Association Analysis of the Circulating Proteome With Sarcopenia-Related Traits Reveals Potential Drug Targets for Sarcopenia

IF 9.1 1区医学 Q1 GERIATRICS & GERONTOLOGY Journal of Cachexia Sarcopenia and Muscle Pub Date : 2025-02-13 DOI:10.1002/jcsm.13720

Simin Wen, Siqi Xu, Xizeng Zong, Shifeng Wen, Wende Xiao, Weipeng Zheng, Han Cen, Zhaohua Zhu, Jingyu Xie, Yan Zhang, Changhai Ding, Guangfeng Ruan

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引用次数: 0

Abstract

Background

Sarcopenia severely affects the physical health of the elderly. Currently, there is no specific drug available for sarcopenia. This study aims to identify pathogenic proteins and druggable targets for sarcopenia through Mendelian randomization (MR)–based analytical framework.

Methods

A sequential stepwise screening method that includes two-sample MR, Steiger filtering test and colocalization (MRSC) was applied to identify causal proteins associated with sarcopenia-related traits. In the MR analyses, 4372 circulating proteins with valid instrumental variables (IVs) from eight proteomic genome-wide association studies were utilized as exposures, and nine sarcopenia-related traits were utilized as outcomes. IVs were classified into cis–protein quantitative trait loci (pQTLs) and trans-pQTLs based on their positions. We conducted cis-only MRSC analyses and cis + trans MRSC analyses using cis-pQTLs and cis + trans pQTLs as IVs, respectively. Post-MRSC analyses were conducted on the prioritized findings of MRSC, including annotation of protein-altering variants (PAVs), assessment of overlap between pQTLs and expression quantitative trait loci (eQTLs), protein–protein interaction (PPI) analysis, pathway enrichment analysis and annotation of drug targets. Utilizing data from the UK Biobank, we performed an observational study to explore the associations between baseline circulating protein levels and the longitudinal changes in nine sarcopenia-related traits.

Results

A total of 181 causal associations for 65 proteins were prioritized by the cis-only MRSC analyses and 227 associations for 91 proteins were prioritized by the cis + trans MRSC analyses. Among the prioritized proteins, the majority of them employed non-PAVs as IVs and most of their cis-pQTLs overlapped with corresponding eQTLs and exhibited consistent directionality, with only one trans-pQTL overlapping with an eQTL. The PPI network of cis-only MRSC-prioritized proteins (p = 4.04 × 10⁻⁴) and cis + trans MRSC-prioritized proteins (p = 8.76 × 10⁻⁵) showed significantly more interactions than expected. Reactome, KEGG and GO pathway enrichment analyses for cis-only MRSC-prioritized proteins identified 52, 12 and 79 enriched pathways, respectively (adjusted p < 0.05). For proteins identified by cis + trans MRSC analyses, only 15 pathways were enriched through the GO pathway enrichment analyses. In the observational study, 197 circulating proteins were identified to be associated with one or more sarcopenia-related traits (p < 0.05/2923). Among them, the significant associations of CTSB (negative association) and ASGR1 (positive association) with sarcopenia-related traits were observed to have consistent directional associations in both MR-based studies and observational studies. Drug target annotations suggested that 52 MRSC-prioritized proteins and 145 biomarkers are drug targets or druggable.

Conclusions

This study identified 89 potential pathogenic proteins and 197 candidate biomarkers for sarcopenia, providing valuable clues for the development of therapeutic drugs for sarcopenia.

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循环蛋白质组与肌少症相关性状的关联分析揭示了肌少症的潜在药物靶点

骨骼肌减少症严重影响老年人的身体健康。目前，还没有针对肌肉减少症的特效药。本研究旨在通过基于孟德尔随机化（MR）的分析框架，确定肌肉减少症的致病蛋白和药物靶点。方法采用双样本MR、Steiger过滤试验和共定位（MRSC）的序贯逐步筛选方法，鉴定与肌少症相关性状相关的致病蛋白。在MR分析中，来自8个蛋白质组学全基因组关联研究的4372个循环蛋白具有有效的工具变量（IVs）作为暴露，9个肌少症相关性状作为结果。根据其位置将IVs分为顺式蛋白数量性状位点（pqtl）和反式pqtl。我们分别使用cis- pqtl和cis + trans pqtl作为iv进行了顺式MRSC分析和cis + trans MRSC分析。对MRSC的优先发现进行MRSC后分析，包括蛋白改变变异（paus）的注释、pqtl与表达数量性状位点（eqtl）的重叠评估、蛋白-蛋白相互作用（PPI）分析、途径富集分析和药物靶点的注释。利用英国生物银行（UK Biobank）的数据，我们进行了一项观察性研究，以探索基线循环蛋白水平与九种肌肉减少症相关特征的纵向变化之间的关系。结果仅顺式MRSC分析优先考虑了65种蛋白质的181种因果关联，顺式+反式MRSC分析优先考虑了91种蛋白质的227种因果关联。在被优先的蛋白中，它们大多数使用非pav作为iv，它们的大部分顺式pqtl与相应的eQTL重叠，并表现出一致的方向性，只有一个反式pqtl与eQTL重叠。仅顺式mrsc优先蛋白（p = 4.04 × 10−4）和顺式+反式mrsc优先蛋白（p = 8.76 × 10−5）的PPI网络显示出比预期更多的相互作用。对顺式mrsc优先蛋白的Reactome、KEGG和GO途径富集分析分别鉴定出52条、12条和79条富集途径（调整p <； 0.05）。对于cis + trans MRSC分析鉴定的蛋白质，通过GO途径富集分析，只有15条途径富集。在观察性研究中，197种循环蛋白被确定与一种或多种肌少症相关特征相关（p < 0.05/2923）。其中，CTSB（负相关）和ASGR1（正相关）与肌少症相关性状显著相关，在磁共振研究和观察性研究中均有一致的方向性关联。药物靶标注释表明，52种mrsc优先蛋白和145种生物标志物是药物靶标或可用药。结论本研究鉴定出89种潜在的肌少症致病蛋白和197种候选生物标志物，为肌少症治疗药物的开发提供了有价值的线索。

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

Journal of Cachexia Sarcopenia and Muscle MEDICINE, GENERAL & INTERNAL-

CiteScore

13.30

自引率

12.40%

发文量

234

审稿时长

16 weeks

期刊介绍： The Journal of Cachexia, Sarcopenia and Muscle is a peer-reviewed international journal dedicated to publishing materials related to cachexia and sarcopenia, as well as body composition and its physiological and pathophysiological changes across the lifespan and in response to various illnesses from all fields of life sciences. The journal aims to provide a reliable resource for professionals interested in related research or involved in the clinical care of affected patients, such as those suffering from AIDS, cancer, chronic heart failure, chronic lung disease, liver cirrhosis, chronic kidney failure, rheumatoid arthritis, or sepsis.