A Functional Genomics Approach to Understand Variation in Cytokine Production in Humans.
As part of the Human Functional Genomics Project, which aims to understand the factors that determine the variability of immune responses, we investigated genetic variants affecting cytokine production in response to ex vivo stimulation in two independent cohorts of 500 and 200 healthy individuals. We demonstrate a strong impact of genetic heritability on cytokine production capacity after challenge with bacterial, fungal, viral, and non-microbial stimuli. In addition to 17 novel genome-wide significant cytokine QTLs (cQTLs), our study provides a comprehensive picture of the genetic variants that influence six different cytokines in whole blood, blood mononuclear cells, and macrophages. Important biological pathways that contain cytokine QTLs map to pattern recognition receptors (TLR1-6-10 cluster), cytokine and complement inhibitors, and the kallikrein system. The cytokine QTLs show enrichment for monocyte-specific enhancers, are more often located in regions under positive selection, and are significantly enriched among SNPs associated with infections and immune-mediated diseases. PAPERCLIP.
Department of Genetics, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, the Netherlands. Electronic address: y.li01@umcg.nl.
Yang
Y
Li
Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, 6525 HP Nijmegen, the Netherlands.
Marije
M
Oosting
Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, 6525 HP Nijmegen, the Netherlands.
Sanne P
SP
Smeekens
Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, 6525 HP Nijmegen, the Netherlands.
Martin
M
Jaeger
Department of Genetics, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, the Netherlands.
Raul
R
Aguirre-Gamboa
Department of Genetics, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, the Netherlands.
Kieu T T
KTT
Le
Department of Genetics, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, the Netherlands; Genomics Coordination Center, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, the Netherlands.
Patrick
P
Deelen
Department of Genetics, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, the Netherlands.
Isis
I
Ricaño-Ponce
Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, 6525 HP Nijmegen, the Netherlands.
Teske
T
Schoffelen
Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, 6525 HP Nijmegen, the Netherlands.
Anne F M
AFM
Jansen
Department of Genetics, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, the Netherlands; Genomics Coordination Center, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, the Netherlands.
Morris A
MA
Swertz
Department of Genetics, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, the Netherlands.
Sebo
S
Withoff
Department of Infectious Diseases, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands.
Esther
E
van de Vosse
Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, 6525 HP Nijmegen, the Netherlands.
Marcel
M
van Deuren
Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, 6525 HP Nijmegen, the Netherlands.
Frank
F
van de Veerdonk
Department of Genetics, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, the Netherlands.
Alexandra
A
Zhernakova
Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, 6525 HP Nijmegen, the Netherlands.
Jos W M
JWM
van der Meer
Center for Computational and Integrative Biology and Gastrointestinal Unit, Massachusetts General Hospital, Harvard School of Medicine, Boston, MA 02114, USA; Broad Institute of MIT and Harvard University, Cambridge, MA 02142, USA.
Ramnik J
RJ
Xavier
Department of Genetics, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, the Netherlands.
Lude
L
Franke
Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, 6525 HP Nijmegen, the Netherlands. Electronic address: leo.joosten@radboudumc.nl.
Leo A B
LAB
Joosten
Department of Genetics, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, the Netherlands; Department of Immunology, University of Oslo, Oslo University Hospital, Rikshospitalet, 0372 Oslo, Norway. Electronic address: c.wijmenga@umcg.nl.
Cisca
C
Wijmenga
Department of Genetics, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, the Netherlands. Electronic address: v.kumar@umcg.nl.
Vinod
V
Kumar
Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, 6525 HP Nijmegen, the Netherlands. Electronic address: mihai.netea@radboudumc.nl.
Mihai G
MG
Netea
D000293:Adolescent; D000328:Adult; D000368:Aged; D001769:Blood / Q000276:immunology; D016207:Cytokines / Q000235:genetics* / Q000276:immunology*; D005260:Female; D055106:Genome-Wide Association Study; D016045:Human Genome Project; D006801:Humans; D007239:Infections / Q000276:immunology* / Q000382:microbiology / Q000821:virology; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008264:Macrophages / Q000276:immunology; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci
D016207:Cytokines
cytokine QTL; cytokine heritability; immunogenomics; innate immune response