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 Ricano-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. JoostenCisca Wijmenga, Vinod Kumar, Mihai G. Netea

OnderzoeksoutputAcademicpeer review

134 Citaten (Scopus)
154 Downloads (Pure)

Samenvatting

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.

Originele taal-2English
Pagina's (van-tot)1099-1110
Aantal pagina's26
TijdschriftCell
Volume167
Nummer van het tijdschrift4
DOI's
StatusPublished - 3-nov-2016

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