Causal effects of systemic inflammatory proteins on Guillain-Barre Syndrome: insights from genome-wide Mendelian randomization, single-cell RNA sequencing analysis, and network pharmacology

Abstract

Background: Evidence from observational studies indicates that inflammatory proteins play a vital role in Guillain-Barre Syndrome (GBS). Nevertheless, it is unclear how circulating inflammatory proteins are causally associated with GBS. Herein, we conducted a two-sample Mendelian randomization (MR) analysis to systematically explore the causal links of genetically determined systemic inflammatory proteins on GBS.

Methods: A total of 8,293 participants of European ancestry were included in a genome-wide association study of 41 inflammatory proteins as instrumental variables. Five MR approaches, encompassing inverse-variance weighted, weighted median, MR-Egger, simple model, and weighted model were employed to explore the causal links between inflammatory proteins and GBS. MR-Egger regression was utilized to explore the pleiotropy. Cochran's Q statistic was implemented to quantify the heterogeneity. Furthermore, we performed single-cell RNA sequencing analysis and predicted potential drug targets through molecular docking technology.

Results: By applying MR analysis, four inflammatory proteins causally associated with GBS were identified, encompassing IFN-γ (OR:1.96, 95%CI: 1.02-3.78, P_IVW=0.045), IL-7 (OR:1.86, 95%CI: 1.07-3.23, P_IVW=0.029), SCGF-β (OR:1.56, 95%CI: 1.11-2.19, P_IVW=0.011), and Eotaxin (OR:1.99, 95%CI: 1.01-3.90, P_IVW=0.046). The sensitivity analysis revealed no evidence of pleiotropy or heterogeneity. Additionally, significant genes were found through single-cell RNA sequencing analysis and several anti-inflammatory or neuroprotective small molecular compounds were identified by utilizing molecular docking technology.

Conclusions: Our MR analysis suggested that IFN-γ, IL-7, SCGF-β, and Eotaxin were causally linked to the occurrence and development of GBS. These findings elucidated potential causal associations and highlighted the significance of these inflammatory proteins in the pathogenesis and prospective therapeutic targets for GBS.

Keywords: Guillain-Barre Syndrome; Mendelian randomization; molecular docking; single-cell RNA-seq; systemic inflammatory proteins.

Figure 1

Study design and flowchart of two-sample Mendelian randomization for systemic inflammatory proteins and Guillain-Barre Syndrome. pQTL, proteins quantitative trait loci; SNP, single nucleotide polymorphism.

Figure 2

The heatmaps of five Mendelian randomization analysis methods. Different color blocks represent different odds ratio values. OR, odds ratio.

Figure 3

Forest plot of the MR estimates for the associations between 41 inflammatory proteins and Guillain-Barre Syndrome. The inverse variance weighted method is considered the main approach. CI, confidence interval; OR, odds ratio.

Figure 4

Forest plot of the reverse MR estimates. The inverse variance weighted method is considered the main approach. CI, confidence interval; OR, odds ratio.

Figure 5

Scatter plots results of MR analysis between four identified inflammatory proteins and Guillain-Barre Syndrome. (A) IFN-γ, (B) IL-7, (C) SCGF-β, (D) Eotaxin. SNP, single nucleotide polymorphism.

Figure 6

Leave-one-out sensitivity analysis results of MR analysis between four identified inflammatory proteins and Guillain-Barre Syndrome. (A) IFN-γ, (B) IL-7, (C) SCGF-β, (D) Eotaxin.

Figure 7

Manhattan plot exhibited the traits of genetic instrumental variables associated with four candidate inflammatory proteins and significant genes were labelled (A). The most significant gene POLR1C expressed levels and distribution in neuroepithelium tissues through single-cell RNA sequencing analysis (C). Protein-protein interactive (PPI) network by using GeneMANIA platform (B, D). Chr, chromosome.

Figure 8

Molecular docking. Note. Binding mode of proteins and ligands. (A) Binding mode of IL-7 with stigmasterol; (B) Binding mode of IL-7 with saffronin; (C) Binding mode of IL-7 with quercetin; (D) Binding mode of IL-7 with kaempferol; (E) Binding mode of IL-7 with naringenin.