Toll-like receptor 1 polymorphisms increase susceptibility to candidemia

Abstract

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.

Figure 1.

Linkage disequilibrium (LD) analysis of TLR1 single nucleotide polymorphisms R80T (rs5743611), S248N (rs4833095), and I602S (rs5743618) in white individuals. Pairwise LD was assessed using the correlation coefficient (r²). Percentage correlation between the 2 markers is noted in each box.

Figure 2.

Correlation of TLR1 haplotypes with cytokine measurements of interleukin 1 β (IL-1β), interleukin 6 (IL-6), and interleukin 8 (IL-8) 24 h after in vitro stimulation of peripheral blood mononuclear cells from healthy volunteers with the Toll-like receptor 1 (TLR1)/TLR2 agonist Pam3Cys (10 μg/mL). On the x-axis the different TLR1 haplotypes are depicted with protective genotypes (not bold) and risk genotypes (bold). Data are presented as means ± SEM (Mann–Whitney U test, *P ≤ .05, **P ≤ .005).

Figure 3.

Correlation of TLR2 R753Q (A) and TLR4 D299G/T399I (B) genotypes with cytokine measurements of interleukin 1 β (IL-1β), interleukin 6 (IL-6), and interleukin 8 (IL-8) 24 h after in vitro stimulation of peripheral blood mononuclear cells from healthy volunteers with either Pam3Cys (A, 10 μg/mL) or lipopolysaccharide (B, 10 ng/mL). Data are presented as means ± SEM. Abbreviation: TLR, Toll-like receptor.