title: Characterizing the genetic basis of innate immune response in TLR4-activated human monocytes.
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.
authors.affiliation: 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.
authors.forename: Sarah
authors.initials: S
authors.lastname: Kim
authors.affiliation: 1] Institute of Human Genetics, University of Bonn, Bonn 53127, Germany [2] Department of Genomics, Life &Brain Center, University of Bonn, Bonn 53127, Germany.
authors.forename: Jessica
authors.initials: J
authors.lastname: Becker
authors.affiliation: Institute of Molecular Medicine, University of Bonn, Bonn 53127, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Bechheim
authors.affiliation: Institute of Molecular Medicine, University of Bonn, Bonn 53127, Germany.
authors.forename: Vera
authors.initials: V
authors.lastname: Kaiser
authors.affiliation: Division of Infection and Immunity, University College London, London WC1E 6BT, UK.
authors.forename: Mahdad
authors.initials: M
authors.lastname: Noursadeghi
authors.affiliation: 1] Institute of Human Genetics, University of Bonn, Bonn 53127, Germany [2] Department of Genomics, Life &Brain Center, University of Bonn, Bonn 53127, Germany.
authors.forename: Nadine
authors.initials: N
authors.lastname: Fricker
authors.affiliation: Institute of Molecular Medicine, University of Bonn, Bonn 53127, Germany.
authors.forename: Esther
authors.initials: E
authors.lastname: Beier
authors.affiliation: Department for Anesthesiology and Intensive Care Medicine, University of Bonn, Bonn 53127, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Klaschik
authors.affiliation: Institute of Pathology and Department of Nephrology, University Clinic of RWTH Aachen, Aachen 52074, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Boor
authors.affiliation: 1] Institute of Human Genetics, University of Bonn, Bonn 53127, Germany [2] Department of Genomics, Life &Brain Center, University of Bonn, Bonn 53127, Germany.
authors.forename: Timo
authors.initials: T
authors.lastname: Hess
authors.affiliation: 1] Institute of Human Genetics, University of Bonn, Bonn 53127, Germany [2] Department of Genomics, Life &Brain Center, University of Bonn, Bonn 53127, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Hofmann
authors.affiliation: Institute for Clinical Chemistry and Clinical Pharmacology, University of Bonn, Bonn 53127, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Holdenrieder
authors.affiliation: Worldwide R&D, Pfizer Inc., Cambridge, Massachusetts 02139, USA.
authors.forename: Jens R
authors.initials: JR
authors.lastname: Wendland
authors.affiliation: Bonn-Aachen International Center for IT (B-IT), University of Bonn, Bonn 53113, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Fröhlich
authors.affiliation: Institute for Clinical Chemistry and Clinical Pharmacology, University of Bonn, Bonn 53127, Germany.
authors.forename: Gunther
authors.initials: G
authors.lastname: Hartmann
authors.affiliation: 1] Institute of Human Genetics, University of Bonn, Bonn 53127, Germany [2] Department of Genomics, Life &Brain Center, University of Bonn, Bonn 53127, Germany.
authors.forename: Markus M
authors.initials: MM
authors.lastname: Nöthen
authors.affiliation: 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.
authors.forename: Bertram
authors.initials: B
authors.lastname: Müller-Myhsok
authors.affiliation: Statistical Genetics, Max Planck Institute of Psychiatry, Munich 80804, Germany.
authors.forename: Benno
authors.initials: B
authors.lastname: Pütz
authors.affiliation: Institute of Molecular Medicine, University of Bonn, Bonn 53127, Germany.
authors.forename: Veit
authors.initials: V
authors.lastname: Hornung
authors.affiliation: 1] Institute of Human Genetics, University of Bonn, Bonn 53127, Germany [2] Department of Genomics, Life &Brain Center, University of Bonn, Bonn 53127, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Schumacher
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D015551:Autoimmunity; D002446:Celiac Disease / Q000235:genetics; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D059647:Gene-Environment Interaction; D055106:Genome-Wide Association Study; D005838:Genotype; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007113:Immunity, Innate; D015212:Inflammatory Bowel Diseases / Q000235:genetics; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D008297:Male; D009000:Monocytes / Q000166:cytology / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism*; D053724:Receptors, Interleukin-18 / Q000378:metabolism*; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D055815:Young Adult
chemical_list: D018950:Lipopolysaccharide Receptors; D053724:Receptors, Interleukin-18; C495345:TLR4 protein, human; D051197:Toll-Like Receptor 4; D020797:Receptor, Platelet-Derived Growth Factor beta