Toll-like receptor 1 polymorphisms increase susceptibility to candidemia.
BACKGROUND
Candidemia is a severe invasive fungal infection with high mortality. Recognition of Candida species is mediated through pattern recognition receptors such as Toll-like receptors (TLRs). This study assessed whether genetic variation in TLR signaling influences susceptibility to candidemia.


METHODS
Thirteen mostly nonsynonymous single nucleotide polymorphisms (SNPs) in genes encoding TLRs and signaling adaptors MyD88 and Mal/TIRAP were genotyped in 338 patients (237 white, 93 African American, 8 other race) with candidemia and 351 noninfected controls (263 white, 88 African American). The SNPs significant in univariate analysis were further analyzed with multivariable logistic regression to determine association with clinical outcomes. Functional consequences of these polymorphisms were assessed via in vitro stimulation assays.


RESULTS
Analyses of TLR SNPs revealed that 3 TLR1 SNPs (R80T, S248N, I602S) were significantly associated with candidemia susceptibility in whites. This association was not found in African Americans, likely due to lower power in this smaller study population. Furthermore, these TLR1 polymorphisms displayed impaired cytokine release by primary monocytes. No associations with susceptibility to candidemia were observed for SNPs in TLR2, TLR4, TLR6, TLR9, MyD88, or TIRAP.


CONCLUSIONS
Nonsynonymous SNPs in TLR1 are associated with impaired TLR1 function, decreased cytokine responses, and predisposition to candidemia in whites.
Department of Medicine, Radboud University Nijmegen Medical Center, the Netherlands.
Theo S
TS
Plantinga
Melissa D
MD
Johnson
William K
WK
Scott
Esther
E
van de Vosse
Digna R
DR
Velez Edwards
P Brian
PB
Smith
Barbara D
BD
Alexander
John C
JC
Yang
Dennis
D
Kremer
Gregory M
GM
Laird
Marije
M
Oosting
Leo A B
LA
Joosten
Jos W M
JW
van der Meer
Jaap T
JT
van Dissel
Thomas J
TJ
Walsh
John R
JR
Perfect
Bart Jan
BJ
Kullberg
Mihai G
MG
Netea
D000328:Adult; D001741:Black or African American / Q000235:genetics; D000368:Aged; D058387:Candidemia / Q000208:ethnology / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D015398:Signal Transduction; D051194:Toll-Like Receptor 1 / Q000235:genetics*; D044465:White People / Q000235:genetics
D051194:Toll-Like Receptor 1