Genetic influence of Toll-like receptors on non-HIV cryptococcal meningitis: An observational cohort study

Ying-Kui Jiang, Ji-Qin Wu, Hua-Zhen Zhao, Xuan Wang, Rui-Ying Wang, Ling-Hong Zhou, Ching-Wan Yip, Li-Ping Huang, Jia-Hui Cheng, Ya-Hong Chen, Hua Li, Li-Ping Zhu, Xin-Hua Weng, Ying-Kui Jiang, Ji-Qin Wu, Hua-Zhen Zhao, Xuan Wang, Rui-Ying Wang, Ling-Hong Zhou, Ching-Wan Yip, Li-Ping Huang, Jia-Hui Cheng, Ya-Hong Chen, Hua Li, Li-Ping Zhu, Xin-Hua Weng

Abstract

Background: Cryptococcal meningitis (CM) is a significant source of mortality, the pathogenesis of which has not been fully understood, especially in non-HIV infected populations. We aimed to explore the potential genetic influence of Toll-like receptor (TLR) on non-HIV CM.

Methods: This observational cohort study was done in two stages: a discovery stage and a validation stage. A case-control genetic association study was conducted between 159 non-HIV CM patients and 468 healthy controls. TLR SNPs significantly related to susceptibility went further validation in a second cohort of 583 subjects from a certain district. Associations among TLR SNPs, cerebrospinal fluid (CSF) cytokine concentrations, and clinical severity were explored in a third cohort of 99 previously untreated non-HIV CM patients. Logistic regression model was used to determine the independent predictors for disease severity.

Findings: In the discovery stage, eight TLR SNPs exhibited significant genetic susceptibility to non-HIV CM, one of which was validated in a population validation of HIV-infected cases while none survived in non-HIV cases. CSF cytokine detections showed that 18 cytokines were significantly over-expressed in severely ill patients. Two of the 8 SNPs (rs5743604 and rs3804099) were also significantly associated with disease severity. Specifically, the rs3804099 C/T genotype was further found to be correlated to 12 of the 18 up-regulated cytokines in severe patients. In addition, high levels of interleukin (IL)-10 in CSF (OR 2·97, 95% CI 1·49-5·90; p = 0·002) was suggested as an independent predictor for severity after adjusted for possible confounders.

Interpretation: TLR participates in both the occurrence and the pathogenesis of non-HIV CM. The in situ immune responses of CM were under genetic influence of TLR and contributed to disease severity. FUND: National Natural Science Foundation of China and National Key Basic Research Program of China (973 Program).

Keywords: CSF cytokine; Disease severity; Genetic susceptibility; Non-HIV cryptococcal meningitis; Toll-like receptor.

Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

Figures

Fig. 1
Fig. 1
Genetic analyses between patients and controls in the discovery stage. (a) Distribution of p values for allele and genotype comparisons between patients and controls in the discovery stage. Dashed line indicates the p value correspond with p = 0·05. (b) Haplotype blocks among SNPs of the TLR1, TLR2, TLR4, TLR6 and TLR9 genes in 623 genotyped subjects. TLR = Toll-like receptor. SNP = single nucleotide polymorphism.
Fig. 2
Fig. 2
Summary of interactions among TLR SNPs, CSF cytokine concentrations and clinical severity. (a) Two cycles represent CSF cytokines associated with TLR SNPs and severity, respectively. The intersection indicates that 12 cytokines are related to both. (b) Three cycles represent TLR SNPs associated with CM susceptibility, CSF cytokine concentrations and clinical severity, respectively. Their intersections show that rs3804099 is correlated to all. CM = cryptococcal meningitis. TLR = Toll-like receptor. SNP = single nucleotide polymorphism. CSF = cerebrospinal fluid. IL = interleukin. IFN = interferon. MIP = macrophage inflammatory protein. MCP = monocyte chemo attractant protein. TNF = tumor necrosis factor. G-CSF = granulocyte-colony stimulating factor. GM-CSF = granulocyte-macrophage colony-stimulating factor. IP = interferon-induced protein. PDGF = platelet-derived growth factor. VEGF = vascular endothelial growth factor.
Fig. 3
Fig. 3
CSF cytokine concentrations in non-HIV CM patients carrying different rs3804099 genotypes. Comparisons were made based on overdominant models (C/T vs T/T + C/C). *p < 0·05. **p < 0·01. CSF = cerebrospinal fluid. HIV = human immunodeficiency virus. CM = cryptococcal meningitis. TLR = Toll-like receptor. IL = interleukin. IFN = interferon. MCP = monocyte chemo attractant protein. MIP = macrophage inflammatory protein. TNF = tumor necrosis factor.

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Source: PubMed

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