Genetic Variation in Pattern Recognition Receptors and Adaptor Proteins Associated With Development of Chronic Q Fever.
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.
Department of Internal Medicine, Radboud University Medical Center.
Teske
T
Schoffelen
Department of Internal Medicine, Radboud University Medical Center.
Anne
A
Ammerdorffer
Department of Surgery, Jeroen Bosch Hospital, 's-Hertogenbosch.
Julia C J P
JC
Hagenaars
Department of Internal Medicine, Radboud University Medical Center.
Chantal P
CP
Bleeker-Rovers
Department of Medical Microbiology, Laboratory for Pathology and Medical Microbiology, Veldhoven.
Marjolijn C
MC
Wegdam-Blans
Department of Medical Microbiology and Infection Control, Jeroen Bosch Hospital, 's-Hertogenbosch.
Peter C
PC
Wever
Department of Internal Medicine, Radboud University Medical Center.
Leo A B
LA
Joosten
Department of Internal Medicine, Radboud University Medical Center.
Jos W M
JW
van der Meer
Department of Internal Medicine, Radboud University Medical Center Department of Medical Microbiology and Infectious Diseases and Department of Internal Medicine, Canisius Wilhelmina Hospital, Nijmegen.
Tom
T
Sprong
Department of Internal Medicine, Radboud University Medical Center.
Mihai G
MG
Netea
Department of Internal Medicine, Radboud University Medical Center.
Marcel
M
van Deuren
Department of Infectious Diseases, Leiden University Medical Center, The Netherlands.
Esther
E
van de Vosse
D000368:Aged; D016997:Coxiella burnetii / Q000276:immunology; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics*; D008875:Middle Aged; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011778:Q Fever / Q000276:immunology*; D017472:Receptors, Interleukin-1 / Q000235:genetics*; D051192:Receptors, Pattern Recognition / Q000235:genetics*
C507779:MYD88 protein, human; D008562:Membrane Glycoproteins; D053594:Myeloid Differentiation Factor 88; D017472:Receptors, Interleukin-1; D051192:Receptors, Pattern Recognition; C434984:TIRAP protein, human
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