title: Inter-individual variability and genetic influences on cytokine responses to bacteria and fungi.
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.
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, the Netherlands.
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Internal Medicine, Radboud University Medical Center, Nijmegen, the Netherlands.|Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Marije
authors.initials: M
authors.lastname: Oosting
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, the Netherlands.|Genomics Coordination Center, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: Patrick
authors.identifier: 0000-0002-5654-3966
authors.initials: P
authors.lastname: Deelen
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, the Netherlands.
authors.forename: Isis
authors.initials: I
authors.lastname: Ricaño-Ponce
authors.affiliation: Department of Internal Medicine, Radboud University Medical Center, Nijmegen, the Netherlands.|Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Sanne
authors.initials: S
authors.lastname: Smeekens
authors.affiliation: Department of Internal Medicine, Radboud University Medical Center, Nijmegen, the Netherlands.|Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Martin
authors.initials: M
authors.lastname: Jaeger
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, the Netherlands.
authors.forename: Vasiliki
authors.initials: V
authors.lastname: Matzaraki
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, the Netherlands.|Genomics Coordination Center, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: Morris A
authors.initials: MA
authors.lastname: Swertz
authors.affiliation: Center for Computational and Integrative Biology, Massachusetts General Hospital, Harvard School of Medicine, Boston, Massachusetts, USA.|Gastrointestinal Unit and Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.|Broad Institute of MIT and Harvard University, Cambridge, Massachusetts, USA.
authors.forename: Ramnik J
authors.initials: RJ
authors.lastname: Xavier
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, the Netherlands.
authors.forename: Lude
authors.initials: L
authors.lastname: Franke
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, the Netherlands.
authors.forename: Cisca
authors.identifier: 0000-0002-5635-1614
authors.initials: C
authors.lastname: Wijmenga
authors.affiliation: Department of Internal Medicine, Radboud University Medical Center, Nijmegen, the Netherlands.|Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Leo A B
authors.initials: LA
authors.lastname: Joosten
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, the Netherlands.
authors.forename: Vinod
authors.initials: V
authors.lastname: Kumar
authors.affiliation: Department of Internal Medicine, Radboud University Medical Center, Nijmegen, the Netherlands.|Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, the Netherlands.
authors.forename: Mihai G
authors.initials: MG
authors.lastname: Netea
mesh_terms: D000328:Adult; D000368:Aged; D001232:Aspergillus fumigatus / Q000276:immunology; D001419:Bacteria / Q000276:immunology*; D001441:Bacteroides fragilis / Q000276:immunology; D002176:Candida albicans / Q000276:immunology; D058387:Candidemia / Q000276:immunology; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics; D002897:Chromosomes, Human, Pair 7 / Q000235:genetics; D016207:Cytokines / Q000276:immunology*; D004926:Escherichia coli / Q000276:immunology; D005260:Female; D005658:Fungi / Q000276:immunology*; D020869:Gene Expression Profiling; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology*; D055261:Immunogenetic Phenomena; D007206:Individuality; D015850:Interleukin-6 / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000276:immunology*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D009169:Mycobacterium tuberculosis / Q000276:immunology; D063211:N-Terminal Acetyltransferase C / Q000235:genetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D013211:Staphylococcus aureus / Q000276:immunology; D044465:White People / Q000235:genetics; D055815:Young Adult
chemical_list: D016207:Cytokines; C410824:GOLM1 protein, human; C508600:IL6 protein, human; D015850:Interleukin-6; D008565:Membrane Proteins; D063211:N-Terminal Acetyltransferase C; C570953:NAA35 protein, human