Genetic Variation in Pattern Recognition Receptors and Adaptor Proteins Associated With Development of Chronic Q Fever

J Infect Dis. 2015 Sep 1;212(5):818-29. doi: 10.1093/infdis/jiv113. Epub 2015 Feb 26.


Background: Q fever is an infection caused by Coxiella burnetii. Persistent infection (chronic Q fever) develops in 1%-5% of patients. We hypothesize that inefficient recognition of C. burnetii and/or activation of host-defense in individuals carrying genetic variants in pattern recognition receptors or adaptors would result in an increased likelihood to develop chronic Q fever.

Methods: Twenty-four single-nucleotide polymorphisms in genes encoding Toll-like receptors, nucleotide-binding oligomerization domain-like receptor-2, αvβ3 integrin, CR3, and adaptors myeloid differentiation primary response protein 88 (MyD88), and Toll interleukin 1 receptor domain-containing adaptor protein (TIRAP) were genotyped in 139 patients with chronic Q fever and in 220 controls with cardiovascular risk-factors and previous exposure to C. burnetii. Associations between these single-nucleotide polymorphisms and chronic Q fever were assessed by means of univariate logistic regression models. Cytokine production in whole-blood stimulation assays was correlated with relevant genotypes.

Results: Polymorphisms in TLR1 (R80T), NOD2 (1007fsX1), and MYD88 (-938C>A) were associated with chronic Q fever. No association was observed for polymorphisms in TLR2, TLR4, TLR6, TLR8, ITGAV, ITGB3, ITGAM, and TIRAP. No correction for multiple testing was performed because only genes with a known role in initial recognition of C. burnetii were included. In the whole-blood assays, individuals carrying the TLR1 80R-allele showed increased interleukin 10 production with C. burnetii exposure.

Conclusions: Polymorphisms in TLR1 (R80T), NOD2 (L1007fsX1), and MYD88 (-938C>A) are associated with predisposition to development of chronic Q fever. For TLR1, increased interleukin 10 responses to C. burnetii in individuals carrying the risk allele may contribute to the increased risk of chronic Q fever.

Keywords: Coxiella burnetii; Q fever; alpha-v beta-3 integrin; complement receptor 3; myeloid differentiation primary response protein 88; nucleotide oligomerization domain 2; pattern recognition receptors; single nucleotide polymorphism; susceptibility; toll-like receptor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Coxiella burnetii / immunology
  • Female
  • Genetic Association Studies
  • Genetic Predisposition to Disease*
  • Genotype
  • Humans
  • Male
  • Membrane Glycoproteins / genetics*
  • Middle Aged
  • Myeloid Differentiation Factor 88 / genetics*
  • Polymorphism, Single Nucleotide*
  • Q Fever / immunology*
  • Receptors, Interleukin-1 / genetics*
  • Receptors, Pattern Recognition / genetics*


  • MYD88 protein, human
  • Membrane Glycoproteins
  • Myeloid Differentiation Factor 88
  • Receptors, Interleukin-1
  • Receptors, Pattern Recognition
  • TIRAP protein, human