A Functional Genomics Approach to Understand Variation in Cytokine Production in Humans

Yang Li; Marije Oosting; Sanne P Smeekens; Martin Jaeger; Raul Aguirre-Gamboa; Kieu T T Le; Patrick Deelen; Isis Ricaño-Ponce; Teske Schoffelen; Anne F M Jansen; Morris A Swertz; Sebo Withoff; Esther van de Vosse; Marcel van Deuren; Frank van de Veerdonk; Alexandra Zhernakova; Jos W M van der Meer; Ramnik J Xavier; Lude Franke; Leo A B Joosten; Cisca Wijmenga; Vinod Kumar; Mihai G Netea

doi:10.1016/j.cell.2016.10.017

A Functional Genomics Approach to Understand Variation in Cytokine Production in Humans

Cell. 2016 Nov 3;167(4):1099-1110.e14. doi: 10.1016/j.cell.2016.10.017.

Authors

Yang Li¹, Marije Oosting², Sanne P Smeekens², Martin Jaeger², Raul Aguirre-Gamboa³, Kieu T T Le³, Patrick Deelen⁴, Isis Ricaño-Ponce³, Teske Schoffelen², Anne F M Jansen², Morris A Swertz⁴, Sebo Withoff³, Esther van de Vosse⁵, Marcel van Deuren², Frank van de Veerdonk², Alexandra Zhernakova³, Jos W M van der Meer², Ramnik J Xavier⁶, Lude Franke³, Leo A B Joosten⁷, Cisca Wijmenga⁸, Vinod Kumar⁹, Mihai G Netea¹⁰

Affiliations

¹ Department of Genetics, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, the Netherlands. Electronic address: y.li01@umcg.nl.
² Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, 6525 HP Nijmegen, the Netherlands.
³ Department of Genetics, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, the Netherlands.
⁴ 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.
⁵ Department of Infectious Diseases, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands.
⁶ 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.
⁷ 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.
⁸ 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.
⁹ Department of Genetics, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, the Netherlands. Electronic address: v.kumar@umcg.nl.
¹⁰ 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.

PMID: 27814507
DOI: 10.1016/j.cell.2016.10.017

Abstract

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.

Keywords: cytokine QTL; cytokine heritability; immunogenomics; innate immune response.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adolescent
Adult
Aged
Blood / immunology
Cytokines / genetics*
Cytokines / immunology*
Female
Genome-Wide Association Study
Human Genome Project
Humans
Infections / immunology*
Infections / microbiology
Infections / virology
Leukocytes, Mononuclear / immunology
Macrophages / immunology
Male
Middle Aged
Polymorphism, Single Nucleotide
Quantitative Trait Loci

Substances

Cytokines