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Cited by 108Malaria Research and ControlHemoglobinopathies and Related DisordersGenetic Associations and Epidemiology

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

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Ndila, Carolyne M, Uyoga, Sophie, Macharia, Alexander W, Nyutu, Gideon, Peshu, Norbert, Ojal, John, Shebe, Mohammed, Awuondo, Kennedy O +289 more·2018·The Lancet Haematology
DOI 10.1016/s2352-3026(18)30107-8PMC PMC6069675
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Abstract

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 –α 3·7 -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.

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  • Human subjects with quantitative or qualitative hemoglobin defects are partially resistant to infections by Plasmodium and Babesia.

    “Therefore, it appears counterintuitive that human subjects with quantitative (thalassemic syndromes) or qualitative (hemoglobinopathies) HB defects are partially resistant to these infections (Atkinson et al., 2014;Ndila et al., 2018;Taylor et al., 2012).”

    From Iron in infection and immunity (2020) · cites this paper as Ndila et al., 2018

    The Discussion reports that sickle-cell trait and –α3·7-thalassaemia protect children against severe malaria. It does not address Babesia, and its findings about severe malaria do not establish resistance to Plasmodium infection generally. (LLM, conf=0.88)

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Research works printed but not linked: 2

  1. [1]Gaur D Chitnis CE Chauhan VS Advances in malaria research (Wiley-IUBMB Series on Biochemistry and Molecular Biology) 2017 John Wiley & Sons Hoboken
  2. [20]Williams TN Host genetics Gaur D Chitnis CE Chauhan VS Advances in malaria research (Wiley-IUBMB Series on Biochemistry and Molecular Biology) 2017 John Wiley & Sons Hoboken 465 494

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Authors
Ndila, C. M., Uyoga, S., Macharia, A. W., Nyutu, G., Peshu, N., Ojal, J., Shebe, M., Awuondo, K. O., Mturi, N., Tsofa, B., Sepúlveda, N., Clark, T. G., Band, G., Clarke, G., Rowlands, K., Hubbart, C., Jeffreys, A., Kariuki, S., Marsh, K., Mackinnon, M., Maitland, K., Kwiatkowski, D. P., Rockett, K. A., Williams, T. N., Abathina, A., Abubakar, I., Achidi, E., Agbenyega, T., Aiyegbo, M., Akoto, A., Allen, A., Allen, S., Amenga-Etego, L., Amodu, F., Amodu, O., Anchang-Kimbi, J., Ansah, N., Ansah, P., Ansong, D., Antwi, S., Anyorigiya, T., Apinjoh, T., Asafo-Agyei, E., Asoala, V., Atuguba, F., Auburn, S., Bah, A., Bamba, K., Bancone, G., Band, G., Barnwell, D., Barry, A., Bauni, E., Besingi, R., Bojang, K., Bougouma, E., Bull, S., Busby, G., Camara, A., Camara, L., Campino, S., Carter, R., Carucci, D., Casals-Pascual, C., Ceesay, N., Ceesay, P., Chau, T., Chuong, L., Clark, T., Clarke, G., Cole-Ceesay, R., Conway, D., Cook, K., Cook, O., Cornelius, V., Corran, P., Correa, S., Cox, S., Craik, R., Danso, B., Davis, T., Day, N., Deloukas, P., Dembele, A., deVries, J., Dewasurendra, R., Diakite, M., Diarra, E., Dibba, Y., Diss, A., Djimdé, A., Dolo, A., Doumbo, O., Doyle, A., Drakeley, C., Drury, E., Duffy, P., Dunstan, S., Ebonyi, A., Elhassan, A., Elhassan, I., Elzein, A., Enimil, A., Esangbedo, P., Evans, J., Evans, J., Farrar, J., Fernando, D., Fitzpatrick, K., Fullah, J., Garcia, J., Ghansah, A., Gottleib, M., Green, A., Hart, L., Hennsman, M., Hien, T., Hieu, N., Hilton, E., Hodgson, A., Horstmann, R., Hubbart, C., Hughes, C., Hussein, A., Hutton, R., Ibrahim, M., Ishengoma, D., Jaiteh, J., Jallow, M., Jallow, M., Jammeh, K., Jasseh, M., Jeffreys, A., Jobarteh, A., Johnson, K., Joseph, S., Jyothi, D., Kachala, D., Kamuya, D., Kanyi, H., Karunajeewa, H., Karunaweera, N., Keita, M., Kerasidou, A., Khan, A., Kivinen, K., Kokwaro, G., Konate, A., Konate, S., Koram, K., Kwiatkowski, D., Laman, M., Le, S., Leffler, E., Lemnge, M., Lin, E., Ly, A., Macharia, A., MacInnis, B., Mai, N., Makani, J., Malangone, C., Mangano, V., Manjurano, A., Manneh, L., Manning, L., Manske, M., Marsh, K., Marsh, V., Maslen, G., Maxwell, C., Mbunwe, E., McCreight, M., Mead, D., Mendy, A., Mendy, A., Mensah, N., Michon, P., Miles, A., Miotto, O., Modiano, D., Mohamed, H., Molloy, S., Molyneux, M., Molyneux, S., Moore, M., Moyes, C., Mtei, F., Mtove, G., Mueller, I., Mugri, R., Munthali, A., Mutabingwa, T., Nadjm, B., Ndi, A., Ndila, C., Newton, C., Niangaly, A., Njie, H., Njie, J., Njie, M., Njie, M., Njie, S., Njiragoma, L., Nkrumah, F., Ntunthama, N., Nyika, A., Nyirongo, V., O'Brien, J., Obu, H., Oduro, A., Ofori, A., Olaniyan, S., Olaosebikan, R., Oluoch, T., Omotade, O., Oni, O., Onykwelu, E., Opi, D., Orimadegun, A., O'Riordan, S., Ouedraogo, I., Oyola, S., Parker, M., Pearson, R., Pensulo, P., Peshu, N., Phiri, A., Phu, N., Pinder, M., Pirinen, M., Plowe, C., Potter, C., Poudiougou, B., Puijalon, O., Quyen, N., Ragoussis, I., Ragoussis, J., Rasheed, O., Reeder, J., Reyburn, H., Riley, E., Risley, P., Rockett, K., Rodford, J., Rogers, J., Rogers, W., Rowlands, K., Ruano-Rubio, V., Sabally-Ceesay, K., Sadiq, A., Saidy-Khan, M., Saine, H., Sakuntabhai, A., Sall, A., Sambian, D., Sambou, I., SanJoaquin, M., Sepúlveda, N., Shah, S., Shelton, J., Siba, P., Silva, N., Simmons, C., Simpore, J., Singhasivanon, P., Sinh, D., Sirima, S., Sirugo, G., Sisay-Joof, F., Sissoko, S., Small, K., Somaskantharajah, E., Spencer, C., Stalker, J., Stevens, M., Suriyaphol, P., Sylverken, J., Taal, B., Tall, A., Taylor, T., Teo, Y., Thai, C., Thera, M., Titanji, V., Toure, O., Troye-Blomberg, M., Usen, S., Uyoga, S., Vanderwal, A., Wangai, H., Watson, R., Williams, T., Wilson, M., Wrigley, R., Yafi, C., & Yamoah, L.
Affiliations
  • Kenya Medical Research Institute (KE)
  • Wellcome Sanger Institute (GB)
  • Centre for Human Genetics (GB)
Corresponding author
  • Anyorigiya, Thomas
  • Rogers, William
ORCID
Venue
The Lancet Haematology
Publisher
Elsevier BV
Published
2018-08
Volume
5
Issue
8
Pages
e333-e345
ISSN
2352-3026 (ISSN-L)
DOI
10.1016/s2352-3026(18)30107-8
PMC
PMC6069675
OpenAlex
W2884636474
Cited by
108
References
31
Citations by year
2026: 6 · 2025: 10 · 2024: 16 · 2023: 14 · 2022: 22 · 2021: 13 · 2020: 14 · 2019: 9 · 2018: 4
FWCI
9.77
Type
journal article
Language
en
Open access
Licence
Locations
  • The Lancet Haematology (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • LSHTM Research Online (London School of Hygiene and Tropical Medicine) (acceptedVersion)
  • IRIS Research product catalog (Sapienza University of Rome) (submittedVersion, cc-by)
  • Minerva Access (University of Melbourne) (submittedVersion, cc-by)
  • Monash University Research Portal (Monash University) (submittedVersion, other-oa)
  • HAL (submittedVersion, cc-by)
  • CINECA IRIS Institutial research information system (University of Pisa) (submittedVersion, cc-by)
  • UCL Discovery (University College London) (submittedVersion)
  • Spiral (Imperial College London) (submittedVersion, other-oa)
  • Greater South Information System
Funders
  • Wellcome Trust (G0600718, FP7/2007–2013, WT077383/Z/05/Z, 204911/Z/16/Z, 090770, 091758, 202800, 090532, MC_PC_15103, 090770/Z/09/Z, 098051, 090532/Z/09/Z, 242095, 090532/Z/09/, 090532/Z, 088634)
  • European Commission (242095, 090532/Z/09/Z, 2007–2013, FP7 2007-2013, FP7/2007)
  • National Institutes of Health (FP7/2007-2013)
  • Medical Research Council (FP7/20072013, MR/M006212/1, 091758, MR/M01360X/1, MC_PC_15103, 098051, G0600718, MR/N010469/1, 202800, 090532/Z09/Z, G19/9, MR/K000551/1)
  • Drug Applied Research Center, Tabriz University of Medical Sciences
Topics
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Malaria Research and Control
  • Health Sciences › Medicine › Genetics › Hemoglobinopathies and Related Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
Keywords
severe malaria, Plasmodium falciparum, genetic susceptibility, candidate gene polymorphisms, sickle cell trait, HBB, ABO blood group system, glucose-6-phosphate dehydrogenase, ATP2B4, IL-10, CD40 ligand, cerebral malaria, respiratory distress, children, Kilifi, Kenya
MeSH terms
Child, Child, Preschool, Female, Gene Frequency, Humans, Kenya, Malaria, Male, Polymorphism, Genetic, Case-Control Studies, Genetic Predisposition to Disease

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