Wang Qijun, Zhao Xuan, Wang Shuaikang, Lu Shibao
Department of Orthopedics & Elderly Spinal Surgery, Xuanwu Hospital of Capital Medical University, National Clinical Research Center for Geriatric Diseases, Beijing, China.
Department of Orthopedics & Elderly Spinal Surgery, Xuanwu Hospital of Capital Medical University, National Clinical Research Center for Geriatric Diseases, Beijing, China.
Int Immunopharmacol. 2025 Jan 10;144:113687. doi: 10.1016/j.intimp.2024.113687. Epub 2024 Nov 26.
An increasing body of evidence has revealed the association between immune-mediated inflammatory diseases (IMIDs) and sarcopenia. However, a genetically direct causality between IMIDs and sarcopenia remains elusive.
To investigate the relationship between IMIDs and sarcopenia-related traits and identify potential therapeutic targets, a Mendelian randomization (MR) was performed. We collected publicly available genome-wide association studies (GWAS) data for seven common IMIDs, including systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD), Crohn's disease (CD), ulcerative colitis (UC), psoriasis (PSO), ankylosing spondylitis (AS), and rheumatoid arthritis (RA). Additionally, summary-level GWAS data for sarcopenia-related traits, including appendicular lean mass (ALM), left-hand grip strength, and right-hand grip strength were collected. To search for therapeutic targets, we used two types of genetic instruments to proxy the exposure of druggable genes, including genetic variants within or nearby drug targets and expression quantitative trait loci (eQTLs) of drug targets. Two-sample MR and summary-data-based MR (SMR) were used to calculate effect estimates, and sensitivity analyses were implemented for robustness. Drug tractability, gene enrichment analysis, and protein-protein interaction (PPI) analysis were used to validate the biological and clinical significance of the selected drug targets.
The two-sample MR analysis indicated the existence of casual associations between IMIDs and sarcopenia-related traits in the overall and sex-stratified populations. In particular, PSO had causal effects on decreased ALM, which showed significance in all six MR analysis tests with directional consistency in the overall population. Grounded in this robust association, HLA-DRB5, HLA-DRB1, and AGER were identified as potential therapeutic targets for ALM decline by drug target MR and further confirmed by SMR analysis. These genes were associated with therapeutic agents currently undergoing evaluations in clinical trials. Gene enrichment and PPI analysis indicated a strong association of these genes with immune functions.
This MR study contributes novel genetic evidence supporting the causal link between IMIDs and sarcopenia, with a particular emphasis on the association between PSO and decreased ALM. Additionally, AGER, HLA-DRB1, and HLA-DRB5 emerge as potential therapeutic targets for ALM decline.
越来越多的证据揭示了免疫介导的炎症性疾病（IMIDs）与肌肉减少症之间的关联。然而，IMIDs与肌肉减少症之间的遗传直接因果关系仍不明确。
为了研究IMIDs与肌肉减少症相关特征之间的关系并确定潜在的治疗靶点，进行了孟德尔随机化（MR）研究。我们收集了七种常见IMIDs的公开全基因组关联研究（GWAS）数据，包括系统性红斑狼疮（SLE）、炎症性肠病（IBD）、克罗恩病（CD）、溃疡性结肠炎（UC）、银屑病（PSO）、强直性脊柱炎（AS）和类风湿关节炎（RA）。此外，还收集了肌肉减少症相关特征的汇总水平GWAS数据，包括四肢瘦体重（ALM）、左手握力和右手握力。为了寻找治疗靶点，我们使用了两种类型的遗传工具来代表可药物化基因的暴露，包括药物靶点内部或附近的遗传变异以及药物靶点的表达定量性状位点（eQTL）。使用两样本MR和基于汇总数据MR（SMR）来计算效应估计值，并进行敏感性分析以确保稳健性。药物可处理性、基因富集分析和蛋白质-蛋白质相互作用（PPI）分析用于验证所选药物靶点的生物学和临床意义。
两样本MR分析表明，在总体人群和按性别分层的人群中，IMIDs与肌肉减少症相关特征之间存在因果关联。特别是，PSO对ALM降低有因果效应，在总体人群的所有六项MR分析测试中均显示出显著性，且方向一致。基于这种稳健的关联，通过药物靶点MR确定HLA-DRB5、HLA-DRB1和AGER为ALM下降的潜在治疗靶点，并通过SMR分析进一步证实。这些基因与目前正在临床试验中评估的治疗药物相关。基因富集和PPI分析表明这些基因与免疫功能密切相关。
这项MR研究提供了新的遗传证据，支持IMIDs与肌肉减少症之间的因果联系，尤其强调了PSO与ALM降低之间的关联。此外，AGER以及HLA-DRB¬1和HLA-DRB5成为ALM下降的潜在治疗靶点。
