Risk of nontyphoidal Salmonella bacteraemia in African children is modified by STAT4

James J. Gilchrist (), Anna Rautanen, Benjamin P. Fairfax, Tara C. Mills, Vivek Naranbhai, Holly Trochet, Matti Pirinen, Esther Muthumbi, Salim Mwarumba, Patricia Njuguna, Neema Mturi, Chisomo L. Msefula, Esther N. Gondwe, Jenny M. MacLennan, Stephen J. Chapman, Malcolm E. Molyneux, Julian C. Knight, Chris C. A. Spencer, Thomas N. Williams, Calman A. MacLennan, J. Anthony G. Scott and Adrian V. S. Hill ()
Additional contact information
James J. Gilchrist: University of Oxford
Anna Rautanen: University of Oxford
Benjamin P. Fairfax: University of Oxford
Tara C. Mills: University of Oxford
Vivek Naranbhai: University of Oxford
Holly Trochet: University of Oxford
Matti Pirinen: University of Oxford
Esther Muthumbi: KEMRI-Wellcome Trust Research Programme
Salim Mwarumba: KEMRI-Wellcome Trust Research Programme
Patricia Njuguna: KEMRI-Wellcome Trust Research Programme
Neema Mturi: KEMRI-Wellcome Trust Research Programme
Chisomo L. Msefula: College of Medicine
Esther N. Gondwe: College of Medicine
Jenny M. MacLennan: College of Medicine
Stephen J. Chapman: University of Oxford
Malcolm E. Molyneux: College of Medicine
Julian C. Knight: University of Oxford
Chris C. A. Spencer: University of Oxford
Thomas N. Williams: KEMRI-Wellcome Trust Research Programme
Calman A. MacLennan: College of Medicine
J. Anthony G. Scott: KEMRI-Wellcome Trust Research Programme
Adrian V. S. Hill: University of Oxford

Nature Communications, 2018, vol. 9, issue 1, 1-11

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-017-02398-z

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