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.
Adolescent, Alleles, Autoimmune Diseases, Bacteremia, Case-Control Studies, Child, Child, Preschool, Female, Follow-Up Studies, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Humans, Immunity, Cellular, Infant, Infant, Newborn, Interferon-gamma, Interleukin-12, Kenya, Killer Cells, Natural, Malawi, Male, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Risk Factors, STAT4 Transcription Factor, Salmonella, Salmonella Infections