Παρασκευή 4 Νοεμβρίου 2016

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

Publication date: 3 November 2016
Source:Cell, Volume 167, Issue 4
Author(s): 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
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

Graphical abstract

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Teaser

As part of the Human Functional Genomics Project, examination of millions of human genetic variants demonstrates that host genetics plays a significant role in inter-individual variability of cytokine production in response to different types of microbial stimuli.


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