Abstract

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

Gilchrist JJ Rautanen A Fairfax BP Mills TC Naranbhai V Trochet H Pirinen M Muthumbi E Mwarumba S Njuguna P Mturi N Msefula CL Gondwe EN MacLennan JM Chapman SJ Molyneux ME Knight JC Spencer CCA Williams TN MacLennan CA Scott JAG Hill AVS
Nat Commun. 2018;91014

Permenent descriptor

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-gamma (IFNgamma) production in stimulated natural killer cells, and decreased circulating IFNgamma 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 IFNgamma-mediated immunity as a determinant of invasive NTS disease in African children, and highlight the shared genetic architecture of infectious and autoimmune disease.