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1. Relation Between the Dantu Blood Group Variant and Bacteremia in Kenyan Children: A Population-Based Case-Control Study.

Author

Kariuki, Silvia N, Gilchrist, James J, Uyoga, Sophie, Macharia, Alexander, Makale, Johnstone, Rayner, Julian C, and Williams, Thomas N

Subjects
BACTERIAL diseases, BACTEREMIA, BLOOD groups, SINGLE nucleotide polymorphisms, KENYANS
Abstract

Background The Dantu blood group variant protects against Plasmodium falciparum infections, but its wider consequences have not been previously explored. Here, we investigate the impact of Dantu on susceptibility to bacteremia. Methods We conducted a case-control study in children presenting with community-acquired bacteremia to Kilifi County Hospital in Kenya between 1998 and 2010. We used logistic regression to test for associations between the Dantu marker single-nucleotide polymorphism rs186873296 A > G and both all-cause and pathogen-specific bacteremia under an additive model. We used date of admission as a proxy measure of malaria transmission intensity, given known differences in malaria prevalence over the course of the study. Results Dantu was associated with protection from all-cause bacteremia (OR, 0.81; P =.014), the association being greatest in homozygotes (OR, 0.30; P =.013). This protection was shared across the major bacterial pathogens but, notably, was only significant during the era of high malaria transmission pre-2003 (OR, 0.79; P =.023). Conclusions Consistent with previous studies showing the indirect impact on bacteremia risk of other malaria-associated red cell variants, our study also shows that Dantu is protective against bacteremia via its effect on malaria risk. Dantu does not appear to be under balancing selection through an increased risk of bacterial infections. [ABSTRACT FROM AUTHOR]

Published
2025
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2. Malaria protection due to sickle haemoglobin depends on parasite genotype

Author

Band, Gavin, Leffler, Ellen M., Jallow, Muminatou, Sisay-Joof, Fatoumatta, Ndila, Carolyne M., Macharia, Alexander W., Hubbart, Christina, Jeffreys, Anna E., Rowlands, Kate, Nguyen, Thuy, Gonçalves, Sónia, Ariani, Cristina V., Stalker, Jim, Pearson, Richard D., Amato, Roberto, Drury, Eleanor, Sirugo, Giorgio, d’Alessandro, Umberto, Bojang, Kalifa A., Marsh, Kevin, Peshu, Norbert, Saelens, Joseph W., Diakité, Mahamadou, Taylor, Steve M., Conway, David J., Williams, Thomas N., Rockett, Kirk A., and Kwiatkowski, Dominic P.

Published
2022
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3. Human candidate gene polymorphisms and risk of severe malaria in children in Kilifi, Kenya: a case-control association study

Author

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, Band, Gavin, 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, Clarke, Geraldine, 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, Hubbart, Christina, Hughes, Catherine, Hussein, Ayman, Hutton, Robert, Ibrahim, Muntaser, Ishengoma, Deus, Jaiteh, Jula, Jallow, Mariatou, Jallow, Muminatou, Jammeh, Kebba, Jasseh, Momodou, Jeffreys, Anna, 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, Le, Si, Leffler, Ellen, Lemnge, Martha, Lin, Enmoore, Ly, Alioune, Macharia, Alexander, MacInnis, Bronwyn, Mai, Nguyen, Makani, Julie, Malangone, Cinzia, Mangano, Valentina, Manjurano, Alphaxard, Manneh, Lamin, Manning, Laurens, Manske, Magnus, Marsh, Kevin, 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, Peshu, Norbert, 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, Rowlands, Kate, Ruano-Rubio, Valentín, Sabally-Ceesay, Kumba, Sadiq, Abubacar, Saidy-Khan, Momodou, Saine, Horeja, Sakuntabhai, Anavaj, Sall, Abdourahmane, Sambian, David, Sambou, Idrissa, SanJoaquin, Miguel, Sepúlveda, Nuno, 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, Uyoga, Sophie, Vanderwal, Aaron, Wangai, Hannah, Watson, Renee, Williams, Thomas, Wilson, Michael, Wrigley, Rebecca, Yafi, Clarisse, Yamoah, Lawrence, Ndila, Carolyne M, Macharia, Alexander W, Nyutu, Gideon, Ojal, John, Shebe, Mohammed, Awuondo, Kennedy O, Mturi, Neema, Tsofa, Benjamin, Clark, Taane G, Kariuki, Silvia, Mackinnon, Margaret, Maitland, Kathryn, Kwiatkowski, Dominic P, Rockett, Kirk A, and Williams, Thomas N

Published
2018
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5. The Dantu blood group prevents parasite growth in vivo: Evidence from a controlled human malaria infection study

Author

Kariuki, Silvia N, Macharia, Alexander W, Makale, Johnstone, Nyamu, Wilfred, Hoffman, Stephen L, Kapulu, Melissa C, Bejon, Philip, Rayner, Julian C, Williams, Thomas N, CHMI-SIKA Study Team, Kariuki, Silvia N [0000-0003-0801-5285], Rayner, Julian C [0000-0002-9835-1014], Williams, Thomas N [0000-0003-4456-2382], and Apollo - University of Cambridge Repository

Subjects
Adult, infectious disease, microbiology, malaria, P. falciparum, Kenya, challenge study, host genetics, genomics, Blood Group Antigens, Animals, Humans, genetics, Parasites, human, Malaria, Falciparum
Abstract

BACKGROUND: The long co-evolution of Homo sapiens and Plasmodium falciparum has resulted in the selection of numerous human genetic variants that confer an advantage against severe malaria and death. One such variant is the Dantu blood group antigen, which is associated with 74% protection against severe and complicated P. falciparum malaria infections in homozygous individuals, similar to that provided by the sickle haemoglobin allele (HbS). Recent in vitro studies suggest that Dantu exerts this protection by increasing the surface tension of red blood cells, thereby impeding the ability of P. falciparum merozoites to invade them and reducing parasite multiplication. However, no studies have yet explored this hypothesis in vivo. METHODS: We investigated the effect of Dantu on early phase P. falciparum (Pf) infections in a controlled human malaria infection (CHMI) study. 141 sickle-negative Kenyan adults were inoculated with 3.2 × 103 aseptic, purified, cryopreserved Pf sporozoites (PfSPZ Challenge) then monitored for blood-stage parasitaemia for 21 days by quantitative polymerase chain reaction (qPCR)analysis of the 18S ribosomal RNA P. falciparum gene. The primary endpoint was blood-stage P. falciparum parasitaemia of ≥500/μl while the secondary endpoint was the receipt of antimalarial treatment in the presence of parasitaemia of any density. On study completion, all participants were genotyped both for Dantu and for four other polymorphisms that are associated with protection against severe falciparum malaria: α+-thalassaemia, blood group O, G6PD deficiency, and the rs4951074 allele in the red cell calcium transporter ATP2B4. RESULTS: The primary endpoint was reached in 25/111 (22.5%) non-Dantu subjects in comparison to 0/27 (0%) Dantu heterozygotes and 0/3 (0.0%) Dantu homozygotes (p=0.01). Similarly, 49/111 (44.1%) non-Dantu subjects reached the secondary endpoint in comparison to only 7/27 (25.9%) and 0/3 (0.0%) Dantu heterozygotes and homozygotes, respectively (p=0.021). No significant impacts on either outcome were seen for any of the other genetic variants under study. CONCLUSIONS: This study reveals, for the first time, that the Dantu blood group is associated with high-level protection against early, non-clinical, P. falciparum malaria infections in vivo. Learning more about the mechanisms involved could potentially lead to new approaches to the prevention or treatment of the disease. Our study illustrates the power of CHMI with PfSPZ Challenge for directly testing the protective impact of genotypes previously identified using other methods. FUNDING: The Kenya CHMI study was supported by an award from Wellcome (grant number 107499). SK was supported by a Training Fellowship (216444/Z/19/Z), TNW by a Senior Research Fellowship (202800/Z/16/Z), JCR by an Investigator Award (220266/Z/20/Z), and core support to the KEMRI-Wellcome Trust Research Programme in Kilifi, Kenya (203077), all from Wellcome. The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. For the purpose of Open Access, the authors have applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission. CLINICAL TRIAL NUMBER: NCT02739763.

Published
2023

6. Sickle cell anaemia and severe Plasmodium falciparum malaria: a secondary analysis of the Transfusion and Treatment of African Children Trial (TRACT)

Author

Uyoga, Sophie, primary, Olupot-Olupot, Peter, additional, Connon, Roisin, additional, Kiguli, Sarah, additional, Opoka, Robert O, additional, Alaroker, Florence, additional, Muhindo, Rita, additional, Macharia, Alexander W, additional, Dondorp, Arjen M, additional, Gibb, Diana M, additional, Walker, A Sarah, additional, George, Elizabeth C, additional, Maitland, Kathryn, additional, and Williams, Thomas N, additional

Published
2022
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7. Case Report: β-thalassemia major on the East African coast

Author

Macharia, Alexander W., primary, Mochamah, George, additional, Makale, Johnstone, additional, Howard, Thad, additional, Mturi, Neema, additional, Olupot-Olupot, Peter, additional, Färnert, Anna, additional, Ware, Russell E., additional, and Williams, Thomas N., additional

Published
2022
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8. The Dantu blood group prevents parasite growth in vivo: Evidence from a controlled human malaria infection study.

Author

Kariuki, Silvia N., Macharia, Alexander W., Makale, Johnstone, Nyamu, Wilfred, Hoffman, Stephen L., Kapulu, Melissa C., Bejon, Philip, Rayner, Julian C., and Williams, Thomas N.

Subjects
*BLOOD groups, *MALARIA, *BLOOD group antigens, *GENETIC variation, *ERYTHROCYTES, *GLUCOSE-6-phosphate dehydrogenase deficiency
Abstract

Background: The long co- evolution of Homo sapiens and Plasmodium falciparum has resulted in the selection of numerous human genetic variants that confer an advantage against severe malaria and death. One such variant is the Dantu blood group antigen, which is associated with 74% protection against severe and complicated P. falciparum malaria infections in homozygous individuals, similar to that provided by the sickle haemoglobin allele (HbS). Recent in vitro studies suggest that Dantu exerts this protection by increasing the surface tension of red blood cells, thereby impeding the ability of P. falciparum merozoites to invade them and reducing parasite multiplication. However, no studies have yet explored this hypothesis in vivo. Methods: We investigated the effect of Dantu on early phase P. falciparum (Pf) infections in a controlled human malaria infection (CHMI) study. 141 sickle- negative Kenyan adults were inoculated with 3.2 103 aseptic, purified, cryopreserved Pf sporozoites (PfSPZ Challenge) then monitored for blood- stage parasitaemia for 21 days by quantitative polymerase chain reaction (qPCR)analysis of the 18S ribosomal RNA P. falciparum gene. The primary endpoint was blood- stage P. falciparum parasitaemia of ≥500/μl while the secondary endpoint was the receipt of antimalarial treatment in the presence of parasitaemia of any density. On study completion, all participants were genotyped both for Dantu and for four other polymorphisms that are associated with protection against severe falciparum malaria: α+- thalassaemia, blood group O, G6PD deficiency, and the rs4951074 allele in the red cell calcium transporter ATP2B4. Results: The primary endpoint was reached in 25/111 (22.5%) non- Dantu subjects in comparison to 0/27 (0%) Dantu heterozygotes and 0/3 (0.0%) Dantu homozygotes (p=0.01). Similarly, 49/111 (44.1%) non- Dantu subjects reached the secondary endpoint in comparison to only 7/27 (25.9%) and 0/3 (0.0%) Dantu heterozygotes and homozygotes, respectively (p=0.021). No significant impacts on either outcome were seen for any of the other genetic variants under study. Conclusions: This study reveals, for the first time, that the Dantu blood group is associated with high- level protection against early, non- clinical, P. falciparum malaria infections in vivo. Learning more about the mechanisms involved could potentially lead to new approaches to the prevention or treatment of the disease. Our study illustrates the power of CHMI with PfSPZ Challenge for directly testing the protective impact of genotypes previously identified using other methods. [ABSTRACT FROM AUTHOR]

Published
2023
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9. A predictive algorithm for identifying children with sickle cell anemia among children admitted to hospital with severe anemia in Africa

Author

Olupot‐Olupot, Peter, primary, Connon, Roisin, additional, Kiguli, Sarah, additional, Opoka, Robert O., additional, Alaroker, Florence, additional, Uyoga, Sophie, additional, Nakuya, Margret, additional, Okiror, William, additional, Nteziyaremye, Julius, additional, Ssenyondo, Tonny, additional, Nabawanuka, Eva, additional, Kayaga, Juliana, additional, Williams Mukisa, Cynthia, additional, Amorut, Denis, additional, Muhindo, Rita, additional, Frost, Gary, additional, Walsh, Kevin, additional, Macharia, Alexander W., additional, Gibb, Diana M., additional, Walker, A. Sarah, additional, George, Elizabeth C., additional, Maitland, Kathryn, additional, and Williams, Thomas N., additional

Published
2022
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10. A novel locus of resistance to severe malaria in a region of ancient balancing selection

Author

Band, Gavin, Rockett, Kirk A., Spencer, Chris C.A., Kwiatkowski, Dominic P., Le, Quang Si, Clarke, Geraldine M., Kivinen, Katja, Leffler, Ellen M., Cornelius, Victoria, Conway, David J., Williams, Thomas N., Taylor, Terrie, Bojang, Kalifa A., Doumbo, Ogobara, Thera, Mahamadou A., Modiano, David, Sirima, Sodiomon B., Wilson, Michael D., Koram, Kwadwo A., Agbenyega, Tsiri, Achidi, Eric, Marsh, Kevin, Reyburn, Hugh, Drakeley, Chris, Riley, Eleanor, Molyneux, Malcolm, Jallow, Muminatou, Pinder, Margaret, Toure, Ousmane B., Konate, Salimata, Sissoko, Sibiri, Bougouma, Edith C., Mangano, Valentina D., Amenga-Etego, Lucas N., Ghansah, Anita K., Hodgson, Abraham V.O., Ansong, Daniel, Enimil, Anthony, Evans, Jennifer, Apinjoh, Tobias O., Macharia, Alexander, Ndila, Carolyne M., Newton, Charles, Peshu, Norbert, Uyoga, Sophie, Manjurano, Alphaxard, Kachala, David, Nyirongo, Vysaul, Mead, Daniel, Drury, Eleanor, Auburn, Sarah, Campino, Susana G., MacInnis, Bronwyn, Stalker, Jim, Gray, Emma, Hubbart, Christina, Jeffreys, Anna E., Rowlands, Kate, Mendy, Alieu, Craik, Rachel, Fitzpatrick, Kathryn, Molloy, Sile, Hart, Lee, Hutton, Robert, Kerasidou, Angeliki, and Johnson, Kimberly J.

Published
2015
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11. Malaria protection due to sickle haemoglobin depends on parasite genotype

Author

Band, Gavin, primary, Leffler, Ellen M., additional, Jallow, Muminatou, additional, Sisay-Joof, Fatoumatta, additional, Ndila, Carolyne M., additional, Macharia, Alexander W., additional, Hubbart, Christina, additional, Jeffreys, Anna E., additional, Rowlands, Kate, additional, Nguyen, Thuy, additional, Gonçalves, Sónia, additional, Ariani, Cristina V., additional, Stalker, Jim, additional, Pearson, Richard D., additional, Amato, Roberto, additional, Drury, Eleanor, additional, Sirugo, Giorgio, additional, d’Alessandro, Umberto, additional, Bojang, Kalifa A., additional, Marsh, Kevin, additional, Peshu, Norbert, additional, Saelens, Joseph W., additional, Diakité, Mahamadou, additional, Taylor, Steve M., additional, Conway, David J., additional, Williams, Thomas N., additional, Rockett, Kirk A., additional, and Kwiatkowski, Dominic P., additional

Published
2021
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12. Improving statistical power in severe malaria genetic association studies by augmenting phenotypic precision

Author

Watson, James A, primary, Ndila, Carolyne M, primary, Uyoga, Sophie, additional, Macharia, Alexander, additional, Nyutu, Gideon, additional, Mohammed, Shebe, additional, Ngetsa, Caroline, additional, Mturi, Neema, additional, Peshu, Norbert, additional, Tsofa, Benjamin, additional, Rockett, Kirk, additional, Leopold, Stije, additional, Kingston, Hugh, additional, George, Elizabeth C, additional, Maitland, Kathryn, additional, Day, Nicholas PJ, additional, Dondorp, Arjen M, additional, Bejon, Philip, additional, Williams, Thomas N, additional, Holmes, Chris C, additional, and White, Nicholas J, additional

Published
2021
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13. Author response: Improving statistical power in severe malaria genetic association studies by augmenting phenotypic precision

Author

Watson, James A, primary, Ndila, Carolyne M, additional, Uyoga, Sophie, additional, Macharia, Alexander, additional, Nyutu, Gideon, additional, Mohammed, Shebe, additional, Ngetsa, Caroline, additional, Mturi, Neema, additional, Peshu, Norbert, additional, Tsofa, Benjamin, additional, Rockett, Kirk, additional, Leopold, Stije, additional, Kingston, Hugh, additional, George, Elizabeth C, additional, Maitland, Kathryn, additional, Day, Nicholas PJ, additional, Dondorp, Arjen M, additional, Bejon, Philip, additional, Williams, Thomas, additional, Holmes, Chris C, additional, and White, Nicholas J, additional

Published
2021
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14. The protective effect of sickle cell haemoglobin against severe malaria depends on parasite genotype

Author

Band, Gavin, primary, Leffler, Ellen M., additional, Jallow, Muminatou, additional, Sisay-Joof, Fatoumatta, additional, Ndila, Carolyne M., additional, Macharia, Alexander W., additional, Hubbart, Christina, additional, Jeffreys, Anna E., additional, Rowlands, Kate, additional, Nguyen, Thuy, additional, Goncalves, Sonia M., additional, Ariani, Cristina V., additional, Stalker, Jim, additional, Pearson, Richard D., additional, Amato, Roberto, additional, Drury, Eleanor, additional, Sirugo, Giorgio, additional, D’Alessandro, Umberto, additional, Bojang, Kalifa A., additional, Marsh, Kevin, additional, Peshu, Norbert, additional, Conway, David J., additional, Williams, Thomas N., additional, Rockett, Kirk A., additional, and Kwiatkowski, Dominic P., additional

Published
2021
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15. Plasma Plasmodium falciparum Histidine-rich Protein 2 Concentrations in Children With Malaria Infections of Differing Severity in Kilifi, Kenya

Author

Uyoga, Sophie, primary, Wanjiku, Perpetual, additional, Rop, Jesse C, additional, Makale, Johnstone, additional, Macharia, Alexander W, additional, Nyutu, Gideon M, additional, Shebe, Mohammed, additional, Awuondo, Kennedy A, additional, Mturi, Neema, additional, Woodrow, Charles J, additional, Dondorp, Arjen M, additional, Maitland, Kathryn, additional, and Williams, Thomas N, additional

Published
2020
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17. 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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18. Sickle cell anaemia and severe Plasmodium falciparummalaria: a secondary analysis of the Transfusion and Treatment of African Children Trial (TRACT)

Author

Uyoga, Sophie, Olupot-Olupot, Peter, Connon, Roisin, Kiguli, Sarah, Opoka, Robert O, Alaroker, Florence, Muhindo, Rita, Macharia, Alexander W, Dondorp, Arjen M, Gibb, Diana M, Walker, A Sarah, George, Elizabeth C, Maitland, Kathryn, and Williams, Thomas N

Abstract

Sickle cell anaemia (SCA) has historically been associated with high levels of childhood mortality in Africa. Although malaria has a major contribution to this mortality, to date, the clinical pathology of malaria among children with SCA has been poorly described. We aimed to explore the relationship between SCA and Plasmodium falciparummalaria in further detail by investigating the burden and severity of malaria infections among children recruited with severe anaemia to the TRACT trial of blood transfusion in Africa.

Published
2022
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19. Plasma Plasmodium falciparum Histidine-rich Protein 2 Concentrations in Children With Malaria Infections of Differing Severity in Kilifi, Kenya.

Author

Uyoga, Sophie, Wanjiku, Perpetual, Rop, Jesse C, Makale, Johnstone, Macharia, Alexander W, Nyutu, Gideon M, Shebe, Mohammed, Awuondo, Kennedy A, Mturi, Neema, Woodrow, Charles J, Dondorp, Arjen M, Maitland, Kathryn, and Williams, Thomas N

Subjects
PROTOZOA, PROTEINS, HISTIDINE, PARASITEMIA, CONFIDENCE intervals, BLOOD plasma, MALARIA, SEVERITY of illness index, RISK assessment, MIXED infections, DESCRIPTIVE statistics, BACTERIAL diseases, ANTIGENS, CHILDREN
Abstract

Background Most previous studies support a direct link between total parasite load and the clinical severity of Plasmodium falciparum malaria infections. Methods We estimated P. falciparum parasite loads in 3 groups of children with malaria infections of differing severity: (1) children with World Health Organization–defined severe malaria (n = 1544), (2) children admitted with malaria but without features of severity (n = 200), and (3) children in the community with asymptomatic parasitemia (n = 33). Results Peripheral parasitemias were highest in those with uncomplicated malaria (geometric mean [GM] parasite count, 111 064/μL; 95% confidence interval, CI, 86 798–141 819/μL), almost 3 times higher than in those with severe malaria (39 588/μL; 34 990–44 791/μL) and >100 times higher than in those with asymptomatic malaria (1092/μL; 523–2280/μL). However, the GM P. falciparum histidine-rich protein 2 (Pf HRP2) values (95% CI) increased with severity, being 7 (4–12) ng/mL in asymptomatic malaria, 843 (655–1084) ng/mL in uncomplicated malaria, and 1369 (1244–1506) ng/mL in severe malaria. Pf HRP2 concentrations were markedly lower in the subgroup of patients with severe malaria and concomitant invasive bacterial infections of blood or cerebrospinal fluid (GM concentration, 312 ng/mL; 95% CI, 175–557 ng/mL; P <.001) than in those without such infections (1439 ng/mL; 1307–1584; P <.001). Conclusions The clinical severity of malaria infections related strongly to the total burden of P. falciparum parasites. A quantitative test for plasma concentrations of Pf HRP2 could be useful in identifying children at the greatest clinical risk and identifying critically ill children in whom malaria is not the primary cause. [ABSTRACT FROM AUTHOR]

Published
2021
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20. Two complement receptor one alleles have opposing associations with cerebral malaria and interact with α+thalassaemia

Author

Opi, D Herbert, primary, Swann, Olivia, additional, Macharia, Alexander, additional, Uyoga, Sophie, additional, Band, Gavin, additional, Ndila, Carolyne M, additional, Harrison, Ewen M, additional, Thera, Mahamadou A, additional, Kone, Abdoulaye K, additional, Diallo, Dapa A, additional, Doumbo, Ogobara K, additional, Lyke, Kirsten E, additional, Plowe, Christopher V, additional, Moulds, Joann M, additional, Shebbe, Mohammed, additional, Mturi, Neema, additional, Peshu, Norbert, additional, Maitland, Kathryn, additional, Raza, Ahmed, additional, Kwiatkowski, Dominic P, additional, Rockett, Kirk A, additional, Williams, Thomas N, additional, and Rowe, J Alexandra, additional

Published
2018
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21. Author response: Two complement receptor one alleles have opposing associations with cerebral malaria and interact with α+thalassaemia

Author

Opi, D Herbert, primary, Swann, Olivia, additional, Macharia, Alexander, additional, Uyoga, Sophie, additional, Band, Gavin, additional, Ndila, Carolyne M, additional, Harrison, Ewen M, additional, Thera, Mahamadou A, additional, Kone, Abdoulaye K, additional, Diallo, Dapa A, additional, Doumbo, Ogobara K, additional, Lyke, Kirsten E, additional, Plowe, Christopher V, additional, Moulds, Joann M, additional, Shebbe, Mohammed, additional, Mturi, Neema, additional, Peshu, Norbert, additional, Maitland, Kathryn, additional, Raza, Ahmed, additional, Kwiatkowski, Dominic P, additional, Rockett, Kirk A, additional, Williams, Thomas N, additional, and Rowe, J Alexandra, additional

Published
2018
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22. Genetic determinants of anti-malarial acquired immunity in a large multi-centre study

Author

Shelton, Jennifer MG, Corran, Patrick, Risley, Paul, Silva, Nilupa, Hubbart, Christina, Jeffreys, Anna, Rowlands, Kate, Craik, Rachel, Cornelius, Victoria, Hensmann, Meike, Molloy, Sile, Sepulveda, Nuno, Clark, Taane G, Band, Gavin, Clarke, Geraldine M, Spencer, Christopher CA, Kerasidou, Angeliki, Campino, Susana, Auburn, Sarah, Tall, Adama, Ly, Alioune Badara, Mercereau-Puijalon, Odile, Sakuntabhai, Anavaj, Djimdé, Abdoulaye, Maiga, Boubacar, Touré, Ousmane, Doumbo, Ogobara K, Dolo, Amagana, Troye-Blomberg, Marita, Mangano, Valentina D, Verra, Frederica, Modiano, David, Bougouma, Edith, Sirima, Sodiomon B, Ibrahim, Muntaser, Hussain, Ayman, Eid, Nahid, Elzein, Abier, Mohammed, Hiba, Elhassan, Ahmed, Elhassan, Ibrahim, Williams, Thomas N, Ndila, Carolyne, Macharia, Alexander, Marsh, Kevin, Manjurano, Alphaxard, Reyburn, Hugh, Lemnge, Martha, Ishengoma, Deus, Carter, Richard, Karunaweera, Nadira, Fernando, Deepika, Dewasurendra, Rajika, Drakeley, Christopher J, Riley, Eleanor M, Kwiatkowski, Dominic P, Rockett, Kirk A, MalariaGEN Consortium, The Wellcome Trust Centre for Human Genetics [Oxford], University of Oxford [Oxford], London School of Hygiene and Tropical Medicine (LSHTM), National Institute for Biological Standards and Control (NIBSC), Medicines and Healthcare Products Regulatory Agency (MHRA), Nuffield Department of Population Health [Oxford], The Wellcome Trust Sanger Institute [Cambridge], Unité d'Epidémiologie des Maladies Infectieuses, Institut Pasteur de Dakar, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Immunologie Moléculaire des Parasites, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Génétique fonctionnelle des Maladies infectieuses - Functional Genetics of Infectious Diseases, Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Malaria Research and Training Center [Bamako, Mali], Université de Bamako, Stockholm University, Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Centre National de Recherche et de Formation sur le Paludisme [Ouagadougou, Burkina Faso] (CNRFP), University of Khartoum, KEMRI-Wellcome Trust Research Programme (KWTRP), Tumaini University Makumira, National Institute for Medical Research [Tanzania] (NIMR), University of Edinburgh, University of Colombo [Sri Lanka], MalariaGEN is supported by the Wellcome Trust (077383/Z/05/Z) and by the Foundation for the National Institutes of Health (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 (090770/Z/09/Z). Support was also provided by the Medical Research Council (G0600718). DPK receives support from the Medical Research Council (G19/9). CCAS was supported by a Wellcome Trust Career Development Fellowship (097364/Z/11/Z). The Wellcome Trust also provides core awards to The Wellcome Trust Centre for Human Genetics (075491/Z/04, 090532/Z/09/Z) and the Wellcome Trust Sanger Institute (077012/Z/05/Z). MTB and BM received funding through the EU Network of Excellence EviMalar. VDM was funded by a Biomalpar (European Community’s Sixth Framework Programme) PhD fellowship. FV was funded by the Italian Malaria Network, sponsored by Compagnia di San Paolo, Turin, Italy. TNW is supported by a Senior Research Fellowship from the Wellcome Trust (091758/Z/10/Z). This study was conducted as part of the Joint Malaria Programme, a collaboration between the National Institute for Medical Research (NIMR), Kilimanjaro Christian Medical College (KCMC), the London School of Hygiene and Tropical Medicine (LSHTM) and the Centre for Medical Parasitology, University of Copenhagen (CMP) with funding from the UK Medical Research Council (GG9901439) and the Danish International Development Agency. CJD is supported by the Wellcome Trust (091924). RD is supported by the University of Colombo Research Grants 2011 (AP/3/2011/PG/15)., European Project: 26843,BIOMALPAR, University of Oxford, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), and Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA)

Subjects
Male, Hemoglobin, Sickle, Antibodies, Protozoan, Sickle, MESH: Linear Models, MESH: Child, Child, HbAS, MESH: Infant, Newborn, Antibody, CD36, Genotype, Malaria, Sickle cell trait, Adolescent, Adult, Africa South of the Sahara, Child, Preschool, Female, Humans, Infant, Infant, Newborn, Linear Models, Sri Lanka, Young Adult, Infectious Diseases, Parasitology, MESH: Infant, MESH: Young Adult, Protozoan, [SDV.IMM]Life Sciences [q-bio]/Immunology, MESH: Malaria, Antibodies, parasitic diseases, MESH: Antibodies, Protozoan, Hemoglobin, MESH: Africa South of the Sahara, Preschool, MESH: Sri Lanka, MESH: Adolescent, MESH: Humans, Research, MESH: Child, Preschool, MESH: Adult, Newborn, MESH: Hemoglobin, Sickle, MESH: Male, antibody, cd36, genotype, hbas, malaria, sickle cell trait, infectious diseases, parasitology, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, MESH: Female
Abstract

Background Many studies report associations between human genetic factors and immunity to malaria but few have been reliably replicated. These studies are usually country-specific, use small sample sizes and are not directly comparable due to differences in methodologies. This study brings together samples and data collected from multiple sites across Africa and Asia to use standardized methods to look for consistent genetic effects on anti-malarial antibody levels. Methods Sera, DNA samples and clinical data were collected from 13,299 individuals from ten sites in Senegal, Mali, Burkina Faso, Sudan, Kenya, Tanzania, and Sri Lanka using standardized methods. DNA was extracted and typed for 202 Single Nucleotide Polymorphisms with known associations to malaria or antibody production, and antibody levels to four clinical grade malarial antigens [AMA1, MSP1, MSP2, and (NANP)4] plus total IgE were measured by ELISA techniques. Regression models were used to investigate the associations of clinical and genetic factors with antibody levels. Results Malaria infection increased levels of antibodies to malaria antigens and, as expected, stable predictors of anti-malarial antibody levels included age, seasonality, location, and ethnicity. Correlations between antibodies to blood-stage antigens AMA1, MSP1 and MSP2 were higher between themselves than with antibodies to the (NANP)4 epitope of the pre-erythrocytic circumsporozoite protein, while there was little or no correlation with total IgE levels. Individuals with sickle cell trait had significantly lower antibody levels to all blood-stage antigens, and recessive homozygotes for CD36 (rs321198) had significantly lower anti-malarial antibody levels to MSP2. Conclusion Although the most significant finding with a consistent effect across sites was for sickle cell trait, its effect is likely to be via reducing a microscopically positive parasitaemia rather than directly on antibody levels. However, this study does demonstrate a framework for the feasibility of combining data from sites with heterogeneous malaria transmission levels across Africa and Asia with which to explore genetic effects on anti-malarial immunity. Electronic supplementary material The online version of this article (doi:10.1186/s12936-015-0833-x) contains supplementary material, which is available to authorized users.

Published
2015
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23. Haplotype heterogeneity and low linkage disequilibrium reduce reliable prediction of genotypes for the ‑α 3.7I form of α-thalassaemia using genome-wide microarray data.

Author

Ndila CM, Nyirongo V, Macharia AW, Jeffreys AE, Rowlands K, Hubbart C, Busby GBJ, Band G, Harding RM, Rockett KA, and Williams TN

Abstract

Background: The -α 3.7I -thalassaemia deletion is very common throughout Africa because it protects against malaria. When undertaking studies to investigate human genetic adaptations to malaria or other diseases, it is important to account for any confounding effects of α-thalassaemia to rule out spurious associations. Methods: In this study, we have used direct α-thalassaemia genotyping to understand why GWAS data from a large malaria association study in Kilifi Kenya did not identify the α-thalassaemia signal. We then explored the potential use of a number of new approaches to using GWAS data for imputing α-thalassaemia as an alternative to direct genotyping by PCR. Results: We found very low linkage-disequilibrium of the directly typed data with the GWAS SNP markers around α-thalassaemia and across the haemoglobin-alpha ( HBA ) gene region, which along with a complex haplotype structure, could explain the lack of an association signal from the GWAS SNP data. Some indirect typing methods gave results that were in broad agreement with those derived from direct genotyping and could identify an association signal, but none were sufficiently accurate to allow correct interpretation compared with direct typing, leading to confusing or erroneous results. Conclusions: We conclude that going forwards, direct typing methods such as PCR will still be required to account for α-thalassaemia in GWAS studies., Competing Interests: No competing interests were disclosed., (Copyright: © 2021 Ndila CM et al.)

Published
2021
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24. Haplotype heterogeneity and low linkage disequilibrium reduce reliable prediction of genotypes for the ‑α 3.7I form of α-thalassaemia using genome-wide microarray data.

Author

Ndila CM, Nyirongo V, Macharia AW, Jeffreys AE, Rowlands K, Hubbart C, Busby GBJ, Band G, Harding RM, Rockett KA, and Williams TN

Abstract

Background: The -α 3.7I -thalassaemia deletion is very common throughout Africa because it protects against malaria. When undertaking studies to investigate human genetic adaptations to malaria or other diseases, it is important to account for any confounding effects of α-thalassaemia to rule out spurious associations. Methods: In this study we have used direct α-thalassaemia genotyping to understand why GWAS data from a large malaria association study in Kilifi Kenya did not identify the α-thalassaemia signal. We then explored the potential use of a number of new approaches to using GWAS data for imputing α-thalassaemia as an alternative to direct genotyping by PCR. Results: We found very low linkage-disequilibrium of the directly typed data with the GWAS SNP markers around α-thalassaemia and across the haemoglobin-alpha ( HBA ) gene region, which along with a complex haplotype structure, could explain the lack of an association signal from the GWAS SNP data. Some indirect typing methods gave results that were in broad agreement with those derived from direct genotyping and could identify an association signal, but none were sufficiently accurate to allow correct interpretation compared with direct typing, leading to confusing or erroneous results. Conclusions: We conclude that going forwards, direct typing methods such as PCR will still be required to account for α-thalassaemia in GWAS studies., Competing Interests: No competing interests were disclosed., (Copyright: © 2020 Ndila CM et al.)

Published
2020
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25. Characterisation of the opposing effects of G6PD deficiency on cerebral malaria and severe malarial anaemia.

Author

Clarke GM, Rockett K, Kivinen K, Hubbart C, Jeffreys AE, Rowlands K, Jallow M, Conway DJ, Bojang KA, Pinder M, Usen S, Sisay-Joof F, Sirugo G, Toure O, Thera MA, Konate S, Sissoko S, Niangaly A, Poudiougou B, Mangano VD, Bougouma EC, Sirima SB, Modiano D, Amenga-Etego LN, Ghansah A, Koram KA, Wilson MD, Enimil A, Evans J, Amodu OK, Olaniyan S, Apinjoh T, Mugri R, Ndi A, Ndila CM, Uyoga S, Macharia A, Peshu N, Williams TN, Manjurano A, Sepúlveda N, Clark TG, Riley E, Drakeley C, Reyburn H, Nyirongo V, Kachala D, Molyneux M, Dunstan SJ, Phu NH, Quyen NN, Thai CQ, Hien TT, Manning L, Laman M, Siba P, Karunajeewa H, Allen S, Allen A, Davis TM, Michon P, Mueller I, Molloy SF, Campino S, Kerasidou A, Cornelius VJ, Hart L, Shah SS, Band G, Spencer CC, Agbenyega T, Achidi E, Doumbo OK, Farrar J, Marsh K, Taylor T, and Kwiatkowski DP

Subjects
Alleles, Anemia pathology, Case-Control Studies, Glucosephosphate Dehydrogenase genetics, Humans, Malaria, Cerebral pathology, Malaria, Falciparum pathology, Risk Assessment, Anemia epidemiology, Glucosephosphate Dehydrogenase Deficiency complications, Malaria, Cerebral epidemiology, Malaria, Falciparum epidemiology
Abstract

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is believed to confer protection against Plasmodium falciparum malaria, but the precise nature of the protective effecthas 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., Competing Interests: JF: Director of the Wellcome Trust, one of the three founding funders of eLife. The other authors declare that no competing interests exist.

Published
2017
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26. Genetic determinants of anti-malarial acquired immunity in a large multi-centre study.

Author

Shelton JM, Corran P, Risley P, Silva N, Hubbart C, Jeffreys A, Rowlands K, Craik R, Cornelius V, Hensmann M, Molloy S, Sepulveda N, Clark TG, Band G, Clarke GM, Spencer CC, Kerasidou A, Campino S, Auburn S, Tall A, Ly AB, Mercereau-Puijalon O, Sakuntabhai A, Djimdé A, Maiga B, Touré O, Doumbo OK, Dolo A, Troye-Blomberg M, Mangano VD, Verra F, Modiano D, Bougouma E, Sirima SB, Ibrahim M, Hussain A, Eid N, Elzein A, Mohammed H, Elhassan A, Elhassan I, Williams TN, Ndila C, Macharia A, Marsh K, Manjurano A, Reyburn H, Lemnge M, Ishengoma D, Carter R, Karunaweera N, Fernando D, Dewasurendra R, Drakeley CJ, Riley EM, Kwiatkowski DP, and Rockett KA

Subjects
Adolescent, Adult, Africa South of the Sahara epidemiology, Antibodies, Protozoan blood, Child, Child, Preschool, Female, Hemoglobin, Sickle genetics, Humans, Infant, Infant, Newborn, Linear Models, Male, Sri Lanka epidemiology, Young Adult, Antibodies, Protozoan immunology, Malaria epidemiology, Malaria genetics, Malaria immunology
Abstract

Background: Many studies report associations between human genetic factors and immunity to malaria but few have been reliably replicated. These studies are usually country-specific, use small sample sizes and are not directly comparable due to differences in methodologies. This study brings together samples and data collected from multiple sites across Africa and Asia to use standardized methods to look for consistent genetic effects on anti-malarial antibody levels., Methods: Sera, DNA samples and clinical data were collected from 13,299 individuals from ten sites in Senegal, Mali, Burkina Faso, Sudan, Kenya, Tanzania, and Sri Lanka using standardized methods. DNA was extracted and typed for 202 Single Nucleotide Polymorphisms with known associations to malaria or antibody production, and antibody levels to four clinical grade malarial antigens [AMA1, MSP1, MSP2, and (NANP)4] plus total IgE were measured by ELISA techniques. Regression models were used to investigate the associations of clinical and genetic factors with antibody levels., Results: Malaria infection increased levels of antibodies to malaria antigens and, as expected, stable predictors of anti-malarial antibody levels included age, seasonality, location, and ethnicity. Correlations between antibodies to blood-stage antigens AMA1, MSP1 and MSP2 were higher between themselves than with antibodies to the (NANP)4 epitope of the pre-erythrocytic circumsporozoite protein, while there was little or no correlation with total IgE levels. Individuals with sickle cell trait had significantly lower antibody levels to all blood-stage antigens, and recessive homozygotes for CD36 (rs321198) had significantly lower anti-malarial antibody levels to MSP2., Conclusion: Although the most significant finding with a consistent effect across sites was for sickle cell trait, its effect is likely to be via reducing a microscopically positive parasitaemia rather than directly on antibody levels. However, this study does demonstrate a framework for the feasibility of combining data from sites with heterogeneous malaria transmission levels across Africa and Asia with which to explore genetic effects on anti-malarial immunity.

Published
2015
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