Article | Published:

Reappraisal of known malaria resistance loci in a large multicenter study

Nature Genetics volume 46, pages 11971204 (2014) | Download Citation

Abstract

Many human genetic associations with resistance to malaria have been reported, but few have been reliably replicated. We collected data on 11,890 cases of severe malaria due to Plasmodium falciparum and 17,441 controls from 12 locations in Africa, Asia and Oceania. We tested 55 SNPs in 27 loci previously reported to associate with severe malaria. There was evidence of association at P < 1 × 10−4 with the HBB, ABO, ATP2B4, G6PD and CD40LG loci, but previously reported associations at 22 other loci did not replicate in the multicenter analysis. The large sample size made it possible to identify authentic genetic effects that are heterogeneous across populations or phenotypes, with a striking example being the main African form of G6PD deficiency, which reduced the risk of cerebral malaria but increased the risk of severe malarial anemia. The finding that G6PD deficiency has opposing effects on different fatal complications of P. falciparum infection indicates that the evolutionary origins of this common human genetic disorder are more complex than previously supposed.

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Acknowledgements

The MalariaGEN Project is supported by the Wellcome Trust (WT077383/Z/05/Z) and the Bill and Melinda Gates Foundation through The Foundation for the National Institutes of Health (FNIH, USA) (566) as part of the Grand Challenges in Global Health Initiative. The Resource Centre for Genomic Epidemiology of Malaria is supported by the Wellcome Trust (090770/Z/09/Z). This research was supported by the UK Medical Research Council (G0600718 and G0600230) and by the Wellcome Trust Biomedical Ethics Enhancement Award (087285) and Strategic Award (096527). D.P.K. receives support from the UK Medical Research Council (G19/9). C.C.A.S. 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 (090532/Z/09/Z) and the Wellcome Trust Sanger Institute (098051/Z/05/Z). The Malaria Research and Training Center–Bandiagara Malaria Project (MRTC-BMP) in Mali group is supported by an Interagency Committee on Disability Research (ICDR) grant from the National Institute of Allergy and Infectious Diseases/US National Institutes of Health (NIAID/NIH) to the University of Maryland and the University of Bamako (USTTB) and by the Mali-NIAID/NIH International Centers for Excellence in Research (ICER) at USTTB. Contributions from Nigeria to CP1 were supported financially by a grant within the BioMalPar European Network of Excellence (LSHP-CT-2004-503578). E.A. received partial funding from the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement 242095-EVIMalaR and the Central African Network for Tuberculosis, HIV/AIDS and Malaria (CANTAM) funded by the European and Developing Countries Clinical Trials Partnership (EDCTP). T.N.W. is funded by Senior Fellowship awards from the Wellcome Trust (076934/Z/05/Z and 091758/Z/10/Z) and through the European Community's Seventh Framework Programme (FP7/2007-2013) under grant agreement 242095-EVIMalaR. The Kenya Medical Research Institute (KEMRI)–Wellcome Trust Programme is funded through core support from the Wellcome Trust. This paper is published with the permission of the director of KEMRI. C.M.N. is supported through a strategic award to the KEMRI–Wellcome Trust Programme from the Wellcome Trust (084538). The Joint Malaria Programme, Kilimanjaro Christian Medical Centre in Tanzania received funding from a UK MRC grant (G9901439). We would like to thank all the Vietnamese individuals who agreed to provide samples for this study. We acknowledge the work of the clinical staff from the Hospital of Tropical Diseases, HCMC and Phuoc Long and Dong Xoai District Hospitals in Binh Phuoc province, Vietnam, who initially diagnosed and studied the individuals with severe malaria. We would like to thank N.T. Hieu and his staff from Hung Vuong Obstetric Hospital for the collection of the cord blood controls. The clinical component of this study was funded through the Wellcome Trust Major Overseas Program in Vietnam (089276/Z/09/Z). L.M. was supported through Basser (Royal Australasian College of Physicians) and National Health and Medical Research Council (NHMRC) scholarships. M.L. was supported through a Fogarty Foundation Scholarship. T.M.E.D. was supported through an NHMRC practitioner fellowship.

Author information

Affiliations

  1. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.

    • Kirk A Rockett
    • , Geraldine M Clarke
    • , Kathryn Fitzpatrick
    • , Christina Hubbart
    • , Anna E Jeffreys
    • , Kate Rowlands
    • , Rachel Craik
    • , Angie Green
    • , Sile Molloy
    • , Kimberly J Johnson
    • , Angeliki Kerasidou
    • , Victoria Cornelius
    • , Lee Hart
    • , Aaron Vanderwal
    • , Miguel SanJoaquin
    • , Gavin Band
    • , Si Quang Le
    • , Matti Pirinen
    • , Chris C A Spencer
    •  & Dominic P Kwiatkowski
  2. Wellcome Trust Sanger Institute, Hinxton, UK.

    • Kirk A Rockett
    •  & Dominic P Kwiatkowski
  3. Medical Research Council Centre for Genomics and Global Health, University of Oxford, Oxford, UK.

    • Kirk A Rockett
    • , Geraldine M Clarke
    • , Chris C A Spencer
    •  & Dominic P Kwiatkowski
  4. Medical Research Council Unit, Serrekunda, The Gambia.

    • Muminatou Jallow
    • , David J Conway
    • , Kalifa A Bojang
    • , Margaret Pinder
    • , Stanley Usen
    • , Fatoumatta Sisay-Joof
    •  & Giorgio Sirugo
  5. Royal Victoria Teaching Hospital, Banjul, The Gambia.

    • Muminatou Jallow
  6. Department of Pathogen Molecular Biology, London School of Hygiene and Tropical Medicine, London, UK.

    • David J Conway
  7. Malaria Research and Training Centre, Faculty of Medicine, University of Bamako, Bamako, Mali.

    • Ousmane Toure
    • , Mahamadou A Thera
    • , Salimata Konate
    • , Sibiry Sissoko
    • , Amadou Niangaly
    • , Belco Poudiougou
    •  & Ogobara Doumbo
  8. Dipartimento di Sanita Publica e Malattie Infettive, University of Rome La Sapienza, Rome, Italy.

    • Valentina D Mangano
    •  & David Modiano
  9. Centre National de Recherche et de Formation sur le Paludisme (CNRFP), Ouagadougou, Burkina Faso.

    • Edith C Bougouma
    •  & Sodiomon B Sirima
  10. Navrongo Health Research Centre, Navrongo, Ghana.

    • Lucas N Amenga-Etego
  11. Noguchi Memorial Institute for Medical Research, Accra, Ghana.

    • Anita Ghansah
    • , Kwadwo A Koram
    •  & Michael D Wilson
  12. Komfo Anokye Teaching Hospital, Kumasi, Ghana.

    • Anthony Enimil
    •  & Tsiri Agbenyega
  13. Department of Molecular Medicine, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany.

    • Jennifer Evans
  14. Kumasi Centre for Collaborative Research, Kumasi, Ghana.

    • Jennifer Evans
  15. Institute of Child Health, College of Medicine, University of Ibadan, Ibadan, Nigeria.

    • Olukemi Amodu
    •  & Subulade Olaniyan
  16. Department of Biochemistry and Molecular Biology, University of Buea, Buea, Cameroon.

    • Tobias Apinjoh
  17. Department of Medical Laboratory Sciences, University of Buea, Buea, Cameroon.

    • Regina Mugri
    • , Andre Ndi
    •  & Eric Achidi
  18. KEMRI–Wellcome Trust Research Programme, Kilifi, Kenya.

    • Carolyne M Ndila
    • , Sophie Uyoga
    • , Alexander Macharia
    • , Norbert Peshu
    • , Thomas N Williams
    •  & Kevin Marsh
  19. Faculty of Medicine, Department of Medicine, Imperial College, London, UK.

    • Thomas N Williams
  20. Joint Malaria Programme, Kilimanjaro Christian Medical Centre, Moshi, Tanzania.

    • Alphaxard Manjurano
    • , Chris Drakeley
    •  & Hugh Reyburn
  21. Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, UK.

    • Alphaxard Manjurano
    • , Eleanor Riley
    • , Chris Drakeley
    •  & Hugh Reyburn
  22. Malawi-Liverpool Wellcome Trust Clinical Research Programme, College of Medicine, University of Malawi, Blantyre, Malawi.

    • Vysaul Nyirongo
  23. Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam.

    • David Kachala
    • , Sarah J Dunstan
    • , Nguyen Hoan Phu
    • , Nguyen Thi Ngoc Quyen
    • , Cao Quang Thai
    • , Tran Tinh Hien
    •  & Jeremy Farrar
  24. Centre for Tropical Medicine, Nuffield Department of Clinical Medicine, Oxford University, Oxford, UK.

    • Malcolm Molyneux
    • , Sarah J Dunstan
    •  & Jeremy Farrar
  25. Nossal Institute of Global Health, University of Melbourne, Melbourne, Victoria, Australia.

    • Sarah J Dunstan
  26. Oxford University Clinical Research Unit, Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.

    • Nguyen Hoan Phu
    • , Cao Quang Thai
    •  & Tran Tinh Hien
  27. Papua New Guinea Institute of Medical Research, Garoka, Papua New Guinea.

    • Laurens Manning
    • , Moses Laman
    • , Peter Siba
    • , Pascal Michon
    •  & Ivo Mueller
  28. School of Medicine and Pharmacology, Fremantle Hospital Unit, University of Western Australia, Fremantle, Western Australia, Australia.

    • Laurens Manning
    • , Harin Karunajeewa
    •  & Timothy M E Davis
  29. College of Medicine, Swansea University, Swansea, UK.

    • Steve Allen
  30. Weatherall Institute of Molecular Medicine, Oxford University, Oxford, UK.

    • Angela Allen
  31. Faculty of Health Sciences, Divine Word University, Madang, Papua New Guinea.

    • Pascal Michon
  32. Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, Australia.

    • Ivo Mueller
  33. Barcelona Centre for International Health Research (CRESIB), Barcelona, Spain.

    • Ivo Mueller
  34. Ethox Centre, Nuffield Department of Population Health, University of Oxford, Oxford, UK.

    • Angeliki Kerasidou
  35. London School of Hygiene and Tropical Medicine, London, UK.

    • Nuno Sepúlveda
    •  & Taane G Clark
  36. School of Medical Sciences, Kwame Nkrumah University of Science and Technology, Kumasi, Ghana.

    • Tsiri Agbenyega
  37. Blantyre Malaria Project, College of Medicine, University of Malawi, Blantyre, Malawi.

    • Terrie Taylor

Consortia

  1. Malaria Genomic Epidemiology Network

Authors

    Contributions

    All senior authors from each partner site have approved the final manuscript and their site authorship, acknowledgments and full contributors list. Writing group: G.M.C., D.P.K., S.M., K.A.R. and C.C.A.S. Project management: E.A., T. Agbenyega, S.A., A.A., O.A., K.A.B., D.J.C., V.C., T.M.E.D., O.D., C.D., S.J.D., J.F., T.T.H., K.J.J., H.K., A.K., S.K., K.A.K., D.P.K., K.M., P.M., D.M., M.M., I.M., A. Niangaly, N.P., M. Pinder, B.P., H.R., E.R., K.A.R., P.S., S.B.S., G.S., S.S., T.T., M.A.T., T.N.W. and M.D.W. Sample clinical data collection and management: S.A., A.A., L.N.A.-E., O.A., T. Apinjoh, K.A.B., E.C.B., G.M.C., D.J.C., S.J.D., A.E., J.E., K.F., A. Ghansah, L.H., M.J., D.K., H.K., A.K., S.K., M.L., A. Macharia, V.D.M., A. Manjurano, L.M., P.M., S.M., R.M., A. Niangaly, C.M.N., A. Ndi, V.N., S.O., N.P., N.H.P., M. Pinder, B.P., N.T.N.Q., H.R., K.A.R., M.S., G.S., F.S.-J., S.S., T.T., C.Q.T., M.A.T., O.T., S. Usen, S. Uyoga and A.V. Sample processing, genotyping and management: A.A., L.N.A.-E., O.A., T. Apinjoh, E.C.B., R.C., A.E., A. Ghansah, A. Green, L.H., C.H., M.J., A.E.J., D.K., H.K., M.L., A. Macharia, V.D.M., A. Manjurano, L.M., S.M., R.M., A. Niangaly, C.M.N., A. Ndi, V.N., S.O., N.H.P., N.T.N.Q., K.A.R., K.R., F.S.-J., C.Q.T., O.T., S. Uyoga and A.V. Analysis: G.B., T.G.C., G.M.C., D.P.K., S.Q.L., S.M., M. Pirinen, K.A.R., N.S. and C.C.A.S. Full details on contribution are given in the supplementary material.

    Competing interests

    The author declare no competing financial interests.

    Corresponding authors

    Correspondence to Kirk A Rockett or Dominic P Kwiatkowski.

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    https://doi.org/10.1038/ng.3107

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