From metabolomics to therapeutics: identifying causal metabolites and potential drugs for the treatment of osteoarthritis.

IF 4.6 2区医学 Q2 IMMUNOLOGY

Inflammopharmacology Pub Date : 2024-11-03 DOI:10.1007/s10787-024-01594-w

Heng Li, Jingyan Sun, Jiewen Zhang, Yang Chen, Yiwei Zhao, Ruomu Cao, Ning Kong, Xudong Duan, Huanshuai Guan, Run Tian, Kunzheng Wang, Pei Yang

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引用次数: 0

Abstract

Background: Osteoarthritis (OA) is a common age-related disease that causes pain and impaired mobility. Various blood metabolites are reportedly associated with bone health; however, their impact on OA remains unclear. Therefore, we conducted a metabolome-wide Mendelian randomization (MR) study to identify causal metabolites and therapeutic targets in OA.

Methods: Genetic associations of metabolites were derived from the largest genome-wide association study (GWAS) of the blood metabolome, which provided summary-level data on 1091 blood metabolites. Genetic associations with OA were obtained from four large-scale GWAS: McDonald's study (140,025 cases, 344,349 controls), Zengini's study (12,658 cases, 50,898 controls), Dönertaş's study (39,515 cases, 445,083 controls), and Tachmazidou's study (39,427 cases, 378,169 controls). MR and colocalization analyses were performed to validate the causal roles of the candidate metabolites. Further analyses were conducted using expression quantitative trait locus-based MR, single-cell sequencing data, protein-protein interaction networks, and druggability assessments. These analyses aimed to identify the differentially expressed genes and prioritize them as potential therapeutic targets.

Results: The genetically predicted levels of 10 metabolites were associated with OA. Elevated levels of five metabolites and reduced levels of another five metabolites were associated with an increased OA risk. Among these, five metabolites were prioritized based on the most compelling evidence. Seven genes were identified as potentially involved and could serve as novel therapeutic targets for OA.

Conclusion: Several blood metabolites were associated with OA, providing new insights into the etiology of OA and highlighting promising therapeutic targets.

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从代谢组学到治疗学：确定治疗骨关节炎的致病代谢物和潜在药物。

背景：骨关节炎（OA）是一种常见的老年性疾病，会导致疼痛和活动障碍。据报道，多种血液代谢物与骨骼健康有关；然而，它们对 OA 的影响仍不清楚。因此，我们进行了一项全代谢组孟德尔随机化（MR）研究，以确定OA的致病代谢物和治疗靶点：代谢物的遗传关联来自最大的血液代谢组全基因组关联研究（GWAS），该研究提供了 1091 种血液代谢物的汇总数据。与 OA 的遗传关联来自四项大规模 GWAS：McDonald 研究（140,025 例病例，344,349 例对照）、Zengini 研究（12,658 例病例，50,898 例对照）、Dönertaş 研究（39,515 例病例，445,083 例对照）和 Tachmazidou 研究（39,427 例病例，378,169 例对照）。为验证候选代谢物的因果作用，进行了磁共振和共定位分析。此外，还利用基于表达定量性状位点的磁共振、单细胞测序数据、蛋白质-蛋白质相互作用网络和可药性评估进行了进一步分析。这些分析旨在确定差异表达基因，并将其优先列为潜在的治疗靶点：结果：10 种代谢物的基因预测水平与 OA 相关。5种代谢物水平升高和另外5种代谢物水平降低与OA风险增加有关。在这些代谢物中，有五种代谢物根据最有说服力的证据被优先考虑。有七个基因可能与之有关，可作为治疗 OA 的新靶点：结论：几种血液代谢物与 OA 相关，为 OA 的病因学提供了新的见解，并突出了有希望的治疗靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Inflammopharmacology IMMUNOLOGYTOXICOLOGY-TOXICOLOGY

CiteScore

8.00

自引率

3.40%

发文量

200

期刊介绍： Inflammopharmacology is the official publication of the Gastrointestinal Section of the International Union of Basic and Clinical Pharmacology (IUPHAR) and the Hungarian Experimental and Clinical Pharmacology Society (HECPS). Inflammopharmacology publishes papers on all aspects of inflammation and its pharmacological control emphasizing comparisons of (a) different inflammatory states, and (b) the actions, therapeutic efficacy and safety of drugs employed in the treatment of inflammatory conditions. The comparative aspects of the types of inflammatory conditions include gastrointestinal disease (e.g. ulcerative colitis, Crohn''s disease), parasitic diseases, toxicological manifestations of the effects of drugs and environmental agents, arthritic conditions, and inflammatory effects of injury or aging on skeletal muscle. The journal has seven main interest areas: -Drug-Disease Interactions - Conditional Pharmacology - i.e. where the condition (disease or stress state) influences the therapeutic response and side (adverse) effects from anti-inflammatory drugs. Mechanisms of drug-disease and drug disease interactions and the role of different stress states -Rheumatology - particular emphasis on methods of measurement of clinical response effects of new agents, adverse effects from anti-rheumatic drugs -Gastroenterology - with particular emphasis on animal and human models, mechanisms of mucosal inflammation and ulceration and effects of novel and established anti-ulcer, anti-inflammatory agents, or antiparasitic agents -Neuro-Inflammation and Pain - model systems, pharmacology of new analgesic agents and mechanisms of neuro-inflammation and pain -Novel drugs, natural products and nutraceuticals - and their effects on inflammatory processes, especially where there are indications of novel modes action compared with conventional drugs e.g. NSAIDs -Muscle-immune interactions during inflammation [...]