TY - JOUR
T1 - Risk of nontyphoidal Salmonella bacteraemia in African children is modified by STAT4
AU - Gilchrist, James J.
AU - Rautanen, Anna
AU - Fairfax, Benjamin P.
AU - Mills, Tara C.
AU - Naranbhai, Vivek
AU - Trochet, Holly
AU - Pirinen, Matti
AU - Muthumbi, Esther
AU - Mwarumba, Salim
AU - Njuguna, Patricia
AU - Mturi, Neema
AU - Msefula, Chisomo L.
AU - Gondwe, Esther N.
AU - MacLennan, Jenny M.
AU - Chapman, Stephen J.
AU - Molyneux, Malcolm E.
AU - Knight, Julian C.
AU - Spencer, Chris C.A.
AU - Williams, Thomas N.
AU - MacLennan, Calman A.
AU - Scott, J. Anthony G.
AU - Hill, Adrian V.S.
N1 - Funding Information:
The principal funding for this study was provided by the Wellcome Trust, as part of the Wellcome Trust Case Control Consortium 2 project (grants 084716/Z/08/Z, 085475/B/ 08/Z and 085475/Z/08/Z). This work was partially supported by Wellcome Trust Centre for Human Genetics core grant 090532/Z/09/Z. The fieldwork and phenotyping in Kenya was supported by the Kenya Medical Research Institute (KEMRI) and the Wellcome Trust of Great Britain. The fieldwork and phenotyping in Malawi was supported by a Wellcome Trust Research Fellowship (067902/Z/02/Z) to C.A.M., and a Wellcome Trust Programme Grant (074124/Z/04/Z) to M.E.M. J.J.G. is supported by a Wellcome Trust Clinical PhD Fellowship (102342/Z/13/Z), A.R. was supported by the Wellcome Trust (084716/Z/08/Z) and the European Research Council, T.N.W. and J.A.G.S. were supported by Senior Research Fellowships from the Wellcome Trust (091758 and 098532 respectively), S.J.C. was supported by the NIHR Biomedical Research Centre, Oxford, C. C.A.S. was supported by a Wellcome Trust Career Development Fellowship (097364/Z/ 11/Z) and A.V.S.H. is supported by a Wellcome Trust Senior Investigator Award (HCUZZ0) and by a European Research Council advanced grant (294557). This study makes use of data generated by MalariaGEN. A full list of the investigators who contributed to the generation of the data is available from www.MalariaGEN.net. Funding for this project was provided by Wellcome Trust (WT077383/Z/05/Z) and the Bill & Melinda Gates Foundation through the Foundation of the National Institutes of Health (566) as part of the Grand Challenges in Global Health Initiative. We thank all the study participants and Kilifi District Hospital and Queen Elizabeth Central Hospital clinical teams and laboratory staff for their involvement in data and sample collection. We thank the volunteers from the Oxford Biobank, NIHR Oxford Biomedical Research Centre, for their participation. The Oxford Biobank (www.oxfordbiobank.org.uk) is also part of the NIHR National Bioresource which supported the recalling process of the volunteers. We thank the High-Throughput Genomics Group at the Wellcome Trust Centre for Human Genetics (funded by Wellcome Trust grant reference 090532/Z/09/Z and MRC Hub grant G0900747 91070) for the generation of the Sequenom data. This paper was published with the permission of the Director of KEMRI.
Publisher Copyright:
© 2018 The Author(s).
PY - 2018/3/9
Y1 - 2018/3/9
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/85043979423
U2 - 10.1038/s41467-017-02398-z
DO - 10.1038/s41467-017-02398-z
M3 - Article
C2 - 29523850
AN - SCOPUS:85043979423
SN - 2041-1723
VL - 9
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 1014
ER -
SDG 3 Good Health and Well-being