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.
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Source: PubMed