TY - JOUR
T1 - Toll-like receptor 1 polymorphisms increase susceptibility to candidemia
AU - Plantinga, Theo S.
AU - Johnson, Melissa D.
AU - Scott, William K.
AU - Van De Vosse, Esther
AU - Velez Edwards, Digna R.
AU - Smith, P. Brian
AU - Alexander, Barbara D.
AU - Yang, John C.
AU - Kremer, Dennis
AU - Laird, Gregory M.
AU - Oosting, Marije
AU - Joosten, Leo A.B.
AU - Van Der Meer, Jos W.M.
AU - Van Dissel, Jaap T.
AU - Walsh, Thomas J.
AU - Perfect, John R.
AU - Kullberg, Bart Jan
AU - Netea, Mihai G.
N1 - Funding Information:
Financial support. This work was supported by a Vici grant from the Netherlands Organization for Scientific Research to M. G. N. and by the National Institutes of Health (AI-51537 to M. D. J.) and (AI-73896 to J. R. P.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Potential conflicts of interest. All authors: No reported conflicts.
PY - 2012/3/15
Y1 - 2012/3/15
N2 - 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.
AB - 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.
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U2 - 10.1093/infdis/jir867
DO - 10.1093/infdis/jir867
M3 - Article
C2 - 22301633
AN - SCOPUS:84863238893
SN - 0022-1899
VL - 205
SP - 934
EP - 943
JO - Journal of Infectious Diseases
JF - Journal of Infectious Diseases
IS - 6
ER -