Abstract

Nontyphoidal Salmonella (NTS) is a major cause of bacteraemia in Africa. The disease typically affects HIV-infected individuals and young children, causing substantial morbidity and mortality. Here we present a genome-wide association study (180 cases, 2677 controls) and replication analysis of NTS bacteraemia in Kenyan and Malawian children. We identify a locus in STAT4, rs13390936, associated with NTS bacteraemia. rs13390936 is a context-specific expression quantitative trait locus for STAT4 RNA expression, and individuals carrying the NTS-risk genotype demonstrate decreased interferon-γ (IFNγ) production in stimulated natural killer cells, and decreased circulating IFNγ concentrations during acute NTS bacteraemia. The NTS-risk allele at rs13390936 is associated with protection against a range of autoimmune diseases. These data implicate interleukin-12-dependent IFNγ-mediated immunity as a determinant of invasive NTS disease in African children, and highlight the shared genetic architecture of infectious and autoimmune disease.

Details

Title
Risk of nontyphoidal Salmonella bacteraemia in African children is modified by STAT4
Author
Gilchrist, James J 1   VIAFID ORCID Logo  ; Rautanen, Anna 2 ; Fairfax, Benjamin P 2 ; Mills, Tara C 2 ; Naranbhai, Vivek 2   VIAFID ORCID Logo  ; Trochet, Holly 2 ; Pirinen, Matti 3   VIAFID ORCID Logo  ; Muthumbi, Esther 4 ; Mwarumba, Salim 4 ; Njuguna, Patricia 4 ; Mturi, Neema 4 ; Msefula, Chisomo L 5 ; Gondwe, Esther N 6 ; MacLennan, Jenny M 7 ; Chapman, Stephen J 8 ; Molyneux, Malcolm E 6 ; Knight, Julian C 2 ; Spencer, Chris C A 2 ; Williams, Thomas N 9 ; MacLennan, Calman A 10 ; Scott, J Anthony G 11   VIAFID ORCID Logo  ; Hill, Adrian V S 12   VIAFID ORCID Logo 

1  Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK; Department of Paediatrics, University of Oxford, Oxford, UK 
2  Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK 
3  Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK; Institute for Molecular Medicine, Finland (FIMM) University of Helsinki, Helsinki, Finland 
4  KEMRI-Wellcome Trust Research Programme, Kilifi, Kenya 
5  Malawi-Liverpool-Wellcome Trust Clinical Research Programme, College of Medicine, Blantyre, Malawi; Pathology Department, College of Medicine, Blantyre, Malawi 
6  Malawi-Liverpool-Wellcome Trust Clinical Research Programme, College of Medicine, Blantyre, Malawi 
7  Malawi-Liverpool-Wellcome Trust Clinical Research Programme, College of Medicine, Blantyre, Malawi; Department of Zoology, University of Oxford, Oxford, UK 
8  Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK; Oxford Centre for Respiratory Medicine, Churchill Hospital Site, Oxford University Hospitals, Oxford, UK 
9  KEMRI-Wellcome Trust Research Programme, Kilifi, Kenya; Department of Medicine, Imperial College, London, UK 
10  Malawi-Liverpool-Wellcome Trust Clinical Research Programme, College of Medicine, Blantyre, Malawi; The Jenner Institute, University of Oxford, Oxford, UK 
11  KEMRI-Wellcome Trust Research Programme, Kilifi, Kenya; Department of Infectious Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK 
12  Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK; The Jenner Institute, University of Oxford, Oxford, UK 
Pages
1-11
Publication year
2018
Publication date
Mar 2018
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-017-02398-z
ProQuest document ID
2012579447
Copyright
© 2018. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.