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Nat Commun. 2014 Oct 20;5:5236. doi: 10.1038/ncomms6236.

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

Author information

1
1] Institute of Human Genetics, University of Bonn, Bonn 53127, Germany [2] Department of Genomics, Life &Brain Center, University of Bonn, Bonn 53127, Germany [3] Institute of Molecular Medicine, University of Bonn, Bonn 53127, Germany.
2
1] Institute of Human Genetics, University of Bonn, Bonn 53127, Germany [2] Department of Genomics, Life &Brain Center, University of Bonn, Bonn 53127, Germany.
3
Institute of Molecular Medicine, University of Bonn, Bonn 53127, Germany.
4
Division of Infection and Immunity, University College London, London WC1E 6BT, UK.
5
Department for Anesthesiology and Intensive Care Medicine, University of Bonn, Bonn 53127, Germany.
6
Institute of Pathology and Department of Nephrology, University Clinic of RWTH Aachen, Aachen 52074, Germany.
7
Institute for Clinical Chemistry and Clinical Pharmacology, University of Bonn, Bonn 53127, Germany.
8
Worldwide R&D, Pfizer Inc., Cambridge, Massachusetts 02139, USA.
9
Bonn-Aachen International Center for IT (B-IT), University of Bonn, Bonn 53113, Germany.
10
1] Statistical Genetics, Max Planck Institute of Psychiatry, Munich 80804, Germany [2] Munich Cluster for Systems Neurology (SyNergy), Munich 80804, Germany [3] Institute of Translational Medicine, University of Liverpool, Liverpool L69 3GL, UK.
11
Statistical Genetics, Max Planck Institute of Psychiatry, Munich 80804, Germany.

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.

PMID:
25327457
DOI:
10.1038/ncomms6236
[Indexed for MEDLINE]

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