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

Gilchrist, JJORCID logo; Rautanen, A; Fairfax, BP; Mills, TC; Naranbhai, VORCID logo; Trochet, H; Pirinen, MORCID logo; Muthumbi, EORCID logo; Mwarumba, S; Njuguna, P; +12 more...Mturi, N; Msefula, CL; Gondwe, EN; MacLennan, JM; Chapman, SJ; Molyneux, ME; Knight, JC; Spencer, CC; Williams, TN; MacLennan, CA; Scott, JAGORCID logo; Hill, AVORCID logo and (2017) Risk of nontyphoidal Salmonella bacteraemia in African children is modified by STAT4. Nature communications, 9 (1). 1014-. ISSN 2041-1723 DOI: 10.1038/s41467-017-02398-z
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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.


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