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

James J Gilchrist,Tara C Mills,Julian C Knight,Anna Rautanen,Benjamin P Fairfax,Calman A Maclennan,S Jonathan Chapman ,Jenny Maclennan ,Patricia Njuguna,Spencer Cca ,Esther Muthumbi,Thomas N Williams,Chisomo Msefula ,Matti Pirinen,Vivek Naranbhai,Neema Mturi,Holly Trochet,Malcolm E Molyneux,Esther N Gondwe,Salim Mwarumba,Scott Jag ,Hill Avs

doi:10.1038/s41467-017-02398-z

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.

Highlights

Nontyphoidal Salmonella (NTS) is a major cause of bacteraemia in Africa
We demonstrate that carriage of the NTSassociated genotype at signal transducer and activator of transcription 4 (STAT4) is associated with reduced IFNγ protein production in stimulated natural killer (NK) cells, and with reduced serum IFNγ levels in African children with invasive NTS (iNTS) infection
While there is no evidence that the observed association between rs13390936 genotype and NTS bacteraemia is the result of confounding secondary to acquired risk factors for NTS, we further investigated whether there is evidence that the effect of rs13390936 genotype on NTS disease risk is modified by HIV, malaria or malnutrition

Summary

Introduction

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. Despite a smaller sample size, an analysis of pneumococcal bacteraemia within the same collection, did demonstrate evidence of novel genetic associations at genome-wide significance[10], suggesting that in this context the loss of study power resulting from a substantial reduction in case numbers is more than offset by the provision of a more precisely defined phenotype This observation and the lack of unbiased, population-based data assessing host genetic susceptibility to iNTS disease in African populations led us to conduct a GWAS of NTS bacteraemia in the Kenyan collection[10] with additional replication in a Malawian case–control sample collection.

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Results

Conclusion