Abstract

Invasive bacterial disease is a major cause of morbidity and mortality in African children. Despite being caused by diverse pathogens, children with sepsis are clinically indistinguishable from one another. In spite of this, most genetic susceptibility loci for invasive infection that have been discovered to date are pathogen specific and are not therefore suggestive of a shared genetic architecture of bacterial sepsis. Here we utilise probabilistic diagnostic models to identify children with a high probability of invasive bacterial disease among critically unwell Kenyan children with P. falciparum parasitaemia. We construct a joint dataset including 1,445 bacteraemia cases and 1,143 severe malaria cases, and population controls, among critically unwell Kenyan children that have previously been genotyped for human genetic variation. Using these data we perform a cross-trait genome-wide association study of invasive bacterial infection, weighting cases according to their probability of bacterial disease. In doing so we identify and validate a novel risk locus for invasive infection secondary to multiple bacterial pathogens, that has no apparent effect on malaria risk. The locus identified modifies splicing of BIRC6 in stimulated monocytes, implicating regulation of apoptosis and autophagy in the pathogenesis of sepsis in Kenyan children.

Data availability

Patient level genotype and phenotype data are available via the European Genome-Phenome Archive, with accession codes EGAD00010000950 (WTCCC2: bacteraemia cases and controls) and EGAD00010000904 (MalariaGEN Consortium: severe malaria cases and controls).Full GWAS summary statistics have been deposited with the GWAS Catalog with accession code GCST90094632.Code and source data underlying each figure (and supplementary figure) are available at: https://github.com/jjgilchrist/Kenya_bacteraemia_malaria

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. James Gilchrist

    Department of Paediatrics, University of Oxford, Oxford, United Kingdom
    For correspondence
    james.gilchrist@paediatrics.ox.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2045-6788
  2. Silvia N Kariuki

    Wellcome Trust Research Programme, Kenya Medical Research Institute, Kilifi, Kenya
    Competing interests
    The authors declare that no competing interests exist.
  3. James A Watson

    Malaria, Mahidol Oxford Tropical Medicine Research Unit, Bangkok, Thailand
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5524-0325
  4. Gavin Band

    Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  5. Sophie Uyoga

    Wellcome Trust Research Programme, Kenya Medical Research Institute, Kilifi, Kenya
    Competing interests
    The authors declare that no competing interests exist.
  6. Carolyne M Ndila

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

    Wellcome Trust Research Programme, Kenya Medical Research Institute, Kilifi, Kenya
    Competing interests
    The authors declare that no competing interests exist.
  8. Salim Mwarumba

    .Wellcome Trust Research Programme, Kenya Medical Research Institute, Kilifi, Kenya
    Competing interests
    The authors declare that no competing interests exist.
  9. Shebe Mohammed

    Wellcome Trust Research Programme, Kenya Medical Research Institute, Kilifi, Kenya
    Competing interests
    The authors declare that no competing interests exist.
  10. Moses Mosobo

    Wellcome Trust Research Programme, Kenya Medical Research Institute, Kilifi, Kenya
    Competing interests
    The authors declare that no competing interests exist.
  11. Kaur Alasoo

    Institute of Computer Science, University of Tartu, Tartu, Estonia
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1761-8881
  12. 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.
  13. Alexander J Mentzer

    Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  14. 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.
  15. Adrian VS Hill

    Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  16. Kathryn Maitland

    Wellcome Trust Research Programme, Kenya Medical Research Institute, Kilifi, Kenya
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0007-0645
  17. J Anthony G Scott

    Wellcome Trust Research Programme, Kenya Medical Research Institute, Kilifi, Kenya
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7533-5006
  18. Thomas N Williams

    Wellcome Trust Research Programme, Kenya Medical Research Institute, Kilifi, Kenya
    For correspondence
    TWilliams@kemri-wellcome.org
    Competing interests
    The authors declare that no competing interests exist.

Funding

Wellcome Trust (202800)

  • Thomas N Williams

Wellcome Trust (098532)

  • J Anthony G Scott

National Institute for Health and Care Research

  • James Gilchrist

National Institute for Health and Care Research

  • Alexander J Mentzer

Wellcome Trust (223253/Z/21/Z)

  • James A Watson

Wellcome Trust (209265/Z/17/Z)

  • Kathryn Maitland
  • Thomas N Williams

Wellcome Trust (HCUZZ0)

  • Adrian VS Hill

European Research Council (294557)

  • Adrian VS Hill

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

Reviewing Editor

  1. Alexander Young, University of California, Los Angeles, United States

Ethics

Human subjects: Following explanation of the study, written informed consent was obtained from the parent or guardian of each child included in the study. Ethical approval was obtained from the Kenya Medical Research Institute (KEMRI) National Scientific Steering and Research Committees (approval numbers; SCC1192 and SCC967) and the Oxford Tropical Research Ethics Committee (OxTREC, approval numbers; 020-06 and 014-01).

Version history

  1. Received: January 31, 2022
  2. Preprint posted: February 21, 2022 (view preprint)
  3. Accepted: July 22, 2022
  4. Accepted Manuscript published: July 22, 2022 (version 1)
  5. Version of Record published: August 19, 2022 (version 2)

Copyright

© 2022, Gilchrist 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. James Gilchrist
  2. Silvia N Kariuki
  3. James A Watson
  4. Gavin Band
  5. Sophie Uyoga
  6. Carolyne M Ndila
  7. Neema Mturi
  8. Salim Mwarumba
  9. Shebe Mohammed
  10. Moses Mosobo
  11. Kaur Alasoo
  12. Kirk A Rockett
  13. Alexander J Mentzer
  14. Dominic P Kwiatkowski
  15. Adrian VS Hill
  16. Kathryn Maitland
  17. J Anthony G Scott
  18. Thomas N Williams
(2022)
BIRC6 modifies risk of invasive bacterial infection in Kenyan children
eLife 11:e77461.
https://doi.org/10.7554/eLife.77461

Share this article

https://doi.org/10.7554/eLife.77461

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