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. 2024 Nov 1:15:1495970.
doi: 10.3389/fphar.2024.1495970. eCollection 2024.

Multi-omics association study integrating GWAS and pQTL data revealed MIP-1α as a potential drug target for erectile dysfunction

Jingwen Liu #  1 , Renbing Pan #  2
Affiliations

Multi-omics association study integrating GWAS and pQTL data revealed MIP-1α as a potential drug target for erectile dysfunction

Jingwen Liu et al. Front Pharmacol. .

Abstract

Background: Erectile dysfunction (ED) brings heavy burden to patients and society. Despite the availability of established therapies, existing medications have restricted efficacy. Therefore, we utilized a two-sample Mendelian randomization (MR) approach to find the drug targets that might enhance the clinical outcome of ED.

Methods: Genetic instruments associated with circulating inflammatory proteins were obtained from a genome-wide association study (GWAS) involving 8,293 European participants. Summary statistics for ED were extracted from a meta-analysis of the United Kingdom Biobank cohort compromised of 6,175 cases and 217,630 controls with European descent. We utilized multi-omics method and MR study to explore potential drug targets by integrating GWAS and protein quantity trait loci (pQTL) data. Inverse-variance weighted (IVW) method was applied as the primary approach. Cochran's Q statistics was employed to investigate the presence of heterogeneity. Furthermore, we identify the potential therapeutic drug targets for the treatment of ED utilizing molecular docking technology.

Results: This MR analysis of integrating GWAS and pQTL data showed that macrophage inflammatory protein-1 alpha (MIP-1α) was causally associated with the risk of ED (OR:1.19, 95%CI:1.02-1.39, p = 0.023). Meanwhile, the results of the weighted median model were consistent with the IVW estimates (OR:1.26, 95%CI:1.04-1.52, p = 0.018). Sensitivity analysis revealed no horizontal pleiotropy and heterogeneity. Furthermore, four anti-inflammatory or tonifying small molecular compounds, encompassing echinacea, pinoresinol diglucoside, hypericin, and icariin were identified through molecular docking technology.

Conclusion: This study identified MIP-1α as an underlying druggable gene and promising novel therapeutic target for ED, necessitating further investigation to detect the potential mechanisms by which MIP-1α might impact the development of ED.

Keywords: GWAS; MIP-1α; drug target; erectile dysfunction; multi-omics.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Datasets, flowchart, and study design of two-sample Mendelian randomization for systemic inflammatory proteins and erectile dysfunction (ED).
FIGURE 2
FIGURE 2
The heatmaps of five Mendelian randomization analysis methods. Different color blocks represent different odds ratio values. OR, odds ratio.
FIGURE 3
FIGURE 3
Forest plot of the Mendelian randomization analysis for the associations between systemic inflammatory proteins and erectile dysfunction. CI, confidence interval; OR, odds ratio. SNP, single nucleotide polymorphism.
FIGURE 4
FIGURE 4
Mendelian randomization (MR) analyses for circulating levels of MIP-1α on erectile dysfunction (ED). (A) Scatter plot; (B) Funnel plot; (C) Leave-one-out analysis; (D) Forest plot. SNP, single nucleotide polymorphism.
FIGURE 5
FIGURE 5
Molecular docking. Binding mode of proteins and ligands. (A) Binding mode of MIP-1α with hypericin; (B) Binding mode of MIP-1α with echinacea; (C) Binding mode of MIP-1α with pinoresinol diglucoside; (D) Binding mode of MIP-1α with icariin.
FIGURE 6
FIGURE 6
The construction of PPI network. (A) The hub genes visualization of PPI network by employing STRING database. (B) PPI network by utilizing GeneMANIA platform.
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