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Inter-individual variability and genetic influences on cytokine responses to bacteria and fungi

A Corrigendum to this article was published on 06 October 2016

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Abstract

Little is known about the inter-individual variation of cytokine responses to different pathogens in healthy individuals. To systematically describe cytokine responses elicited by distinct pathogens and to determine the effect of genetic variation on cytokine production, we profiled cytokines produced by peripheral blood mononuclear cells from 197 individuals of European origin from the 200 Functional Genomics (200FG) cohort in the Human Functional Genomics Project (http://www.humanfunctionalgenomics.org), obtained over three different years. We compared bacteria- and fungi-induced cytokine profiles and found that most cytokine responses were organized around a physiological response to specific pathogens, rather than around a particular immune pathway or cytokine. We then correlated genome-wide single-nucleotide polymorphism (SNP) genotypes with cytokine abundance and identified six cytokine quantitative trait loci (QTLs). Among them, a cytokine QTL at the NAA35-GOLM1 locus markedly modulated interleukin (IL)-6 production in response to multiple pathogens and was associated with susceptibility to candidemia. Furthermore, the cytokine QTLs that we identified were enriched among SNPs previously associated with infectious diseases and heart diseases. These data reveal and begin to explain the variability in cytokine production by human immune cells in response to pathogens.

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Figure 1: Inter-individual variability in cytokine production following PBMC stimulation.
Figure 2: Cytokine responses are organized around a physiological response toward specific pathogens.
Figure 3: Genome-wide cytokine QTL mapping identifies stimulation-induced cQTLs.
Figure 4: Genome-wide significant cQTLs affect cytokine production induced by both bacterial and fungal stimulation.
Figure 5: GOLM1 genotype correlates with IL-6 production.
Figure 6: Association of cQTLs with infectious diseases.

Change history

  • 28 July 2016

    In the version of this article initially published online, the url in the Online database section of the Methods was incorrect. The original version included the url http://www.bbmri.nl/molgenis/500FG. The correct url is http://hfgp.bbmri.nl/. The error has been corrected for the print, PDF and HTML versions of this article.

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Acknowledgements

The authors thank all volunteers from the 200 Functional Genomics cohort of the Human Functional Genomics Project for participation in the study. The authors would like to thank K. McIntyre for editing the final text. This study was partially supported by a ERC Consolidator Grant (3310372) to M.G.N. and by the ERC Advanced Grant (FP/2007-2013/ERC grant 2012-322698 to C.W.), the Dutch Digestive Diseases Foundation (MLDS WO11-30 to C.W. and V.K.), the European Union′s Seventh Framework Programme (EU FP7) TANDEM project (HEALTH-F3-2012-305279 to C.W. and V.K.), and a Netherlands Organization for Scientific Research (NWO) VENI grant (863.13.011 to Y.L.). This study made use of data generated by the 'Genome of the Netherlands' project, which is funded by the Netherlands Organization for Scientific Research (grant no. 184021007). The data were made available as a Rainbow Project of BBMRI-NL.

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Contributions

M.G.N. and C.W. coordinated the recruitment of cohorts and data generation. M.G.N., V.K., L.A.B.J. and C.W. conceived and directed the study with input from all of the other authors. Y.L. analyzed and interpreted the data. P.D., I.R.-P., V.M. and V.K. performed genotyping and imputation. M.O., S.S. and M.J. conducted the stimulation experiments and cytokine quantification. M.A.S., R.J.X. and L.F. provided the computational framework for the study and critical inputs to the study design. M.G.N., V.K., C.W., Y.L. and M.O. wrote the manuscript with input from all of the authors.

Corresponding authors

Correspondence to Vinod Kumar or Mihai G Netea.

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The authors declare no competing financial interests.

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Li, Y., Oosting, M., Deelen, P. et al. Inter-individual variability and genetic influences on cytokine responses to bacteria and fungi. Nat Med 22, 952–960 (2016). https://doi.org/10.1038/nm.4139

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