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

  1. D Herbert Opi
  2. Olivia Swann  Is a corresponding author
  3. Alexander Macharia
  4. Sophie Uyoga
  5. Gavin Band
  6. Carolyne M Ndila
  7. Ewen Harrison
  8. Mahamadou A Thera
  9. Abdoulaye K Kone
  10. Dapa A Diallo
  11. Ogobara K Doumbo
  12. Kirsten E Lyke
  13. Christopher Plowe
  14. Joann M Moulds
  15. Mohammed Shebbe
  16. Neema Mturi
  17. Norbert Peshu
  18. Kathryn Maitland
  19. Ahmed Raza
  20. Dominic P Kwiatkowski
  21. Kirk A Rockett
  22. Thomas Williams
  23. J Alexandra Rowe
  1. Kenya Medical Research Institute-Wellcome Trust Research Programme, Kenya
  2. University of Edinburgh, United Kingdom
  3. University of Oxford, United Kingdom
  4. University of Bamako, Mali
  5. University of Maryland, United States
  6. Lifeshare Blood Centers, United States

Abstract

Malaria has been a major driving force in the evolution of the human genome. In sub-Saharan African populations, two neighbouring polymorphisms in the Complement Receptor One (CR1) gene, named Sl2 and McCb, occur at high frequencies, consistent with selection by malaria. Previous studies have been inconclusive. Using a large case-control study of severe malaria in Kenyan children and statistical models adjusted for confounders, we estimate the relationship between Sl2 and McCb and malaria phenotypes, and find they have opposing associations. The Sl2 polymorphism is associated with markedly reduced odds of cerebral malaria and death, while the McCb polymorphism is associated with increased odds of cerebral malaria. We also identify an apparent interaction between Sl2 and α+thalassaemia, with the protective association of Sl2 greatest in children with normal α-globin. The complex relationship between these three mutations may explain previous conflicting findings, highlighting the importance of considering genetic interactions in disease-association studies.

Data availability

The following previously published data sets were used
    1. Rockett K
    2. Clarke GM
    3. Fitzpatrick K
    4. Hubbart C
    5. Jeffrys AE
    6. Rowlands K
    7. et al
    (2014) MalariaGEN Consortial Project 1
    Application for access to data: https://www.malariagen.net/data/terms-use/human-gwas-data.

Article and author information

Author details

  1. D Herbert Opi

    Kenya Medical Research Institute-Wellcome Trust Research Programme, Kilifi, Kenya
    Competing interests
    The authors declare that no competing interests exist.
  2. Olivia Swann

    Centre for Immunity, Infection and Evolution, University of Edinburgh, Edinburgh, United Kingdom
    For correspondence
    Olivia.Swann@ed.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7386-2849
  3. Alexander Macharia

    Kenya Medical Research Institute-Wellcome Trust Research Programme, Kilifi, Kenya
    Competing interests
    The authors declare that no competing interests exist.
  4. Sophie Uyoga

    Kenya Medical Research Institute-Wellcome Trust Research Programme, Kilifi, Kenya
    Competing interests
    The authors declare that no competing interests exist.
  5. Gavin Band

    Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  6. Carolyne M Ndila

    Kenya Medical Research Institute-Wellcome Trust Research Programme, Kilifi, Kenya
    Competing interests
    The authors declare that no competing interests exist.
  7. Ewen Harrison

    Centre for Immunity, Infection and Evolution, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  8. Mahamadou A Thera

    Malaria Research and Training Centre, University of Bamako, Bamako, Mali
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2679-035X
  9. Abdoulaye K Kone

    Malaria Research and Training Centre, University of Bamako, Bamako, Mali
    Competing interests
    The authors declare that no competing interests exist.
  10. Dapa A Diallo

    Malaria Research and Training Centre, University of Bamako, Bamako, Mali
    Competing interests
    The authors declare that no competing interests exist.
  11. Ogobara K Doumbo

    Malaria Research and Training Centre, University of Bamako, Bamako, Mali
    Competing interests
    The authors declare that no competing interests exist.
  12. Kirsten E Lyke

    Division of Malaria Research, Institute for Global Health, University of Maryland, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Christopher Plowe

    Division of Malaria Research, Institute for Global Health, University of Maryland, Baltimore, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. Joann M Moulds

    Lifeshare Blood Centers, Shreveport, United States
    Competing interests
    The authors declare that no competing interests exist.
  15. Mohammed Shebbe

    Kenya Medical Research Institute-Wellcome Trust Research Programme, Kilifi, Kenya
    Competing interests
    The authors declare that no competing interests exist.
  16. Neema Mturi

    Kenya Medical Research Institute-Wellcome Trust Research Programme, Kilifi, Kenya
    Competing interests
    The authors declare that no competing interests exist.
  17. Norbert Peshu

    Kenya Medical Research Institute-Wellcome Trust Research Programme, Kilifi, Kenya
    Competing interests
    The authors declare that no competing interests exist.
  18. Kathryn Maitland

    Kenya Medical Research Institute-Wellcome Trust Research Programme, Kilifi, Kenya
    Competing interests
    The authors declare that no competing interests exist.
  19. Ahmed Raza

    Centre for Immunity, Infection and Evolution, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  20. Dominic P Kwiatkowski

    Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  21. Kirk A Rockett

    Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6369-9299
  22. Thomas Williams

    Kenya Medical Research Institute-Wellcome Trust Research Programme, Kilifi, Kenya
    Competing interests
    The authors declare that no competing interests exist.
  23. J Alexandra Rowe

    Centre for Immunity, Infection and Evolution, University of Edinburgh, Edinburgh, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7702-1892

Funding

Wellcome Trust (Senior Research Fellowship 091758)

  • Thomas Williams

Wellcome Trust (Senior Research Fellowship202800)

  • Thomas Williams

Wellcome Trust (Senior Research Fellowship084226)

  • J Alexandra Rowe

Wellcome Trust (203077)

  • D Herbert Opi

Wellcome Trust (84538)

  • D Herbert Opi

Wellcome Trust (101910/Z/13/Z)

  • Olivia Swann

Medical Research Council (G19/9)

  • Dominic P Kwiatkowski

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Human subjects: This work involved analysing blood samples from patients with malaria and from healthy controls. Written informed consent was obtained from the parents or legal guardians of all participants. The Kenyan studies received ethical approval from the Kenya Medical Research Institute National Ethical Review Committee (approval number SCC1192 for the case-control study and SCC3149 for the longitudinal cohort study), and the Malian studies received ethical approval from the University of Bamako and the University of Maryland (approval number #0899139), and were conducted in accordance with the Declaration of Helsinki.

Reviewing Editor

  1. Madhukar Pai, McGill University, Canada

Publication history

  1. Received: August 27, 2017
  2. Accepted: April 1, 2018
  3. Accepted Manuscript published: April 25, 2018 (version 1)
  4. Version of Record published: May 15, 2018 (version 2)

Copyright

© 2018, Opi et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. D Herbert Opi
  2. Olivia Swann
  3. Alexander Macharia
  4. Sophie Uyoga
  5. Gavin Band
  6. Carolyne M Ndila
  7. Ewen Harrison
  8. Mahamadou A Thera
  9. Abdoulaye K Kone
  10. Dapa A Diallo
  11. Ogobara K Doumbo
  12. Kirsten E Lyke
  13. Christopher Plowe
  14. Joann M Moulds
  15. Mohammed Shebbe
  16. Neema Mturi
  17. Norbert Peshu
  18. Kathryn Maitland
  19. Ahmed Raza
  20. Dominic P Kwiatkowski
  21. Kirk A Rockett
  22. Thomas Williams
  23. J Alexandra Rowe
(2018)
Two complement receptor one alleles have opposing associations with cerebral malaria and interact with α+thalassaemia
eLife 7:e31579.
https://doi.org/10.7554/eLife.31579

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    Conclusions:

    Low-cost side-effect framing strategies can meaningfully affect vaccine intentions at a population level.

    Funding:

    Heidelberg Institute of Global Health.

    Clinical trial number:

    German Clinical Trials Registry (#DRKS00025551).

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