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.