BIRC6 modifies risk of invasive bacterial infection in Kenyan children
- University of Oxford, United Kingdom
- Kenya Medical Research Institute, Kenya
- Mahidol Oxford Tropical Medicine Research Unit, Thailand
- University of Tartu, Estonia
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
Article and author information
Author details
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
- 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
- Received: January 31, 2022
- Preprint posted: February 21, 2022 (view preprint)
- Accepted: July 22, 2022
- Accepted Manuscript published: July 22, 2022 (version 1)
- 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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BIRC6 modifies risk of invasive bacterial infection in Kenyan children
eLife 11:e77461.
https://doi.org/10.7554/eLife.77461
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