Insights from bidirectional Mendelian randomization: Evaluating the influence of circulating inflammatory cytokines on prostatitis

Abstract

Research on prostatitis has primarily focused on inflammatory cytokines in semen or prostatic secretions, with relatively few studies investigating circulating inflammatory cytokines. To explore the relationship between prostatitis and circulating inflammatory cytokines, this study employed bidirectional two-sample Mendelian randomization (MR) to assess the potential associations between prostatitis and 91 circulating inflammatory cytokines. We performed bidirectional MR to explore causal links between 91 circulating inflammatory cytokines and prostatitis. Data were sourced from 14,824 individuals of European ancestry and the Finngen database for prostatitis. The inverse variance-weighted (IVW) method was the primary tool, complemented by MR-Egger, weighted median, weighted mode, and MR-PRESSO to enhance result robustness. Heterogeneity and pleiotropy evaluations were conducted, and GO/KEGG enrichment analyses were used to explore the biological pathways linked to these inflammatory factors and prostatitis. The MR results revealed that Interleukin-10 receptor A (IL-10RA), Natural Killer Cell Receptor 2B4 (CD244), and urokinase-type plasminogen activator (uPA) were identified as risk factors for prostatitis (IVWIL-10RA: OR = 1.242, 95% CI: 1.043-1.478, P = .015; IVWCD244: OR = 1.143, 95% CI: 1.002-1.305, P = .047; IVWuPA: OR = 1.141, 95% CI: 1.009-1.290, P = .035). Conversely, Interleukin-12B (IL-12B) exhibited a protective effect against prostatitis (IVWIL-12B: OR = 0.909, 95% CI: 0.842-0.981, P = .014). Moreover, reverse MR analysis results indicate that prostatitis decreases plasma levels of chemokine (C-C motif) ligand 23 (CCL23), IL-5, and TNF-related activation-induced cytokine (TRANCE) (IVWCCL23: OR = 0.949, 95% CI: 0.906-0.993, P = .025; IVWIL-5: OR = 0.938, 95% CI: 0.890-0.988, P = .016; IVWTRANCE: OR = 0.947, 95% CI: 0.905-0.992, P = .021). This bidirectional MR study identified potential causal links between 7 circulating inflammatory cytokines and prostatitis, offering insights into its pathogenesis and potential targets for future therapies.

Keywords: Mendelian randomization; acupuncture; biomarkers; causal relationship; inflammation; prostatitis.

Figure 1.

Overview of research design. Assumption1: IVs must be associated with the risk factor. Assumption2: IVs must be independent of any confounding factors between the risk factor and the outcome. Assumption3: IVs must only affect the outcome through the risk factor instead of any other pathway. IV = instrumental variables, MR analysis = Mendelian Randomization analysis, SNPs = single nucleotide polymorphisms.

Figure 2.

The forest plot illustrates the results of MR analysis on the impact of 91 cytokines on prostatitis. CI = confidence interval, MR analysis = Mendelian Randomization analysis, OR = odds ratio, SNP = single nucleotide polymorphism.

Figure 3.

This heatmap illustrates the MR analysis outcomes concerning the influence of 91 inflammatory cytokines on prostatitis. It includes the names of all inflammatory cytokine phenotypes and the P values of 4 MR analyses, along with the corresponding OR values from the IVW analysis method. The outer circle represents the names of the inflammatory cytokine phenotypes, while the middle circle uses different colors to indicate the P value results of different MR analyses. The inner circle employs various colors to represent the OR value results from the IVW analysis. IVW = inverse variance-weighted, MR analysis = Mendelian Randomization analysis, OR = odds ratio.

Figure 4.

scatter plots (A) IL-10RA on prostatitis; (B) IL-12B on prostatitis; (C) CD244 on prostatitis; (D) uPA on prostatitis. CD244 = Natural Killer Cell Receptor 2B4, IL-10RA = Interleukin-10 receptor A, IL-12B = Interleukin-12B, uPA = urokinase-type plasminogen activator.

Figure 5.

The forest plot illustrates the results of MR analysis on the impact of prostatitis on 91 cytokines. CI = confidence interval, MR analysis = Mendelian Randomization analysis, OR = odds ratio, SNP = single nucleotide polymorphism.

Figure 6.

This heatmap illustrates the MR analysis outcomes concerning the influence of prostatitis on 91 inflammatory cytokines. It includes the names of all inflammatory cytokine phenotypes and the P values of 4 MR analyses, along with the corresponding OR values from the IVW analysis method. The outer circle represents the names of the inflammatory cytokine phenotypes, while the middle circle uses different colors to indicate the P value results of different MR analyses. The inner circle employs various colors to represent the OR value results from the IVW analysis. IVW = inverse variance-weighted, MR analysis = Mendelian Randomization analysis, OR = odds ratio.

Figure 7.

Scatter plots (A) prostatitis on CCL23; (B) prostatitis on IL-5; (C) prostatitis on TRANCE. CCL23 = chemokine (C-C motif) ligand 23, IL-5 = Interleukin-5, TRANCE = TNF-related activation-induced cytokine.

Figure 8.

The bar plots illustrates the GO and KEGG enrichment analyses of IL-10RA, IL-12B, CD244, and uPA. CD244 = Natural Killer Cell Receptor 2B4, GO = gene ontology, IL-10RA = Interleukin-10 receptor A, IL-12B = Interleukin-12B, KEGG = kyoto encyclopedia of genes and genomes, uPA = urokinase-type plasminogen activator.

Figure 9.

Leave-one-out analysis (A) IL-10RA on prostatitis; (B) IL-12B on prostatitis; (C) CD244 on prostatitis; (D) uPA on prostatitis. CD244 = Natural Killer Cell Receptor 2B4, IL-10RA = Interleukin-10 receptor A, IL-12B = Interleukin-12B, IL-10RA = Interleukin-10 receptor A, IL-12B = Interleukin-12B,

Figure 10.

Leave-one-out analysis (A) prostatitis on CCL23; (B) prostatitis on IL-5; (C) prostatitis on TRANCE. CCL23 = chemokine (C-C motif) ligand 23, IL-5 = Interleukin-5, TRANCE = TNF-related activation-induced cytokine.