Supplementary file 5_Blood metabolites as mediators in erectile dysfunction: insights from a multi-center proteomics and genetic study.docx

ObjectiveThis study aims to identify circulating proteins causally associated with erectile dysfunction (ED) using Mendelian randomization (MR) analysis.
MethodsWe utilized two of the largest multi-center proteomics databases as exposures and the FinnGen database as the outcome source. A large-scale two-sample MR analysis, including coloc colocalization analysis and SMR (Summary data-based Mendelian Randomization) analysis, was conducted to evaluate the reliability of proteomic effects on ED outcomes. Additionally, MR mediation analysis involving 1,400 blood metabolites was performed to investigate how these proteins mediate the effect of blood metabolites on ED. Finally, protein-protein interaction analysis, pathway enrichment analysis, druggability assessments, and molecular docking were employed to further elucidate the mechanisms of ED and identify potential therapeutic targets.
ResultsEight circulating proteins (AMN, ESM1, KIR2DL2, PIGR, SPINT1, SPP1, TNFRSF6B, TMEM9) were identified as causally associated with ED based on two-sample MR and coloc colocalization criteria. Among these, five proteins (AMN, ESM1, KIR2DL2, PIGR, TNFRSF6B) satisfied SMR validation, while SPINT1, TMEM9, and SPP1 were excluded. Several of these proteins were found to mediate the relationship between metabolites and ED. These proteins are recognized as either druggable targets or existing drug targets, with molecular docking results demonstrating favorable interactions with various drug candidates.
ConclusionUsing MR analysis, we identified five proteins associated with ED, clarified protein-mediated mechanisms, and proposed promising therapeutic targets for ED.

研究目的 本研究旨在通过孟德尔随机化（Mendelian randomization, MR）分析，筛选与勃起功能障碍（erectile dysfunction, ED）存在因果关联的循环蛋白。
研究方法 本研究选取两个规模最大的多中心蛋白质组学数据库作为暴露组数据来源，以FinnGen数据库作为结局组数据来源。开展大规模两样本孟德尔随机化分析，包括共定位分析（coloc分析）及基于汇总数据的孟德尔随机化（Summary data-based Mendelian Randomization, SMR）分析，以评估蛋白质组特征对勃起功能障碍结局的效应可靠性。此外，本研究纳入1400种血液代谢物开展孟德尔随机化中介分析，以探究上述蛋白质如何介导血液代谢物对勃起功能障碍的影响。最后，通过蛋白质相互作用分析、通路富集分析、成药性评估及分子对接，进一步阐明勃起功能障碍的发病机制并筛选潜在治疗靶点。
研究结果 基于两样本孟德尔随机化分析及coloc共定位分析标准，本研究共鉴定出8种与勃起功能障碍存在因果关联的循环蛋白（AMN、ESM1、KIR2DL2、PIGR、SPINT1、SPP1、TNFRSF6B、TMEM9）。其中5种蛋白（AMN、ESM1、KIR2DL2、PIGR、TNFRSF6B）通过了SMR验证，SPINT1、TMEM9及SPP1则被排除。研究发现部分上述蛋白可介导代谢物与勃起功能障碍之间的关联。这些蛋白均被认定为可成药靶点或现有药物靶点，分子对接结果显示其与多种候选药物均具有良好的相互作用。
研究结论 本研究通过孟德尔随机化分析鉴定出5种与勃起功能障碍相关的蛋白质，阐明了蛋白质介导的发病机制，并为勃起功能障碍提出了具有应用前景的治疗靶点。