BIRC6 modifies risk of invasive bacterial infection in Kenyan children
Issued Date
2022-07-01
Resource Type
eISSN
2050084X
Scopus ID
2-s2.0-85136816561
Pubmed ID
35866869
Journal Title
eLife
Volume
2022
Issue
11
Rights Holder(s)
SCOPUS
Bibliographic Citation
eLife Vol.2022 No.11 (2022)
Suggested Citation
Gilchrist J.J. BIRC6 modifies risk of invasive bacterial infection in Kenyan children. eLife Vol.2022 No.11 (2022). doi:10.7554/ELIFE.77461 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/83678
Title
BIRC6 modifies risk of invasive bacterial infection in Kenyan children
Author(s)
Author's Affiliation
Faculty of Tropical Medicine, Mahidol University
The Wellcome Centre for Human Genetics
Tartu Ülikool
Wellcome Trust Research Laboratories Nairobi
London School of Hygiene & Tropical Medicine
University of Oxford
Imperial College London
Nuffield Department of Medicine
Wellcome Sanger Institute
University of Oxford Medical Sciences Division
The Wellcome Centre for Human Genetics
Tartu Ülikool
Wellcome Trust Research Laboratories Nairobi
London School of Hygiene & Tropical Medicine
University of Oxford
Imperial College London
Nuffield Department of Medicine
Wellcome Sanger Institute
University of Oxford Medical Sciences Division
Other Contributor(s)
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.