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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adolescent
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Alleles
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Autoimmune Diseases / epidemiology
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Autoimmune Diseases / genetics*
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Autoimmune Diseases / immunology
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Autoimmune Diseases / microbiology
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Bacteremia / epidemiology*
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Bacteremia / genetics
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Bacteremia / immunology
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Bacteremia / microbiology
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Case-Control Studies
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Child
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Child, Preschool
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Female
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Follow-Up Studies
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Genetic Predisposition to Disease*
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Genome-Wide Association Study
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Genotype
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Humans
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Immunity, Cellular / genetics
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Infant
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Infant, Newborn
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Interferon-gamma / blood
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Interferon-gamma / immunology
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Interferon-gamma / metabolism
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Interleukin-12 / immunology
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Interleukin-12 / metabolism
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Kenya / epidemiology
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Killer Cells, Natural / immunology
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Killer Cells, Natural / metabolism
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Malawi / epidemiology
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Male
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Polymorphism, Single Nucleotide
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Quantitative Trait Loci / genetics
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Risk Factors
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STAT4 Transcription Factor / genetics*
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Salmonella / isolation & purification
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Salmonella / pathogenicity*
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Salmonella Infections / epidemiology*
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Salmonella Infections / genetics
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Salmonella Infections / immunology
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Salmonella Infections / microbiology
Substances
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STAT4 Transcription Factor
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STAT4 protein, human
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Interleukin-12
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Interferon-gamma