Characterizing the genetic basis of innate immune response in TLR4-activated human monocytes

Sarah Kim, Jessica Becker, Matthias Bechheim, Vera Kaiser, Mahdad Noursadeghi, Nadine Fricker, Esther Beier, Sven Klaschik, Peter Boor, Timo Hess, Andrea Hofmann, Stefan Holdenrieder, Jens R. Wendland, Holger Fröhlich, Gunther Hartmann, Markus M. Nöthen, Bertram Müller-Myhsok, Benno Pütz, Veit Hornung () and Johannes Schumacher ()
Additional contact information
Sarah Kim: Institute of Human Genetics, University of Bonn
Jessica Becker: Institute of Human Genetics, University of Bonn
Matthias Bechheim: Institute of Molecular Medicine, University of Bonn
Vera Kaiser: Institute of Molecular Medicine, University of Bonn
Mahdad Noursadeghi: University College London
Nadine Fricker: Institute of Human Genetics, University of Bonn
Esther Beier: Institute of Molecular Medicine, University of Bonn
Sven Klaschik: University of Bonn
Peter Boor: University Clinic of RWTH Aachen
Timo Hess: Institute of Human Genetics, University of Bonn
Andrea Hofmann: Institute of Human Genetics, University of Bonn
Stefan Holdenrieder: Institute for Clinical Chemistry and Clinical Pharmacology, University of Bonn
Jens R. Wendland: Worldwide R&D, Pfizer Inc.
Holger Fröhlich: Bonn-Aachen International Center for IT (B-IT), University of Bonn
Gunther Hartmann: Institute for Clinical Chemistry and Clinical Pharmacology, University of Bonn
Markus M. Nöthen: Institute of Human Genetics, University of Bonn
Bertram Müller-Myhsok: Statistical Genetics, Max Planck Institute of Psychiatry
Benno Pütz: Statistical Genetics, Max Planck Institute of Psychiatry
Veit Hornung: Institute of Molecular Medicine, University of Bonn
Johannes Schumacher: Institute of Human Genetics, University of Bonn

Nature Communications, 2014, vol. 5, issue 1, 1-7

Abstract: Abstract Toll-like receptors (TLRs) play a key role in innate immunity. Apart from their function in host defense, dysregulation in TLR signalling can confer risk to autoimmune diseases, septic shock or cancer. Here we report genetic variants and transcripts that are active only during TLR signalling and contribute to interindividual differences in immune response. Comparing unstimulated versus TLR4-stimulated monocytes reveals 1,471 expression quantitative trait loci (eQTLs) that are unique to TLR4 stimulation. Among these we find functional SNPs for the expression of NEU4, CCL14, CBX3 and IRF5 on TLR4 activation. Furthermore, we show that SNPs conferring risk to primary biliary cirrhosis (PBC), inflammatory bowel disease (IBD) and celiac disease are immune response eQTLs for PDGFB and IL18R1. Thus, PDGFB and IL18R1 represent plausible candidates for studying the pathophysiology of these disorders in the context of TLR4 activation. In summary, this study presents novel insights into the genetic basis of the innate immune response and exemplifies the value of eQTL studies in the context of exogenous cell stimulation.

Date: 2014
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DOI: 10.1038/ncomms6236

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