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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Alleles
  • Autoimmunity
  • Celiac Disease / genetics
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Gene-Environment Interaction
  • Genome-Wide Association Study
  • Genotype
  • Heterozygote
  • Homozygote
  • Humans
  • Immunity, Innate*
  • Inflammatory Bowel Diseases / genetics
  • Lipopolysaccharide Receptors / metabolism
  • Male
  • Monocytes / cytology
  • Monocytes / metabolism*
  • Polymorphism, Single Nucleotide
  • Quantitative Trait Loci
  • Receptor, Platelet-Derived Growth Factor beta / metabolism*
  • Receptors, Interleukin-18 / metabolism*
  • Signal Transduction
  • Toll-Like Receptor 4 / metabolism*
  • Young Adult

Substances

  • Lipopolysaccharide Receptors
  • Receptors, Interleukin-18
  • TLR4 protein, human
  • Toll-Like Receptor 4
  • Receptor, Platelet-Derived Growth Factor beta