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11 results on '"Garcia, Jacob"'

1. Drug resistance and vaccine target surveillance of Plasmodium falciparum using nanopore sequencing in Ghana.

Author

Girgis ST, Adika E, Nenyewodey FE, Senoo Jnr DK, Ngoi JM, Bandoh K, Lorenz O, van de Steeg G, Harrott AJR, Nsoh S, Judge K, Pearson RD, Almagro-Garcia J, Saiid S, Atampah S, Amoako EK, Morang'a CM, Asoala V, Adjei ES, Burden W, Roberts-Sengier W, Drury E, Pierce ML, Gonçalves S, Awandare GA, Kwiatkowski DP, Amenga-Etego LN, and Hamilton WL

Subjects
Child, Humans, Child, Preschool, Plasmodium falciparum genetics, Ghana epidemiology, Drug Resistance genetics, Nanopore Sequencing, Antimalarials pharmacology, Malaria epidemiology, Malaria, Falciparum epidemiology, Malaria, Falciparum prevention & control, Malaria, Falciparum drug therapy
Abstract

Malaria results in over 600,000 deaths annually, with the highest burden of deaths in young children living in sub-Saharan Africa. Molecular surveillance can provide important information for malaria control policies, including detection of antimalarial drug resistance. However, genome sequencing capacity in malaria-endemic countries is limited. We designed and implemented an end-to-end workflow to detect Plasmodium falciparum antimalarial resistance markers and diversity in the vaccine target circumsporozoite protein (csp) using nanopore sequencing in Ghana. We analysed 196 clinical samples and showed that our method is rapid, robust, accurate and straightforward to implement. Importantly, our method could be applied to dried blood spot samples, which are readily collected in endemic settings. We report that P. falciparum parasites in Ghana are mostly susceptible to chloroquine, with persistent sulfadoxine-pyrimethamine resistance and no evidence of artemisinin resistance. Multiple single nucleotide polymorphisms were identified in csp, but their significance is uncertain. Our study demonstrates the feasibility of nanopore sequencing for malaria genomic surveillance in endemic countries., (© 2023. The Author(s).)

Published
2023
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2. Genetic surveillance in the Greater Mekong subregion and South Asia to support malaria control and elimination.

Author

Jacob CG, Thuy-Nhien N, Mayxay M, Maude RJ, Quang HH, Hongvanthong B, Vanisaveth V, Ngo Duc T, Rekol H, van der Pluijm R, von Seidlein L, Fairhurst R, Nosten F, Hossain MA, Park N, Goodwin S, Ringwald P, Chindavongsa K, Newton P, Ashley E, Phalivong S, Maude R, Leang R, Huch C, Dong LT, Nguyen KT, Nhat TM, Hien TT, Nguyen H, Zdrojewski N, Canavati S, Sayeed AA, Uddin D, Buckee C, Fanello CI, Onyamboko M, Peto T, Tripura R, Amaratunga C, Myint Thu A, Delmas G, Landier J, Parker DM, Chau NH, Lek D, Suon S, Callery J, Jittamala P, Hanboonkunupakarn B, Pukrittayakamee S, Phyo AP, Smithuis F, Lin K, Thant M, Hlaing TM, Satpathi P, Satpathi S, Behera PK, Tripura A, Baidya S, Valecha N, Anvikar AR, Ul Islam A, Faiz A, Kunasol C, Drury E, Kekre M, Ali M, Love K, Rajatileka S, Jeffreys AE, Rowlands K, Hubbart CS, Dhorda M, Vongpromek R, Kotanan N, Wongnak P, Almagro Garcia J, Pearson RD, Ariani CV, Chookajorn T, Malangone C, Nguyen T, Stalker J, Jeffery B, Keatley J, Johnson KJ, Muddyman D, Chan XHS, Sillitoe J, Amato R, Simpson V, Gonçalves S, Rockett K, Day NP, Dondorp AM, Kwiatkowski DP, and Miotto O

Subjects
Animals, Asia, Southeastern, Bangladesh, Democratic Republic of the Congo, India, Plasmodium drug effects, Communicable Disease Control statistics & numerical data, Disease Eradication statistics & numerical data, Drug Resistance genetics, Malaria prevention & control, Plasmodium genetics
Abstract

Background: National Malaria Control Programmes (NMCPs) currently make limited use of parasite genetic data. We have developed GenRe-Mekong, a platform for genetic surveillance of malaria in the Greater Mekong Subregion (GMS) that enables NMCPs to implement large-scale surveillance projects by integrating simple sample collection procedures in routine public health procedures., Methods: Samples from symptomatic patients are processed by SpotMalaria, a high-throughput system that produces a comprehensive set of genotypes comprising several drug resistance markers, species markers and a genomic barcode. GenRe-Mekong delivers Genetic Report Cards, a compendium of genotypes and phenotype predictions used to map prevalence of resistance to multiple drugs., Results: GenRe-Mekong has worked with NMCPs and research projects in eight countries, processing 9623 samples from clinical cases. Monitoring resistance markers has been valuable for tracking the rapid spread of parasites resistant to the dihydroartemisinin-piperaquine combination therapy. In Vietnam and Laos, GenRe-Mekong data have provided novel knowledge about the spread of these resistant strains into previously unaffected provinces, informing decision-making by NMCPs., Conclusions: GenRe-Mekong provides detailed knowledge about drug resistance at a local level, and facilitates data sharing at a regional level, enabling cross-border resistance monitoring and providing the public health community with valuable insights. The project provides a rich open data resource to benefit the entire malaria community., Funding: The GenRe-Mekong project is funded by the Bill and Melinda Gates Foundation (OPP11188166, OPP1204268). Genotyping and sequencing were funded by the Wellcome Trust (098051, 206194, 203141, 090770, 204911, 106698/B/14/Z) and Medical Research Council (G0600718). A proportion of samples were collected with the support of the UK Department for International Development (201900, M006212), and Intramural Research Program of the National Institute of Allergy and Infectious Diseases., Competing Interests: CJ, NT, MM, RM, HQ, BH, VV, TN, HR, Rv, Lv, RF, FN, MH, NP, SG, PR, KC, PN, EA, SP, RM, RL, CH, LD, KN, TN, TH, AS, DU, CB, CF, MO, TP, RT, CA, AM, GD, JL, DP, NC, DL, SS, JC, PJ, BH, SP, AP, FS, KL, MT, TH, PS, SS, PB, AT, SB, NV, AA, AU, AF, CK, ED, MK, MA, KL, SR, AJ, KR, CH, MD, RV, NK, PW, JA, RP, CA, TC, CM, TN, JS, BJ, JK, KJ, DM, XC, JS, RA, VS, SG, KR, ND, AD, DK, OM No competing interests declared, HN, NZ, SC is an employee of Vysnova Partners Inc

Published
2021
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3. Genetic surveillance in the Greater Mekong subregion and South Asia to support malaria control and elimination.

Author

Jacob, Christopher G, Thuy-Nhien, Nguyen, Mayxay, Mayfong, Maude, Richard J, Quang, Huynh Hong, Hongvanthong, Bouasy, Vanisaveth, Viengxay, Ngo Duc, Thang, Rekol, Huy, van der Pluijm, Rob, von Seidlein, Lorenz, Fairhurst, Rick, Nosten, François, Hossain, Md Amir, Park, Naomi, Goodwin, Scott, Ringwald, Pascal, Chindavongsa, Keobouphaphone, Newton, Paul, Ashley, Elizabeth, Phalivong, Sonexay, Maude, Rapeephan, Leang, Rithea, Huch, Cheah, Dong, Le Thanh, Nguyen, Kim-Tuyen, Nhat, Tran Minh, Hien, Tran Tinh, Nguyen, Hoa, Zdrojewski, Nicole, Canavati, Sara, Sayeed, Abdullah Abu, Uddin, Didar, Buckee, Caroline, Fanello, Caterina I, Onyamboko, Marie, Peto, Thomas, Tripura, Rupam, Amaratunga, Chanaki, Myint Thu, Aung, Delmas, Gilles, Landier, Jordi, Parker, Daniel M, Chau, Nguyen Hoang, Lek, Dysoley, Suon, Seila, Callery, James, Jittamala, Podjanee, Hanboonkunupakarn, Borimas, Pukrittayakamee, Sasithon, Phyo, Aung Pyae, Smithuis, Frank, Lin, Khin, Thant, Myo, Hlaing, Tin Maung, Satpathi, Parthasarathi, Satpathi, Sanghamitra, Behera, Prativa K, Tripura, Amar, Baidya, Subrata, Valecha, Neena, Anvikar, Anupkumar R, Ul Islam, Akhter, Faiz, Abul, Kunasol, Chanon, Drury, Eleanor, Kekre, Mihir, Ali, Mozam, Love, Katie, Rajatileka, Shavanthi, Jeffreys, Anna E, Rowlands, Kate, Hubbart, Christina S, Dhorda, Mehul, Vongpromek, Ranitha, Kotanan, Namfon, Wongnak, Phrutsamon, Almagro Garcia, Jacob, Pearson, Richard D, Ariani, Cristina V, Chookajorn, Thanat, Malangone, Cinzia, Nguyen, T, Stalker, Jim, Jeffery, Ben, Keatley, Jonathan, Johnson, Kimberly J, Muddyman, Dawn, Chan, Xin Hui S, Sillitoe, John, Amato, Roberto, Simpson, Victoria, Gonçalves, Sonia, Rockett, Kirk, Day, Nicholas P, Dondorp, Arjen M, Kwiatkowski, Dominic P, and Miotto, Olivo

Subjects
asia, drug resistance, epidemiology, genetic surveillance, global health, infectious disease, malaria, microbiology, Biochemistry and Cell Biology
Abstract

BackgroundNational Malaria Control Programmes (NMCPs) currently make limited use of parasite genetic data. We have developed GenRe-Mekong, a platform for genetic surveillance of malaria in the Greater Mekong Subregion (GMS) that enables NMCPs to implement large-scale surveillance projects by integrating simple sample collection procedures in routine public health procedures.MethodsSamples from symptomatic patients are processed by SpotMalaria, a high-throughput system that produces a comprehensive set of genotypes comprising several drug resistance markers, species markers and a genomic barcode. GenRe-Mekong delivers Genetic Report Cards, a compendium of genotypes and phenotype predictions used to map prevalence of resistance to multiple drugs.ResultsGenRe-Mekong has worked with NMCPs and research projects in eight countries, processing 9623 samples from clinical cases. Monitoring resistance markers has been valuable for tracking the rapid spread of parasites resistant to the dihydroartemisinin-piperaquine combination therapy. In Vietnam and Laos, GenRe-Mekong data have provided novel knowledge about the spread of these resistant strains into previously unaffected provinces, informing decision-making by NMCPs.ConclusionsGenRe-Mekong provides detailed knowledge about drug resistance at a local level, and facilitates data sharing at a regional level, enabling cross-border resistance monitoring and providing the public health community with valuable insights. The project provides a rich open data resource to benefit the entire malaria community.FundingThe GenRe-Mekong project is funded by the Bill and Melinda Gates Foundation (OPP11188166, OPP1204268). Genotyping and sequencing were funded by the Wellcome Trust (098051, 206194, 203141, 090770, 204911, 106698/B/14/Z) and Medical Research Council (G0600718). A proportion of samples were collected with the support of the UK Department for International Development (201900, M006212), and Intramural Research Program of the National Institute of Allergy and Infectious Diseases.

Published
2021

4. Global and local patterns of population structure and their role in the evolution and demography of Plasmodium falciparum

Author

Almagro-Garcia, Jacob, McVean, Gilean, and Kwiatkowski, Dominic

Subjects
616.9, Malaria
Abstract

In this thesis, I study the role of genetic population structure in the evolution and demography of Plasmodium falciparum by focusing on the recent onset of artemisinin resistance in Southeast Asia, an alarming event for global public health. I describe the population structure of Plasmodium falciparum in the Thai-Cambodian border region, characterizing sympatric but differentiated subpopulations associated with artemisinin resistance. I show evidence that they are the product of recent founder events and seem the primary force spreading resistance. Next, I study a superset of the kelch13 mutations associated with artemisinin resistance, assessing their relationship with population structure and recent founder effects. Each resistant subpopulation possesses a distinct kelch13 allele that, in conjunction with a particular genetic background, seem to have driven recent founder effects. I examine the demography of these resistance alleles using patterns of haplotype sharing and show that the primary mode of spread consists of independent mutational events, with limited gene flow within countries in East Southeast Asia. Subsequently, I assess the origin of kelch13 mutations observed in African isolates, concluding that they are indigenous and have originated independently. These observations undermine localized resistance containment as a strategy for malaria control and suggest that population structure and founder effects may predate and facilitate the emergence of resistance. Therefore, monitoring these phenomena could warn about the development of resistance before phenotypic evidence materializes. Next, given the importance of demographic inference to inform malaria control programs and the advent of large genomic datasets, I develop a fast and scalable method to build the ancestral haplotype graph. I show that this data structure, composed of a collection of local haplotype trees, is informative about the recent genealogical history of the sequences and can be used to summarize and study shared haplotype patterns along the genome. I describe a set of algorithms with quasilinear time complexity as a first step in the development of scalable demographic inferential methods that can be applied to several thousands of sequences. I also evaluate how mixed infections affect the analysis of deep sequencing data and review the FWS statistic, a relative measure of inbreeding and complexity of infection. In doing so, I show that the original FWS estimator discards the diversity encoded by rare variants and provide an alternative estimator without such bias that is simpler, more intuitive and has a better resolution.

Published
2016

5. Pf7: an open dataset of Plasmodium falciparum genome variation in 20,000 worldwide samples

Author

Abdel Hamid, Muzamil Mahdi, Abdelraheem, Mohamed Hassan, Acheampong, Desmond Omane, Ahouidi, Ambroise, Ali, Mozam, Almagro-Garcia, Jacob, Amambua-Ngwa, Alfred, Amaratunga, Chanaki, Amenga-Etego, Lucas, Andagalu, Ben, Anderson, Tim, Andrianaranjaka, Voahangy, Aniebo, Ifeyinwa, Aninagyei, Enoch, Ansah, Felix, Ansah, Patrick, Apinjoh, Tobias, Arnaldo, Paulo, Ashley, Elizabeth, Auburn, Sarah, Awandare, Gordon, Ba, Hampate, Baraka, Vito, Barry, Alyssa, Bejon, Philip, Bertin, Gwladys, Boni, Maciej, Borrmann, Steffen, Bousema, Teun, Bouyou-Akotet, Marielle, Branch, Oralee, Bull, Peter, Cheah, Huch, Chindavongsa, Keobouphaphone, Chookajorn, Thanat, Chotivanich, Kesinee, Claessens, Antoine, Conway, David, Corredor, Vladimir, Courtier, Erin, Craig, Alister, d'Alessandro, Umberto, Dama, Souleymane, Day, Nicholas, Denis, Brigitte, Dhorda, Mehul, Diakite, Mahamadou, Djimde, Abdoulaye, Dolecek, Christiane, Dondorp, Arjen, Doumbia, Seydou, Drakeley, Chris, Drury, Eleanor, Duffy, Patrick, Echeverry, Diego, Egwang, Thomas, Enosse, Sonia Maria Mauricio, Erko, Berhanu, Fairhurst, Rick, Faiz, Abdul, Fanello, Caterina, Fleharty, Mark, Forbes, Matthew, Fukuda, Mark, Gamboa, Dionicia, Ghansah, Anita, Golassa, Lemu, Goncalves, Sonia, Harrison, G, Healy, Sara Anne, Hendry, Jason, Hernandez-Koutoucheva, Anastasia, Hien, Tran Tinh, Hill, Catherine, Hombhanje, Francis, Hott, Amanda, Htut, Ye, Hussein, Mazza, Imwong, Mallika, Ishengoma, Deus, Jackson, Scott, Jacob, Chris, Jeans, Julia, Johnson, Kimberly, Kamaliddin, Claire, Kamau, Edwin, Keatley, Jon, Kochakarn, Theerarat, Konate, Drissa, Konaté, Abibatou, Kone, Aminatou, Kwiatkowski, Dominic, Kyaw, Myat, Kyle, Dennis, Lawniczak, Mara, Lee, Samuel, Lemnge, Martha, Lim, Pharath, Lon, Chanthap, Loua, Kovana, Mandara, Celine, Marfurt, Jutta, Marsh, Kevin, Maude, Richard James, Mayxay, Mayfong, Maïga-Ascofaré, Oumou, Miotto, Olivo, Mita, Toshihiro, Mobegi, Victor, Mohamed, Abdelrahim Osman, Mokuolu, Olugbenga, Montgomery, Jaqui, Morang'A, Collins Misita, Mueller, Ivo, Murie, Kathryn, Newton, Paul, Ngo Duc, Thang, Nguyen, Thuy, Nguyen, Thuy-Nhien, Nguyen Thi Kim, Tuyen, Nguyen Van, Hong, Noedl, Harald, Nosten, François, Noviyanti, Rintis, Ntui, Vincent Ntui-Njock, Nzila, Alexis, Ochola-Oyier, Lynette Isabella, Ocholla, Harold, Oduro, Abraham, Omedo, Irene, Onyamboko, Marie, Ouedraogo, Jean-Bosco, Oyebola, Kolapo, Oyibo, Wellington Aghoghovwia, Pearson, Richard, Peshu, Norbert, Phyo, Aung, Plowe, Christopher, Price, Ric, Pukrittayakamee, Sasithon, Quang, Huynh Hong, Randrianarivelojosia, Milijaona, Rayner, Julian, Ringwald, Pascal, Rosanas-Urgell, Anna, Rovira-Vallbona, Eduard, Ruano-Rubio, Valentin, Ruiz, Lastenia, Saunders, David, Shayo, Alex, Siba, Peter, Simpson, Victoria, Sissoko, Mahamadou, Smith, Christen, Su, Xin-Zhuan, Sutherland, Colin, Takala-Harrison, Shannon, Talman, Arthur, Tavul, Livingstone, Thanh, Ngo Viet, Thathy, Vandana, Thu, Aung Myint, Toure, Mahamoudou, Tshefu, Antoinette, Verra, Federica, Vinetz, Joseph, Wellems, Thomas, Wendler, Jason, White, Nicholas, Whitton, Georgia, Yavo, William, van der Pluijm, Rob, MalariaGEN, University of Khartoum, University of Cape Coast [Ghana], Université Cheikh Anta Diop [Dakar, Sénégal] (UCAD), The Wellcome Trust Sanger Institute [Cambridge], London School of Hygiene and Tropical Medicine [Fajara, Gambia], London School of Hygiene and Tropical Medicine (LSHTM), National Institute of Allergy and Infectious Diseases [Bethesda] (NIAID-NIH), National Institutes of Health [Bethesda] (NIH), West African Centre for Cell Biology of Infectious Pathogens [Legon, Ghana] (WACCBIP), University of Ghana, Navrongo Health Research Centre [Navrongo, Ghana] (NHRC), Kenya Medical Research Institute (KEMRI), Texas Biomedical Research Institute [San Antonio, TX], Université d'Antananarivo, University of Buéa, Instituto Nacional de Saude [Maputo, Mozambique] (INS), Centre for Tropical Medicine and Global Health [Oxford, UK], Nuffield Department of Medicine [Oxford, UK] (Big Data Institute), University of Oxford-University of Oxford, Mahidol Oxford Tropical Medicine Research Unit (MORU), University of Oxford-Mahidol University [Bangkok]-Wellcome Trust, Menzies School of Health Research [Australia], Charles Darwin University [Australia], Nuffield Department of Clinical Medicine [Oxford], University of Oxford, Institut de Recherche pour le Développement (IRD), Laboratory of Pathogen and Host Immunity [Montpellier] (LPHI), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Maladies infectieuses et vecteurs : écologie, génétique, évolution et contrôle (MIVEGEC), and Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud])-Université de Montpellier (UM)

Subjects
data resource, lnfectious Diseases and Global Health Radboud Institute for Health Sciences [Radboudumc 4], plasmodium falciparum, genomics, malaria, Medicine (miscellaneous), genomic epidemiology, General Biochemistry, Genetics and Molecular Biology, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

Contains fulltext : 291985.pdf (Publisher’s version ) (Open Access) 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
Full Text
View/download PDF

6. Pf7: an open dataset of Plasmodium falciparum genome variation in 20,000 worldwide samples

Author

MalariaGEN, Abdel Hamid, Muzamil Mahdi, Abdelraheem, Mohamed Hassan, Acheampong, Desmond Omane, Ahouidi, Ambroise, Ali, Mozam, Almagro-Garcia, Jacob, Amambua-Ngwa, Alfred, Amaratunga, Chanaki, Amenga-Etego, Lucas, Andagalu, Ben, Anderson, Tim, Andrianaranjaka, Voahangy, Aniebo, Ifeyinwa, Aninagyei, Enoch, Ansah, Felix, Ansah, Patrick O, Apinjoh, Tobias, Arnaldo, Paulo, Ashley, Elizabeth, Auburn, Sarah, Awandare, Gordon A, Ba, Hampate, Baraka, Vito, Barry, Alyssa, Bejon, Philip, Bertin, Gwladys I, Boni, Maciej F, Borrmann, Steffen, Bousema, Teun, Bouyou-Akotet, Marielle, Branch, Oralee, Bull, Peter C, Cheah, Huch, Chindavongsa, Keobouphaphone, Chookajorn, Thanat, Chotivanich, Kesinee, Claessens, Antoine, Conway, David J, Corredor, Vladimir, Courtier, Erin, Craig, Alister, D'Alessandro, Umberto, Dama, Souleymane, Day, Nicholas, Denis, Brigitte, Dhorda, Mehul, Diakite, Mahamadou, Djimde, Abdoulaye, Dolecek, Christiane, Dondorp, Arjen, Doumbia, Seydou, Drakeley, Chris, Drury, Eleanor, Duffy, Patrick, Echeverry, Diego F, Egwang, Thomas G, Enosse, Sonia Maria Mauricio, Erko, Berhanu, Fairhurst, Rick M, Faiz, Abdul, Fanello, Caterina A, Fleharty, Mark, Forbes, Matthew, Fukuda, Mark, Gamboa, Dionicia, Ghansah, Anita, Golassa, Lemu, Goncalves, Sonia, Harrison, GL Abby, Healy, Sara Anne, Hendry, Jason A, Hernandez-Koutoucheva, Anastasia, Hien, Tran Tinh, Hill, Catherine A, Hombhanje, Francis, Hott, Amanda, Htut, Ye, Hussein, Mazza, Imwong, Mallika, Ishengoma, Deus, Jackson, Scott A, Jacob, Chris G, Jeans, Julia, Johnson, Kimberly J, Kamaliddin, Claire, Kamau, Edwin, Keatley, Jon, Kochakarn, Theerarat, Konate, Drissa S, Konaté, Abibatou, Kone, Aminatou, Kwiatkowski, Dominic P, Kyaw, Myat P, Kyle, Dennis, Lawniczak, Mara, Lee, Samuel K, Lemnge, Martha, Lim, Pharath, Lon, Chanthap, Loua, Kovana M, Mandara, Celine I, Marfurt, Jutta, Marsh, Kevin, Maude, Richard James, Mayxay, Mayfong, Maïga-Ascofaré, Oumou, Miotto, Olivo, Mita, Toshihiro, Mobegi, Victor, Mohamed, Abdelrahim Osman, Mokuolu, Olugbenga A, Montgomery, Jaqui, Morang'a, Collins Misita, Mueller, Ivo, Murie, Kathryn, Newton, Paul N, Ngo Duc, Thang, Nguyen, Thuy, Nguyen, Thuy-Nhien, Nguyen Thi Kim, Tuyen, Nguyen Van, Hong, Noedl, Harald, Nosten, Francois, Noviyanti, Rintis, Ntui, Vincent Ntui-Njock, Nzila, Alexis, Ochola-Oyier, Lynette Isabella, Ocholla, Harold, Oduro, Abraham, Omedo, Irene, Onyamboko, Marie A, Ouedraogo, Jean-Bosco, Oyebola, Kolapo, Oyibo, Wellington Aghoghovwia, Pearson, Richard, Peshu, Norbert, Phyo, Aung P, Plowe, Christopher V, Price, Ric N, Pukrittayakamee, Sasithon, Quang, Huynh Hong, Randrianarivelojosia, Milijaona, Rayner, Julian C, Ringwald, Pascal, Rosanas-Urgell, Anna, Rovira-Vallbona, Eduard, Ruano-Rubio, Valentin, Ruiz, Lastenia, Saunders, David, Shayo, Alex, Siba, Peter, Simpson, Victoria J, Sissoko, Mahamadou S, Smith, Christen, Su, Xin-Zhuan, Sutherland, Colin, Takala-Harrison, Shannon, Talman, Arthur, Tavul, Livingstone, Thanh, Ngo Viet, Thathy, Vandana, Thu, Aung Myint, Toure, Mahamoudou, Tshefu, Antoinette, Verra, Federica, Vinetz, Joseph, Wellems, Thomas E, Wendler, Jason, White, Nicholas J, Whitton, Georgia, Yavo, William, Van Der Pluijm, Rob W, Amenga-Etego, Lucas [0000-0003-4468-0506], Anderson, Tim [0000-0002-0191-0204], Ansah, Patrick O [0000-0002-3214-5621], Ashley, Elizabeth [0000-0002-7620-4822], Ba, Hampate [0000-0002-9299-5775], Baraka, Vito [0000-0001-9694-9293], Bejon, Philip [0000-0002-2135-7549], Bertin, Gwladys I [0000-0002-2218-9591], Boni, Maciej F [0000-0002-0830-9630], Bousema, Teun [0000-0003-2666-094X], Chookajorn, Thanat [0000-0003-2876-6203], Claessens, Antoine [0000-0002-4277-0914], Conway, David J [0000-0002-8711-3037], Craig, Alister [0000-0003-0914-6164], D'Alessandro, Umberto [0000-0001-6341-5009], Day, Nicholas [0000-0003-2309-1171], Diakite, Mahamadou [0000-0002-4268-8857], Djimde, Abdoulaye [0000-0003-0062-2283], Dondorp, Arjen [0000-0001-5190-2395], Drakeley, Chris [0000-0003-4863-075X], Echeverry, Diego F [0000-0003-0301-4478], Erko, Berhanu [0000-0003-1685-752X], Faiz, Abdul [0000-0002-3460-7535], Fanello, Caterina A [0000-0003-1932-9562], Gamboa, Dionicia [0000-0002-1420-7729], Golassa, Lemu [0000-0002-1216-8711], Healy, Sara Anne [0000-0003-3078-6094], Ishengoma, Deus [0000-0003-2040-3416], Jackson, Scott A [0000-0002-3172-1607], Kamaliddin, Claire [0000-0001-8198-6235], Kamau, Edwin [0000-0002-5761-7883], Konate, Drissa S [0000-0002-4177-9642], Kwiatkowski, Dominic P [0000-0002-5023-0176], Kyle, Dennis [0000-0002-0238-965X], Lawniczak, Mara [0000-0002-3006-2080], Loua, Kovana M [0000-0003-0571-0944], Marsh, Kevin [0000-0001-8377-5466], Mayxay, Mayfong [0000-0002-6056-4516], Miotto, Olivo [0000-0001-8060-6771], Mita, Toshihiro [0000-0001-8180-2344], Mobegi, Victor [0000-0002-1962-5583], Morang'a, Collins Misita [0000-0002-6988-150X], Nguyen, Thuy-Nhien [0000-0002-4101-5706], Nosten, Francois [0000-0002-7951-0745], Ntui, Vincent Ntui-Njock [0000-0002-7532-9930], Oduro, Abraham [0000-0002-4191-7419], Onyamboko, Marie A [0000-0002-7501-5931], Ouedraogo, Jean-Bosco [0000-0003-0412-8733], Oyebola, Kolapo [0000-0002-1003-2570], Pearson, Richard [0000-0002-7386-3566], Phyo, Aung P [0000-0002-0383-9624], Price, Ric N [0000-0003-2000-2874], Rayner, Julian C [0000-0002-9835-1014], Rosanas-Urgell, Anna [0000-0002-0432-5203], Shayo, Alex [0000-0002-7099-8537], Su, Xin-Zhuan [0000-0003-3246-3248], Vinetz, Joseph [0000-0001-8344-2004], Wellems, Thomas E [0000-0003-3899-8454], and Apollo - University of Cambridge Repository

Subjects
data resource, plasmodium falciparum, genomics, malaria, genomic epidemiology
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

7. Human candidate gene polymorphisms and risk of severe malaria in children in Kilifi, Kenya: a case-control association study

Author

Ndila, Carolyne M, Uyoga, Sophie, Macharia, Alexander W, Nyutu, Gideon, Peshu, Norbert, Ojal, John, Shebe, Mohammed, Awuondo, Kennedy O, Mturi, Neema, Tsofa, Benjamin, Sepúlveda, Nuno, Clark, Taane G, Band, Gavin, Clarke, Geraldine, Rowlands, Kate, Hubbart, Christina, Jeffreys, Anna, Kariuki, Silvia, Marsh, Kevin, Mackinnon, Margaret, Maitland, Kathryn, Kwiatkowski, Dominic P, Rockett, Kirk A, Williams, Thomas N, Abathina, Amadou, Abubakar, Ismaela, Achidi, Eric, Agbenyega, Tsiri, Aiyegbo, Mohammed, Akoto, Alex, Allen, Angela, Allen, Stephen, Amenga-Etego, Lucas, Amodu, Folakemi, Amodu, Olukemi, Anchang-Kimbi, Judith, Ansah, Nana, Ansah, Patrick, Ansong, Daniel, Antwi, Sampson, Anyorigiya, Thomas, Apinjoh, Tobias, Asafo-Agyei, Emmanuel, Asoala, Victor, Atuguba, Frank, Auburn, Sarah, Bah, Abdou, Bamba, Kariatou, Bancone, Germana, Barnwell, David, Barry, Abdoulaye, Bauni, Evasius, Besingi, Richard, Bojang, Kalifa, Bougouma, Edith, Bull, Susan, Busby, George, Camara, Abdoulie, Camara, Landing, Campino, Susana, Carter, Richard, Carucci, Dan, Casals-Pascual, Climent, Ceesay, Ndey, Ceesay, Pa, Chau, Tran, Chuong, Ly, Clark, Taane, Cole-Ceesay, Ramou, Conway, David, Cook, Katharine, Cook, Olivia, Cornelius, Victoria, Corran, Patrick, Correa, Simon, Cox, Sharon, Craik, Rachel, Danso, Bakary, Davis, Timothy, Day, Nicholas, Deloukas, Panos, Dembele, Awa, Devries, Jantina, Dewasurendra, Rajika, Diakite, Mahamadou, Diarra, Elizabeth, Dibba, Yaya, Diss, Andrea, Djimdé, Abdoulaye, Dolo, Amagana, Doumbo, Ogobara, Doyle, Alan, Drakeley, Chris, Drury, Eleanor, Duffy, Patrick, Dunstan, Sarah, Ebonyi, Augustine, Elhassan, Ahmed, Elhassan, Ibrahim, Elzein, Abier, Enimil, Anthony, Esangbedo, Pamela, Evans, Jennifer, Evans, Julie, Farrar, Jeremy, Fernando, Deepika, Fitzpatrick, Kathryn, Fullah, Janet, Garcia, Jacob, Ghansah, Anita, Gottleib, Michael, Green, Angie, Hart, Lee, Hennsman, Meike, Hien, Tran, Hieu, Nguyen, Hilton, Eliza, Hodgson, Abraham, Horstmann, Rolf, Hughes, Catherine, Hussein, Ayman, Hutton, Robert, Ibrahim, Muntaser, Ishengoma, Deus, Jaiteh, Jula, Jallow, Mariatou, Jallow, Muminatou, Jammeh, Kebba, Jasseh, Momodou, Jobarteh, Amie, Johnson, Kimberly, Joseph, Sarah, Jyothi, Dushyanth, Kachala, David, Kamuya, Dorcas, Kanyi, Haddy, Karunajeewa, Harin, Karunaweera, Nadira, Keita, Momodou, Kerasidou, Angeliki, Khan, Aja, Kivinen, Katja, Kokwaro, Gilbert, Konate, Amadou, Konate, Salimata, Koram, Kwadwo, Kwiatkowski, Dominic, Laman, Moses, Si, Le, Leffler, Ellen, Lemnge, Martha, Lin, Enmoore, Alioune, Ly, Macharia, Alexander, Macinnis, Bronwyn, Mai, Nguyen, Makani, Julie, Malangone, Cinzia, Mangano, Valentina, Manjurano, Alphaxard, Manneh, Lamin, Manning, Laurens, Manske, Magnus, Marsh, Vicki, Maslen, Gareth, Maxwell, Caroline, Mbunwe, Eric, Mccreight, Marilyn, Mead, Daniel, Mendy, Alieu, Mendy, Anthony, Mensah, Nathan, Michon, Pascal, Miles, Alistair, Miotto, Olivo, Modiano, David, Mohamed, Hiba, Molloy, Sile, Molyneux, Malcolm, Molyneux, Sassy, Moore, Mike, Moyes, Catherine, Mtei, Frank, Mtove, George, Mueller, Ivo, Mugri, Regina, Munthali, Annie, Mutabingwa, Theonest, Nadjm, Behzad, Ndi, Andre, Ndila, Carolyne, Newton, Charles, Niangaly, Amadou, Njie, Haddy, Njie, Jalimory, Njie, Madi, Njie, Malick, Njie, Sophie, Njiragoma, Labes, Nkrumah, Francis, Ntunthama, Neema, Nyika, Aceme, Nyirongo, Vysaul, O'Brien, John, Obu, Herbert, Oduro, Abraham, Ofori, Alex, Olaniyan, Subulade, Olaosebikan, Rasaq, Oluoch, Tom, Omotade, Olayemi, Oni, Olajumoke, Onykwelu, Emmanuel, Opi, Daniel, Orimadegun, Adebola, O'Riordan, Sean, Ouedraogo, Issa, Oyola, Samuel, Parker, Michael, Pearson, Richard, Pensulo, Paul, Phiri, Ajib, Phu, Nguyen, Pinder, Margaret, Pirinen, Matti, Plowe, Chris, Potter, Claire, Poudiougou, Belco, Puijalon, Odile, Quyen, Nguyen, Ragoussis, Ioannis, Ragoussis, Jiannis, Rasheed, Oba, Reeder, John, Reyburn, Hugh, Riley, Eleanor, Risley, Paul, Rockett, Kirk, Rodford, Joanne, Rogers, Jane, Rogers, William, Ruano-Rubio, Valentín, Sabally-Ceesay, Kumba, Sadiq, Abubacar, Saidy-Khan, Momodou, Saine, Horeja, Sakuntabhai, Anavaj, Sall, Abdourahmane, Sambian, David, Sambou, Idrissa, Sanjoaquin, Miguel, Shah, Shivang, Shelton, Jennifer, Siba, Peter, Silva, Nilupa, Simmons, Cameron, Simpore, Jaques, Singhasivanon, Pratap, Sinh, Dinh, Sirima, Sodiomon, Sirugo, Giorgio, Sisay-Joof, Fatoumatta, Sissoko, Sibiry, Small, Kerrin, Somaskantharajah, Elilan, Spencer, Chris, Stalker, Jim, Stevens, Marryat, Suriyaphol, Prapat, Sylverken, Justice, Taal, Bintou, Tall, Adama, Taylor, Terrie, Teo, Yik, Thai, Cao, Thera, Mahamadou, Titanji, Vincent, Toure, Ousmane, Troye-Blomberg, Marita, Usen, Stanley, Vanderwal, Aaron, Wangai, Hannah, Watson, Renee, Williams, Thomas, Wilson, Michael, Wrigley, Rebecca, Yafi, Clarisse, Yamoah, Lawrence, The Wellcome Trust Centre for Human Genetics [Oxford], University of Oxford, London School of Hygiene and Tropical Medicine (LSHTM), The Wellcome Trust Sanger Institute [Cambridge], St Mary's Hospital, Imperial College, TNW and MM are funded through awards from the Wellcome Trust (grants 091758 and 202800 [to TNW] and grant 088634 [to MM]) and DPK and TGC receive support from the Medical Research Council (grant G19/9 [to DPK] and grants MR/K000551/1, MR/M01360X/1, MR/N010469/1, and MC_PC_15103 [to TGC]). The research leading to these results received funding from the European Community's Seventh Framework Programme (FP7/2007-2013, under grant agreement 242095) and from the Medical Research Council (grant G0600718). MalariaGEN is supported by the Wellcome Trust (WT077383/Z/05/Z) and by the Foundation for the National Institutes of Health (grant 566) as part of the Bill & Melinda Gates' Grand Challenges in Global Health Initiative. The Resource Centre for Genomic Epidemiology of Malaria is supported by the Wellcome Trust (grant 090770/Z/09/Z). Support was also provided by the Medical Research Council (grant G0600718). The Wellcome Trust also provides core awards to the Wellcome Trust Centre for Human Genetics (grant 090532/Z/09/Z) and to the Wellcome Trust Sanger Institute (grant 098051). This work forms part of a larger collaboration with the MalariaGEN Consortium, whose members are listed at http://www.malariagen.net/projects/host/consortium-members. This paper is published with permission from the Director of the Kenya Medical Research Institute (KEMRI)., MalariaGEN Consortium (Anavaj Sakuntabhai), and European Project: 242095,EC:FP7:HEALTH,FP7-HEALTH-2009-single-stage,EVIMALAR(2009)

Subjects
Case-Control Studies, Child, Child, Preschool, Female, Gene Frequency, Genetic Predisposition to Disease, Humans, Kenya, Malaria, Male, Polymorphism, Genetic, Hematology, macromolecular substances, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Article, Genetic, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, parasitic diseases, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Polymorphism, Preschool
Abstract

Summary Background Human genetic factors are important determinants of malaria risk. We investigated associations between multiple candidate polymorphisms—many related to the structure or function of red blood cells—and risk for severe Plasmodium falciparum malaria and its specific phenotypes, including cerebral malaria, severe malaria anaemia, and respiratory distress. Methods We did a case-control study in Kilifi County, Kenya. We recruited as cases children presenting with severe malaria to the high-dependency ward of Kilifi County Hospital. We included as controls infants born in the local community between Aug 1, 2006, and Sept 30, 2010, who were part of a genetics study. We tested for associations between a range of candidate malaria-protective genes and risk for severe malaria and its specific phenotypes. We used a permutation approach to account for multiple comparisons between polymorphisms and severe malaria. We judged p values less than 0·005 significant for the primary analysis of the association between candidate genes and severe malaria. Findings Between June 11, 1995, and June 12, 2008, 2244 children with severe malaria were recruited to the study, and 3949 infants were included as controls. Overall, 263 (12%) of 2244 children with severe malaria died in hospital, including 196 (16%) of 1233 with cerebral malaria. We investigated 121 polymorphisms in 70 candidate severe malaria-associated genes. We found significant associations between risk for severe malaria overall and polymorphisms in 15 genes or locations, of which most were related to red blood cells: ABO, ATP2B4, ARL14, CD40LG, FREM3, INPP4B, G6PD, HBA (both HBA1 and HBA2), HBB, IL10, LPHN2 (also known as ADGRL2), LOC727982, RPS6KL1, CAND1, and GNAS. Combined, these genetic associations accounted for 5·2% of the variance in risk for developing severe malaria among individuals in the general population. We confirmed established associations between severe malaria and sickle-cell trait (odds ratio [OR] 0·15, 95% CI 0·11–0·20; p=2·61 × 10−58), blood group O (0·74, 0·66–0·82; p=6·26 × 10−8), and –α3·7-thalassaemia (0·83, 0·76–0·90; p=2·06 × 10−6). We also found strong associations between overall risk of severe malaria and polymorphisms in both ATP2B4 (OR 0·76, 95% CI 0·63–0·92; p=0·001) and FREM3 (0·64, 0·53–0·79; p=3·18 × 10−14). The association with FREM3 could be accounted for by linkage disequilibrium with a complex structural mutation within the glycophorin gene region (comprising GYPA, GYPB, and GYPE) that encodes for the rare Dantu blood group antigen. Heterozygosity for Dantu was associated with risk for severe malaria (OR 0·57, 95% CI 0·49–0·68; p=3·22 × 10−11), as was homozygosity (0·26, 0·11–0·62; p=0·002). Interpretation Both ATP2B4 and the Dantu blood group antigen are associated with the structure and function of red blood cells. ATP2B4 codes for plasma membrane calcium-transporting ATPase 4 (the major calcium pump on red blood cells) and the glycophorins are ligands for parasites to invade red blood cells. Future work should aim at uncovering the mechanisms by which these polymorphisms can result in severe malaria protection and investigate the implications of these associations for wider health. 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
2018
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8. Genomic epidemiology of artemisinin resistant malaria

Author

Amato, Roberto, Miotto, Olivo, Woodrow, Charles J, Almagro-Garcia, Jacob, Sinha, Ipsita, Campino, Susana, Mead, Daniel, Drury, Eleanor, Kekre, Mihir, Sanders, Mandy, Amambua-Ngwa, Alfred, Amaratunga, Chanaki, Amenga-Etego, Lucas, Andrianaranjaka, Voahangy, Apinjoh, Tobias, Ashley, Elizabeth, Auburn, Sarah, Awandare, Gordon, Baraka, Vito, Barry, Alyssa, Boni, Maciej, Borrmann, Steffen, Bousema, Teun, Branch, Oralee, Bull, Peter, Chotivanich, Kesinee, Conway, David, Craig, Alister, Day, Nicholas, Djimde, Abdoulaye, Dolecek, Christiane, Dondorp, Arjen M, Drakeley, Chris, Duffy, Patrick, Echeverry, Diego F, Egwang, Thomas, Fairhurst, Rick, Faiz, Abul, Fanello, Caterina, Hien, Tran Tinh, Hodgson, Abraham, Imwong, Mallika, Ishengoma, Deus, Lim, Pharath, Lon, Chanthap, Marfurt, Jutta, Marsh, Kevin, Mayxay, Mayfong, Michon, Pascal, Mobegi, Victor, Mokuolu, Olugbenga, Montgomery, Jacqui, Mueller, Ivo, Kyaw, Myat Phone, Newton, Paul N, Nosten, François, Noviyanti, Rintis, Nzila, Alexis, Ocholla, Harold, Oduro, Abraham, Onyamboko, Marie, Ouédraogo, Jean-Bosco, Phyo, Aung, Plowe, Christopher, Price, Ric, Pukrittayakamee, Sasithon, Randrianarivelojosia, Milijaona, Ringwald, Pascal, Ruiz, Lastenia, Saunders, David, Shayo, Alex, Siba, Peter, Takala-Harrison, Shannon, Thanh, Thuy-Nhien, Thathy, Vandana, Verra, Federica, Wendler, Jason, White, Nicholas, Ye, Htut, Cornelius, Victoria, Giacomantonio, Rachel, Muddyman, Dawn, Henrichs, Christa, Malangone, Cinzia, Jyothi, Dushyanth, Pearson, Richard, Rayner, Julian, McVean, Gilean, Rockett, Kirk, Miles, Alistair, Vauterin, Paul, Jeffery, Ben, Manske, Magnus, Stalker, Jim, MacInnis, Bronwyn, Kwiatkowski, Dominic, The Wellcome Trust Sanger Institute [Cambridge], Mahidol Oxford Tropical Medicine Research Unit, University of Oxford [Oxford]-Mahidol University [Bangkok], The Wellcome Trust Centre for Human Genetics [Oxford], University of Oxford [Oxford], Medical Research Council Unit The Gambia (MRC), National Institute of Allergy and Infectious Diseases [Bethesda] (NIAID-NIH), National Institutes of Health [Bethesda] (NIH), Navrongo Health Research Centre [Navrongo, Ghana] (NHRC), G4 malaria group [Antananarivo, Madagascar] (IPM), Institut Pasteur de Madagascar, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), University of Buéa, Global and Tropical Health Division [Rocklands, Australia], Menzies School of Health Research [Australia], Charles Darwin University-Charles Darwin University, West African Centre for Cell Biology of Infectious Pathogens [Legon, Ghana] (WACCBIP), University of Ghana, National Institute for Medical Research [Tanzania] (NIMR), The Walter and Eliza Hall Institute of Medical Research (WEHI), Oxford University Clinical Research Unit [Ho Chi Minh City] (OUCRU), KEMRI-Wellcome Trust Research Programme (KWTRP), London School of Hygiene and Tropical Medicine (LSHTM), New York University School of Medicine, NYU System (NYU), Faculty of Tropical Medicine [Bangkok, Thailand], Mahidol University [Bangkok], Liverpool School of Tropical Medicine (LSTM), Faculté de Médecine, de pharmacie et d’Odonto-Stomatologie [Bamako, Mali] (FMPOS), Université de Bamako, Department of Entomology [West Lafayette], Purdue University [West Lafayette], Med Biotech Laboratories [Kampala, Ouganda] (MBL), Armed Forces Research Institute of Medical Sciences [Bangkok] (AFRIMS), Lao-Oxford-Mahosot Hospital-Wellcome Trust Research Unit (LOMWRU), Mahidol University [Bangkok]-Mahosot Hospital, Faculty of Medicine and Health Sciences [Madang, Papouasie-Nouvelle-Guinée], Divine Word University [Papouasie-Nouvelle-Guinée] (DWU), University of Ilorin, Department of Entomology [University Park], Pennsylvania State University (Penn State), Penn State System-Penn State System, University of Melbourne, Ministry of health and sport [Yangon, Myanmar] (MoHS), Eijkman Institute for Molecular Biology [Jakarta], King Fahd University of Petroleum and Minerals (KFUPM), Malawi Liverpool Wellcome Trust Clinical Research Programme (MLW), Liverpool School of Tropical Medicine (LSTM)-University of Liverpool-Wellcome Trust-University of Malawi, University of Kinshasa (UNIKIN), Institut de Recherche en Sciences de la Santé (IRSS) / Centre Muraz, Shoklo Malaria Research Unit [Mae Sot, Thailand] (SMRU), Mahidol Oxford Tropical Medicine Research Unit (MORU), Wellcome Trust-Mahidol University [Bangkok]-University of Oxford [Oxford]-Wellcome Trust-Mahidol University [Bangkok]-University of Oxford [Oxford], University of Maryland School of Medicine, University of Maryland System, Centre for Tropical Medicine and Global Health [Oxford, UK], Nuffield Department of Medicine [Oxford, UK] (Big Data Institute), University of Oxford [Oxford]-University of Oxford [Oxford], Department of Clinical Tropical Medicine [Bangkok, Thailand] (Faculty of Tropical Medicine), Global Malaria Programme, Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), Universidad Nacional de la Amazonía Peruana [Loreto, Perou] (UNAP), University of Dodoma [Tanzanie] (UDOM), Papua New Guinea Institute of Medical Research (PNG-IMR), Wellcome Trust-Mahidol University [Bangkok]-University of Oxford [Oxford], The sequencing, analysis, informatics and management of the Community Project are supported by the Wellcome Trust through Sanger Institute core funding (098051) and a Strategic Award (090770/Z/09/Z) and by the MRC Centre for Genomics and Global Health which is jointly funded by the Medical Research Council and the Department for International Development (DFID) (G0600718, M006212). AEB and IM acknowledge the Victorian State Government Operational Infrastructure Support and Australian Government NHMRC IRIISS., This study was conducted by the MalariaGEN Plasmodium falciparum Community Project, and was made possible by clinical parasite samples contributed by partner studies, whose investigators are represented in the author list. RA and OM contributed equally. In addition, the authors would like to thank the following individuals, who contributed to partner studies or to the MalariaGEN Resource Centre, making this study possible: James Abugri, Nicholas Amoako, Steven M Kiara, John Okombo, Rogelin Raherinjafy, Seheno Razanatsiorimalala, Hongying Jiang, Xin-zhuan Su., and MalariaGEN Plasmodium Falciparum C

Subjects
0301 basic medicine, Drug resistance, Pharmacology, MESH: Asia, Southeastern/epidemiology, MESH: Malaria, Falciparum/epidemiology, Malaria, Falciparum, Artemisinin, Biology (General), GeneralLiterature_REFERENCE(e.g.,dictionaries,encyclopedias,glossaries), Asia, Southeastern, Genetics, Molecular Epidemiology, Microbiology and Infectious Disease, education.field_of_study, MESH: Plasmodium falciparum/genetics, General Neuroscience, General Medicine, MESH: Artemisinins/pharmacology, Artemisinins, 3. Good health, Genomics and Evolutionary Biology, kelch13, Medicine, MESH: Plasmodium falciparum/drug effects, Research Article, medicine.drug, Combination therapy, plasmodium falciparum, QH301-705.5, infectious disease, MESH: Antimalarials/pharmacology, Science, 030106 microbiology, Population, malaria, MESH: Plasmodium falciparum/classification, MESH: Malaria, Falciparum/parasitology, Biology, General Biochemistry, Genetics and Molecular Biology, Antimalarials, 03 medical and health sciences, parasitic diseases, medicine, genomics, MESH: Molecular Epidemiology, education, MESH: Drug Resistance, [SDV.GEN]Life Sciences [q-bio]/Genetics, drug resistance, General Immunology and Microbiology, Molecular epidemiology, evolutionary biology, microbiology, Plasmodium falciparum, medicine.disease, biology.organism_classification, MESH: Africa/epidemiology, lnfectious Diseases and Global Health Radboud Institute for Health Sciences [Radboudumc 4], 030104 developmental biology, artemisinin, Infectious disease (medical specialty), Africa, Other, Human medicine, MESH: Plasmodium falciparum/isolation & purification, Malaria
Abstract

The current epidemic of artemisinin resistant Plasmodium falciparum in Southeast Asia is the result of a soft selective sweep involving at least 20 independent kelch13 mutations. In a large global survey, we find that kelch13 mutations which cause resistance in Southeast Asia are present at low frequency in Africa. We show that African kelch13 mutations have originated locally, and that kelch13 shows a normal variation pattern relative to other genes in Africa, whereas in Southeast Asia there is a great excess of non-synonymous mutations, many of which cause radical amino-acid changes. Thus, kelch13 is not currently undergoing strong selection in Africa, despite a deep reservoir of variations that could potentially allow resistance to emerge rapidly. The practical implications are that public health surveillance for artemisinin resistance should not rely on kelch13 data alone, and interventions to prevent resistance must account for local evolutionary conditions, shown by genomic epidemiology to differ greatly between geographical regions. DOI: http://dx.doi.org/10.7554/eLife.08714.001, eLife digest Malaria is an infectious disease caused by a microscopic parasite called Plasmodium, which is transferred between humans by mosquitos. One species of malaria parasite called Plasmodium falciparum can cause particularly severe and life-threatening forms of the disease. Currently, the most widely used treatment for P. falciparum infections is artemisinin combination therapy, a treatment that combines the drug artemisinin (or a closely related molecule) with another antimalarial drug. However, resistance to artemisinin has started to spread throughout Southeast Asia. Artemisinin resistance is caused by mutations in a parasite gene called kelch13, and researchers have identified over 20 different mutations in P. falciparum that confer artemisinin resistance. The diversity of mutations involved, and the fact that the same mutation can arise independently in different locations, make it difficult to track the spread of resistance using conventional molecular marker approaches. Here, Amato, Miotto et al. sequenced the entire genomes of more than 3,000 clinical samples of P. falciparum from Southeast Asia and Africa, collected as part of a global network of research groups called the MalariaGEN Plasmodium falciparum Community Project. Amato, Miotto et al. found that African parasites had independently acquired many of the same kelch13 mutations that are known to cause resistance to artemisinin in Southeast Asia. However the kelch13 mutations seen in Africa remained at low levels in the parasite population, and appeared to be under much less pressure for evolutionary selection than those found in Southeast Asia. These findings demonstrate that the emergence and spread of resistance to antimalarial drugs does not depend solely on the mutational process, but also on other factors that influence whether the mutations will spread in the population. Understanding how this is affected by different patterns of drug treatments and other environmental conditions will be important in developing more effective strategies for combating malaria. DOI: http://dx.doi.org/10.7554/eLife.08714.002

Published
2016
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9. Genomic epidemiology of the current wave of artemisinin resistant malaria

Author

Amato, Roberto, Miotto, Olivo, Woodrow, Charles, Almagro-Garcia, Jacob, Sinha, Ipsita, Campino, Susana, Mead, Daniel, Drury, Eleanor, Kekre, Mihir, Sanders, Mandy, Amambua-Ngwa, Alfred, Amaratunga, Chanaki, Amenga-Etego, Lucas, Anderson, Tim JC, Andrianaranjaka, Voahangy, Apinjoh, Tobias, Ashley, Elizabeth, Auburn, Sarah, Awandare, Gordon A, Baraka, Vito, Barry, Alyssa, Boni, Maciej F, Borrmann, Steffen, Bousema, Teun, Branch, Oralee, Bull, Peter C, Chotivanich, Kesinee, Conway, David J, Craig, Alister, Day, Nicholas P, Djimdé, Abdoulaye, Dolecek, Christiane, Dondorp, Arjen M, Drakeley, Chris, Duffy, Patrick, Echeverri-Garcia, Diego F, Egwang, Thomas G, Fairhurst, Rick M, Faiz, Md. Abul, Fanello, Caterina I, Hien, Tran Tinh, Hodgson, Abraham, Imwong, Mallika, Ishengoma, Deus, Lim, Pharath, Lon, Chanthap, Marfurt, Jutta, Marsh, Kevin, Mayxay, Mayfong, Mobegi, Victor, Mokuolu, Olugbenga, Montgomery, Jacqui, Mueller, Ivo, Kyaw, Myat Phone, Newton, Paul N, Nosten, Francois, Noviyanti, Rintis, Nzila, Alexis, Ocholla, Harold, Oduro, Abraham, Onyamboko, Marie, Ouedraogo, Jean-Bosco, Phyo, Aung Pyae, Plowe, Christopher V, Price, Ric N, Pukrittayakamee, Sasithon, Randrianarivelojosia, Milijaona, Ringwald, Pascal, Ruiz, Lastenia, Saunders, David, Shayo, Alex, Siba, Peter, Takala-Harrison, Shannon, Thanh, Thuy-Nhien Nguyen, Thathy, Vandana, Verra, Federica, White, Nicholas J, Htut, Ye, Cornelius, Victoria J, Giacomantonio, Rachel, Muddyman, Dawn, Henrichs, Christa, Malangone, Cinzia, Jyothi, Dushyanth, Pearson, Richard D, Rayner, Julian C, McVean, Gilean, Rockett, Kirk, Miles, Alistair, Vauterin, Paul, Jeffery, Ben, Manske, Magnus, Stalker, Jim, MacInnis, Bronwyn, and Kwiatkowski, Dominic P

Subjects
0303 health sciences, medicine.medical_specialty, biology, Resistance (ecology), business.industry, 030231 tropical medicine, Plasmodium falciparum, medicine.disease, biology.organism_classification, 3. Good health, Biotechnology, 03 medical and health sciences, 0302 clinical medicine, Public health surveillance, Evolutionary biology, parasitic diseases, Epidemiology, medicine, Artemisinin, Current wave, Selective sweep, business, Malaria, 030304 developmental biology, medicine.drug
Abstract

Artemisinin resistant Plasmodium falciparum is advancing across Southeast Asia in a soft selective sweep involving at least 20 independent kelch13 mutations. In a large global survey, we find that kelch13 mutations which cause resistance in Southeast Asia are present at low frequency in Africa. We show that African kelch13 mutations have originated locally, and that kelch13 shows a normal variation pattern relative to other genes in Africa, whereas in Southeast Asia there is a great excess of non‐synonymous mutations, many of which cause radical amino‐acid changes. Thus, kelch13 is not currently undergoing strong selection in Africa, despite a deep reservoir of standing variation that could potentially allow resistance to emerge rapidly. The practical implications are that public health surveillance for artemisinin resistance should not rely on kelch13 data alone, and interventions to prevent resistance must account for local evolutionary conditions, shown by genomic epidemiology to differ greatly between geographical regions.

Published
2015
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10. Origins of the current outbreak of multidrug-resistant malaria in southeast Asia: a retrospective genetic study.

Author

Drury, Eleanor, Stalker, Jim, Amato, Roberto, Pearson, Richard D, Almagro-Garcia, Jacob, Kwiatkowski, Dominic P, Miotto, Olivo, Amaratunga, Chanaki, Fairhurst, Rick M, Lim, Pharath, Suon, Seila, and Sreng, Sokunthea

Subjects
*MALARIA, *MULTIDRUG resistance, *DISEASE outbreaks, *RETROSPECTIVE studies, *GENETICS
Abstract

Summary Background Antimalarial resistance is rapidly spreading across parts of southeast Asia where dihydroartemisinin–piperaquine is used as first-line treatment for Plasmodium falciparum malaria. The first published reports about resistance to antimalarial drugs came from western Cambodia in 2013. Here, we analyse genetic changes in the P falciparum population of western Cambodia in the 6 years before those reports. Methods We analysed genome sequence data on 1492 P falciparum samples from 11 locations across southeast Asia, including 464 samples collected in western Cambodia between 2007 and 2013. Different epidemiological origins of resistance were identified by haplotypic analysis of the kelch13 artemisinin resistance locus and the plasmepsin 2–3 piperaquine resistance locus. Findings We identified more than 30 independent origins of artemisinin resistance, of which the KEL1 lineage accounted for 140 (91%) of 154 parasites resistant to dihydroartemisinin–piperaquine. In 2008, KEL1 combined with PLA1, the major lineage associated with piperaquine resistance. By 2013, the KEL1/PLA1 co-lineage had reached a frequency of 63% (24/38) in western Cambodia and had spread to northern Cambodia. Interpretation The KEL1/PLA1 co-lineage emerged in the same year that dihydroartemisinin–piperaquine became the first-line antimalarial drug in western Cambodia and spread rapidly thereafter, displacing other artemisinin-resistant parasite lineages. These findings have important implications for management of the global health risk associated with the current outbreak of multidrug-resistant malaria in southeast Asia. Funding Wellcome Trust, Bill & Melinda Gates Foundation, Medical Research Council, UK Department for International Development, and the Intramural Research Program of the National Institute of Allergy and Infectious Diseases. [ABSTRACT FROM AUTHOR]

Published
2018
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11. Genetic markers associated with dihydroartemisinin-piperaquine failure in Plasmodium falciparum malaria in Cambodia: a genotype-phenotype association study.

Author

Amato, Roberto, Lim, Pharath, Miotto, Olivo, Amaratunga, Chanaki, Dek, Dalin, Pearson, Richard D, Almagro-Garcia, Jacob, Neal, Aaron T, Sreng, Sokunthea, Suon, Seila, Drury, Eleanor, Jyothi, Dushyanth, Stalker, Jim, Kwiatkowski, Dominic P, and Fairhurst, Rick M

Subjects
*PLASMODIUM falciparum, *GENETIC markers, *ARTEMISININ, *MALARIA treatment, *GENOTYPES, *DISEASE prevalence, *THERAPEUTICS, *DRUG therapy for malaria, *QUINOLINE, *ANTIMALARIALS, *COMBINATION drug therapy, *DRUG resistance, *GENETIC polymorphisms, *GENETIC techniques, *MALARIA, *PROTOZOA, *RESEARCH funding, *TREATMENT effectiveness, *SEQUENCE analysis, *PHARMACODYNAMICS
Abstract

Background: As the prevalence of artemisinin-resistant Plasmodium falciparum malaria increases in the Greater Mekong subregion, emerging resistance to partner drugs in artemisinin combination therapies seriously threatens global efforts to treat and eliminate this disease. Molecular markers that predict failure of artemisinin combination therapy are urgently needed to monitor the spread of partner drug resistance, and to recommend alternative treatments in southeast Asia and beyond.Methods: We did a genome-wide association study of 297 P falciparum isolates from Cambodia to investigate the relationship of 11 630 exonic single-nucleotide polymorphisms (SNPs) and 43 copy number variations (CNVs) with in-vitro piperaquine 50% inhibitory concentrations (IC50s), and tested whether these genetic variants are markers of treatment failure with dihydroartemisinin-piperaquine. We then did a survival analysis of 133 patients to determine whether candidate molecular markers predicted parasite recrudescence following dihydroartemisinin-piperaquine treatment.Findings: Piperaquine IC50s increased significantly from 2011 to 2013 in three Cambodian provinces (2011 vs 2013 median IC50s: 20·0 nmol/L [IQR 13·7-29·0] vs 39·2 nmol/L [32·8-48·1] for Ratanakiri, 19·3 nmol/L [15·1-26·2] vs 66·2 nmol/L [49·9-83·0] for Preah Vihear, and 19·6 nmol/L [11·9-33·9] vs 81·1 nmol/L [61·3-113·1] for Pursat; all p≤10-3; Kruskal-Wallis test). Genome-wide analysis of SNPs identified a chromosome 13 region that associates with raised piperaquine IC50s. A non-synonymous SNP (encoding a Glu415Gly substitution) in this region, within a gene encoding an exonuclease, associates with parasite recrudescence following dihydroartemisinin-piperaquine treatment. Genome-wide analysis of CNVs revealed that a single copy of the mdr1 gene on chromosome 5 and a novel amplification of the plasmepsin 2 and plasmepsin 3 genes on chromosome 14 also associate with raised piperaquine IC50s. After adjusting for covariates, both exo-E415G and plasmepsin 2-3 markers significantly associate (p=3·0 × 10-8 and p=1·7 × 10-7, respectively) with decreased treatment efficacy (survival rates 0·38 [95% CI 0·25-0·51] and 0·41 [0·28-0·53], respectively).Interpretation: The exo-E415G SNP and plasmepsin 2-3 amplification are markers of piperaquine resistance and dihydroartemisinin-piperaquine failures in Cambodia, and can help monitor the spread of these phenotypes into other countries of the Greater Mekong subregion, and elucidate the mechanism of piperaquine resistance. Since plasmepsins are involved in the parasite's haemoglobin-to-haemozoin conversion pathway, targeted by related antimalarials, plasmepsin 2-3 amplification probably mediates piperaquine resistance.Funding: Intramural Research Program of the US National Institute of Allergy and Infectious Diseases, National Institutes of Health, Wellcome Trust, Bill & Melinda Gates Foundation, Medical Research Council, and UK Department for International Development. [ABSTRACT FROM AUTHOR]

Published
2017
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