, Irene Omedo, Marie A. Onyamboko, Jean-Bosco Ouedraogo, Kolapo Oyebola, Richard D. Pearson, Norbert Peshu, Aung Pyae Phyo, Chris V. Plowe, Ric N. Price, Sasithon Pukrittayakamee, Milijaona Randrianarivelojosia, Julian C. Rayner, Pascal Ringwald, Kirk A. Rockett, Katherine Rowlands, Lastenia Ruiz, David Saunders, Alex Shayo, Peter Siba, Victoria J. Simpson, Jim Stalker, Xin-zhuan Su, Colin Sutherland, Shannon Takala-Harrison, Livingstone Tavul, Vandana Thathy, Antoinette Tshefu, Federica Verra, Joseph Vinetz, Thomas E. Wellems, Jason Wendler, Nicholas J. White, Ian Wright, William Yavo, and Htut Ye

Subjects
Medicine, Science
Abstract

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.

Published
2021
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5. Characterisation of the opposing effects of G6PD deficiency on cerebral malaria and severe malarial anaemia

Author

Geraldine M Clarke, Kirk Rockett, Katja Kivinen, Christina Hubbart, Anna E Jeffreys, Kate Rowlands, Muminatou Jallow, David J Conway, Kalifa A Bojang, Margaret Pinder, Stanley Usen, Fatoumatta Sisay-Joof, Giorgio Sirugo, Ousmane Toure, Mahamadou A Thera, Salimata Konate, Sibiry Sissoko, Amadou Niangaly, Belco Poudiougou, Valentina D Mangano, Edith C Bougouma, Sodiomon B Sirima, David Modiano, Lucas N Amenga-Etego, Anita Ghansah, Kwadwo A Koram, Michael D Wilson, Anthony Enimil, Jennifer Evans, Olukemi K Amodu, Subulade Olaniyan, Tobias Apinjoh, Regina Mugri, Andre Ndi, Carolyne M Ndila, Sophie Uyoga, Alexander Macharia, Norbert Peshu, Thomas N Williams, Alphaxard Manjurano, Nuno Sepúlveda, Taane G Clark, Eleanor Riley, Chris Drakeley, Hugh Reyburn, Vysaul Nyirongo, David Kachala, Malcolm Molyneux, Sarah J Dunstan, Nguyen Hoan Phu, Nguyen Ngoc Quyen, Cao Quang Thai, Tran Tinh Hien, Laurens Manning, Moses Laman, Peter Siba, Harin Karunajeewa, Steve Allen, Angela Allen, Timothy ME Davis, Pascal Michon, Ivo Mueller, Síle F Molloy, Susana Campino, Angeliki Kerasidou, Victoria J Cornelius, Lee Hart, Shivang S Shah, Gavin Band, Chris CA Spencer, Tsiri Agbenyega, Eric Achidi, Ogobara K Doumbo, Jeremy Farrar, Kevin Marsh, Terrie Taylor, Dominic P Kwiatkowski, and MalariaGEN Consortium

Subjects
G6PD deficiency, genetic association, infectious disease, selection, Medicine, Science, Biology (General), QH301-705.5
Abstract

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is believed to confer protection against Plasmodium falciparum malaria, but the precise nature of the protective effect has proved difficult to define as G6PD deficiency has multiple allelic variants with different effects in males and females, and it has heterogeneous effects on the clinical outcome of P. falciparum infection. Here we report an analysis of multiple allelic forms of G6PD deficiency in a large multi-centre case-control study of severe malaria, using the WHO classification of G6PD mutations to estimate each individual’s level of enzyme activity from their genotype. Aggregated across all genotypes, we find that increasing levels of G6PD deficiency are associated with decreasing risk of cerebral malaria, but with increased risk of severe malarial anaemia. Models of balancing selection based on these findings indicate that an evolutionary trade-off between different clinical outcomes of P. falciparum infection could have been a major cause of the high levels of G6PD polymorphism seen in human populations.

Published
2017
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6. Admixture into and within sub-Saharan Africa

Author

George BJ Busby, Gavin Band, Quang Si Le, Muminatou Jallow, Edith Bougama, Valentina D Mangano, Lucas N Amenga-Etego, Anthony Enimil, Tobias Apinjoh, Carolyne M Ndila, Alphaxard Manjurano, Vysaul Nyirongo, Ogobara Doumba, Kirk A Rockett, Dominic P Kwiatkowski, Chris CA Spencer, and Malaria Genomic Epidemiology Network

Subjects
admixture, chromosome painting, Africa, gene-flow, Medicine, Science, Biology (General), QH301-705.5
Abstract

Similarity between two individuals in the combination of genetic markers along their chromosomes indicates shared ancestry and can be used to identify historical connections between different population groups due to admixture. We use a genome-wide, haplotype-based, analysis to characterise the structure of genetic diversity and gene-flow in a collection of 48 sub-Saharan African groups. We show that coastal populations experienced an influx of Eurasian haplotypes over the last 7000 years, and that Eastern and Southern Niger-Congo speaking groups share ancestry with Central West Africans as a result of recent population expansions. In fact, most sub-Saharan populations share ancestry with groups from outside of their current geographic region as a result of gene-flow within the last 4000 years. Our in-depth analysis provides insight into haplotype sharing across different ethno-linguistic groups and the recent movement of alleles into new environments, both of which are relevant to studies of genetic epidemiology.

Published
2016
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7. An open dataset of

Author

Ambroise, Ahouidi, Mozam, Ali, Jacob, Almagro-Garcia, Alfred, Amambua-Ngwa, Chanaki, Amaratunga, Roberto, Amato, Lucas, Amenga-Etego, Ben, Andagalu, Tim J C, Anderson, Voahangy, Andrianaranjaka, Tobias, Apinjoh, Cristina, Ariani, Elizabeth A, Ashley, Sarah, Auburn, Gordon A, Awandare, Hampate, Ba, Vito, Baraka, Alyssa E, Barry, Philip, Bejon, Gwladys I, Bertin, Maciej F, Boni, Steffen, Borrmann, Teun, Bousema, Oralee, Branch, Peter C, Bull, George B J, Busby, Thanat, Chookajorn, Kesinee, Chotivanich, Antoine, Claessens, David, Conway, Alister, Craig, Umberto, D'Alessandro, Souleymane, Dama, Nicholas Pj, Day, Brigitte, Denis, Mahamadou, Diakite, Abdoulaye, Djimdé, Christiane, Dolecek, Arjen M, Dondorp, Chris, Drakeley, Eleanor, Drury, Patrick, Duffy, Diego F, Echeverry, Thomas G, Egwang, Berhanu, Erko, Rick M, Fairhurst, Abdul, Faiz, Caterina A, Fanello, Mark M, Fukuda, Dionicia, Gamboa, Anita, Ghansah, Lemu, Golassa, Sonia, Goncalves, William L, Hamilton, G L Abby, Harrison, Lee, Hart, Christa, Henrichs, Tran Tinh, Hien, Catherine A, Hill, Abraham, Hodgson, Christina, Hubbart, Mallika, Imwong, Deus S, Ishengoma, Scott A, Jackson, Chris G, Jacob, Ben, Jeffery, Anna E, Jeffreys, Kimberly J, Johnson, Dushyanth, Jyothi, Claire, Kamaliddin, Edwin, Kamau, Mihir, Kekre, Krzysztof, Kluczynski, Theerarat, Kochakarn, Abibatou, Konaté, Dominic P, Kwiatkowski, Myat Phone, Kyaw, Pharath, Lim, Chanthap, Lon, Kovana M, Loua, Oumou, Maïga-Ascofaré, Cinzia, Malangone, Magnus, Manske, Jutta, Marfurt, Kevin, Marsh, Mayfong, Mayxay, Alistair, Miles, Olivo, Miotto, Victor, Mobegi, Olugbenga A, Mokuolu, Jacqui, Montgomery, Ivo, Mueller, Paul N, Newton, Thuy, Nguyen, Thuy-Nhien, Nguyen, Harald, Noedl, Francois, Nosten, Rintis, Noviyanti, Alexis, Nzila, Lynette I, Ochola-Oyier, Harold, Ocholla, Abraham, Oduro, Irene, Omedo, Marie A, Onyamboko, Jean-Bosco, Ouedraogo, Kolapo, Oyebola, Richard D, Pearson, Norbert, Peshu, Aung Pyae, Phyo, Chris V, Plowe, Ric N, Price, Sasithon, Pukrittayakamee, Milijaona, Randrianarivelojosia, Julian C, Rayner, Pascal, Ringwald, Kirk A, Rockett, Katherine, Rowlands, Lastenia, Ruiz, David, Saunders, Alex, Shayo, Peter, Siba, Victoria J, Simpson, Jim, Stalker, Xin-Zhuan, Su, Colin, Sutherland, Shannon, Takala-Harrison, Livingstone, Tavul, Vandana, Thathy, Antoinette, Tshefu, Federica, Verra, Joseph, Vinetz, Thomas E, Wellems, Jason, Wendler, Nicholas J, White, Ian, Wright, William, Yavo, and Htut, Ye

Subjects
data resource, drug resistance, plasmodium falciparum, parasitic diseases, evolution, malaria, genomics, rapid diagnostic test failure, population genetics, Articles, genomic epidemiology, Research Article
Abstract

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.

Published
2021

8. Glucose-6-phosphate dehydrogenase deficiency and the risk of malaria and other diseases in children in Kenya: a case-control and a cohort study

Author

Magnus Manske, Taane Clark, Deus Ishengoma, Valentina D Mangano, Kerrin Small, Issa Nebie, Dushyanth Jyothi, Catherine Moyes, Katja Kivinen, George Mtove, Dominic Kwiatkowski, Jacques Simporé, Behzad Nadjm, Adebola Orimadegun, Kalifa Bojang, Panos Deloukas, Nadira Karunaweera, Kimberly J Johnson, Mahamadou A Thera, Gareth Maslen, Nuno Sepúlveda, Daniel Mead, Sophie Uyoga, Tobias Apinjoh, John Reeder, Lee Hart, Climent Casals-Pascual, Sarah Auburn, Sharon Cox, KEMRI-Wellcome Trust Research Programme (KWTRP), The Wellcome Trust Centre for Human Genetics [Oxford], University of Oxford [Oxford], National Institute of Allergy and Infectious Diseases [Bethesda] (NIAID-NIH), National Institutes of Health [Bethesda] (NIH), Imperial College London, Institut Pasteur [Paris], TNW is funded by the Wellcome Trust (091758) and DPK receives support from the UK Medical Research Council (G19/9). SS is supported by the Medical Scientist Training Program at the US National Institutes of Health and received travel funds from Wolfson College, Oxford, and from the Oxford University Exploration Club. This research received funding from the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement 242095 and from the UK Medical Research Council (G0600718). The MalariaGEN Project is supported by the Wellcome Trust (077383) and by the Foundation for the National Institutes of Health (566) as part of the Bill & Melinda Gates Grand Challenges in Global Health Initiative and through a Wellcome Trust Strategic Award (090770). The Wellcome Trust provides core support to The KEMRI–Wellcome Trust Research Programme in Kilifi (084535) and the Wellcome Trust Centre for Human Genetics (090532), Oxford, UK., the MalariaGEN Consortium: members listed at http://www.malariagen.net/projects/host/consortium-members, European Project: 242095,EC:FP7:HEALTH,FP7-HEALTH-2009-single-stage,EVIMALAR(2009), University of Oxford, and Institut Pasteur [Paris] (IP)

Subjects
Male, Pediatrics, Rate ratio, Cohort Studies, Risk Factors, MESH: Risk Factors, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, MESH: Child, Child, MESH: Cohort Studies, media_common, MESH: Heterozygote, 2. Zero hunger, hematology, Incidence (epidemiology), 1. No poverty, Articles, glucosephosphate dehydrogenase deficiency, glucosephosphate dehydrogenase, glucose-6-phosphate dehydrogenase, MESH: Case-Control Studies, MESH: Infant, 3. Good health, MESH: Glucosephosphate Dehydrogenase Deficiency, Child, Preschool, Female, Cohort study, Heterozygote, medicine.medical_specialty, Adolescent, MESH: Kenya, MESH: Malaria, parasitic diseases, medicine, MESH: United States, Humans, media_common.cataloged_instance, European union, MESH: Adolescent, Polymorphism, Genetic, MESH: Humans, business.industry, MESH: Child, Preschool, Case-control study, Infant, Odds ratio, medicine.disease, Kenya, United States, MESH: Male, Malaria, Case-Control Studies, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, MESH: Female, Glucose-6-phosphate dehydrogenase deficiency
Abstract

Summary Background The global prevalence of X-linked glucose-6-phosphate dehydrogenase (G6PD) deficiency is thought to be a result of selection by malaria, but epidemiological studies have yielded confusing results. We investigated the relationships between G6PD deficiency and both malaria and non-malarial illnesses among children in Kenya. Methods We did this study in Kilifi County, Kenya, where the G6PD c.202T allele is the only significant cause of G6PD deficiency. We tested the associations between G6PD deficiency and severe and complicated Plasmodium falciparum malaria through a case-control study of 2220 case and 3940 control children. Cases were children aged younger than 14 years, who visited the high dependency ward of Kilifi County Hospital with severe malaria between March 1, 1998, and Feb 28, 2010. Controls were children aged between 3–12 months who were born within the same study area between August 2006, and September 2010. We assessed the association between G6PD deficiency and both uncomplicated malaria and other common diseases of childhood in a cohort study of 752 children aged younger than 10 years. Participants of this study were recruited from a representative sample of households within the Ngerenya and Chonyi areas of Kilifi County between Aug 1, 1998, and July 31, 2001. The primary outcome measure for the case-control study was the odds ratio for hospital admission with severe malaria (computed by logistic regression) while for the cohort study it was the incidence rate ratio for uncomplicated malaria and non-malaria illnesses (computed by Poisson regression), by G6PD deficiency category. Findings 2863 (73%) children in the control group versus 1643 (74%) in the case group had the G6PD normal genotype, 639 (16%) versus 306 (14%) were girls heterozygous for G6PD c.202T, and 438 (11%) versus 271 (12%) children were either homozygous girls or hemizygous boys. Compared with boys and girls without G6PD deficiency, we found significant protection from severe malaria (odds ratio [OR] 0·82, 95% CI 0·70–0·97; p=0·020) among G6PD c.202T heterozygous girls but no evidence for protection among G6PD c.202T hemizygous boys and homozygous girls (OR 1·18, 0·99–1·40; p=0·056). Median follow-up for the mild disease cohort study was 2·24 years (IQR 2·22–2·85). G6PD c.202T had no effect on other common diseases of childhood in heterozygous girls (incidence rate ratio 0·98, 95% CI 0·86–1·11; p=0·82) or homozygous girls or hemizygous boys (0·93, 0·82–1·04; p=0·25), with the sole exception of a marginally significant increase in the incidence of helminth infections among heterozygous girls. Interpretation Heterozygous girls might be the driving force for the positive selection of G6PD deficiency alleles. Further studies are needed to definitively establish the mechanisms by which G6PD deficiency confers an advantage against malaria in heterozygous individuals. Such studies could lead to the development of new treatments. Funding Wellcome Trust, UK Medical Research Council, European Union, and Foundation for the National Institutes of Health (as part of the Bill & Melinda Gates Grand Challenges in Global Health Initiative).

Published
2015

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