MR results of circulating proteins and five OA.

BackgroundOsteoarthritis (OA) is a prevalent chronic joint disease for which there is a lack of effective treatments. In this study, we used Mendelian randomization analysis to identify circulating proteins that are causally associated with OA-related traits, providing important insights into potential drug targets for OA.MethodCausal associations between 1553 circulating proteins and five OA-related traits were assessed in large-scale two-sample MR analyses using Wald ratio or inverse variance weighting, and the results were corrected for Bonferroni. In addition, sensitivity analyses were performed to validate the reliability of the MR results, including reverse MR analysis and Steiger filtering to ensure the causal direction between circulating proteins and OA; Bayesian co-localization and phenotypic scanning were used to eliminate confounding effects and horizontal pleiotropy. External validation was performed to exclude incidental findings using novel plasma protein quantitative trait loci. Finally, the online analysis tool Enrichr was utilized to screen drugs and molecular docking was performed to predict binding modes and energies between proteins and drugs to identify the most stable and likely binding modes and drugs.ResultFour proteins were ultimately found to be reliably and causally associated with three OA-related features: DNAJB12 and USP8 were associated with knee OA, IL12B with spinal OA, and RGMB with thumb OA. The ORs for the above proteins were 1.51 (95% CI, 1.26–1.81), 1.72 (95% CI, 1.42–2.08), 0.87 (95% CI, 0.81–0.92), and 0.59 (95% CI, 0.47–0.75), respectively. Drug-predicting small molecules (doxazosin, XEN 103, and montelukast) that simultaneously target three proteins, DNAJB12, USP8, and IL12B, docked well.ConclusionBased on our comprehensive analysis, we can draw the conclusion that there is a causal relationship between the genetic levels of DNAJB12, USP8, IL12B, and RGMB and the risk of respective OA.They may be potential options for OA screening and prevention in clinical practice. They can also serve as candidate molecules for future mechanism exploration and drug target selection.

背景：骨关节炎（Osteoarthritis, OA）是一种高发的慢性关节疾病，目前缺乏有效的治疗方案。本研究采用孟德尔随机化（Mendelian randomization）分析方法，鉴定与骨关节炎相关性状存在因果关联的循环蛋白，为骨关节炎潜在药物靶点的探索提供重要见解。
方法：本研究采用沃尔德比值法（Wald ratio）或逆方差加权法（inverse variance weighting），在大规模双样本孟德尔随机化分析中，评估了1553种循环蛋白与5种骨关节炎相关性状之间的因果关联，并对结果进行Bonferroni校正。此外，本研究开展敏感性分析以验证孟德尔随机化结果的可靠性：包括反向孟德尔随机化分析与Steiger过滤，以明确循环蛋白与骨关节炎之间的因果方向；采用贝叶斯共定位分析（Bayesian co-localization）与表型扫描，以排除混杂效应与水平多效性（horizontal pleiotropy）。本研究使用新型血浆蛋白数量性状位点（plasma protein quantitative trait loci）进行外部验证，以排除偶然发现的结果。最后，本研究借助在线分析工具Enrichr筛选潜在药物，并通过分子对接（molecular docking）预测蛋白与药物的结合模式及结合能，以鉴定最稳定且最具生物学可能性的结合模式与药物候选。
结果：最终共发现4种蛋白与3种骨关节炎相关特征存在可靠的因果关联：DNAJB12、USP8与膝骨关节炎相关，IL12B与脊柱骨关节炎相关，RGMB与拇指骨关节炎相关。上述蛋白的比值比（Odds Ratio, OR）分别为1.51（95% CI：1.26–1.81）、1.72（95% CI：1.42–2.08）、0.87（95% CI：0.81–0.92）以及0.59（95% CI：0.47–0.75）。可同时靶向DNAJB12、USP8与IL12B三种蛋白的预测药物小分子（多沙唑嗪doxazosin、XEN 103与孟鲁司特montelukast）对接效果良好。
结论：基于本研究的综合分析，我们可得出以下结论：DNAJB12、USP8、IL12B与RGMB的遗传水平与对应骨关节炎的发病风险存在因果关联。上述蛋白或可成为临床骨关节炎筛查与预防的潜在标志物，亦可作为未来机制探索与药物靶点筛选的候选分子。