Chen Bin-Bin, Wang Jia-Qi, Meng Xiang-He, Luo Zhe, Liu Xiao-Wen, Shen Hui, Xiao Hong-Mei, Deng Hong-Wen
Center for System Biology, Data Sciences and Reproductive Health, School of Basic Medical Science, Central South University, Changsha, China.
Tulane Center of Biomedical Informatics and Genomics, Deming Department of Medicine, School of Medicine, Tulane University School, New Orleans, LA, United States.
Front Genet. 2022 Jul 22;13:923429. doi: 10.3389/fgene.2022.923429. eCollection 2022.
The increasing prevalence of sarcopenia remains an ongoing challenge to health care systems worldwide. The lack of treatments encouraged the discovery of human proteomes to find potential therapeutic targets. As one of the major components of the human proteome, plasma proteins are functionally connected with various organs of the body to regulate biological processes and mediate overall homeostasis, which makes it crucial in various complex processes such as aging and chronic diseases. By performing a systematic causal analysis of the plasma proteome, we attempt to reveal the etiological mechanism and discover drug targets for sarcopenia. By using data from four genome-wide association studies for blood proteins and the UK Biobank data for sarcopenia-related traits, we applied two-sample Mendelian randomization (MR) analysis to evaluate 310 plasma proteins as possible causal mediators of sarcopenia-related traits: appendicular lean mass (ALM) and handgrip strength (right and left). Then we performed a two-sample bidirectional Mendelian randomization analysis for the identified putatively causal proteins to assess potential reverse causality that the trait values may influence protein levels. Finally, we performed phenome-wide MR analysis of the identified putatively causal proteins for 784 diseases to test the possible side effects of these proteins on other diseases. Five plasma proteins were identified as putatively causal mediators of sarcopenia-related traits. Specifically, leukocyte immunoglobulin-like receptor subfamily B member 2 (LILRB2), asporin (ASPN), and contactin-2 (CNTN2) had potential causal effects on appendicular lean mass, and ecto-ADP-ribosyltransferase 4 (ART4) and superoxide dismutase 2 (SOD2) had putative causal effects on the handgrip strength, respectively. None of the five putatively causal proteins had a reverse causality relationship with sarcopenia-related traits, and no side effects on other diseases were identified. We identified five plasma proteins that may serve as putatively potential novel drug targets for sarcopenia. Our study attested to the value of two-sample MR analysis in identifying and prioritizing putatively potential therapeutic targets for complex diseases.
肌肉减少症患病率的不断上升仍然是全球医疗保健系统面临的一项持续挑战。由于缺乏有效的治疗方法，促使人们通过研究人类蛋白质组来寻找潜在的治疗靶点。作为人类蛋白质组的主要组成部分之一，血浆蛋白在功能上与身体的各个器官相连，以调节生物过程并介导整体内环境稳态，这使其在衰老和慢性疾病等各种复杂过程中至关重要。通过对血浆蛋白质组进行系统的因果分析，我们试图揭示肌肉减少症的病因机制并发现其药物靶点。利用四项血液蛋白质全基因组关联研究的数据以及英国生物银行中与肌肉减少症相关性状的数据，我们应用两样本孟德尔随机化（MR）分析来评估310种血浆蛋白作为肌肉减少症相关性状（四肢瘦体重（ALM）和握力（右手和左手））可能的因果中介因素。然后，我们对已确定的可能具有因果关系的蛋白质进行了两样本双向孟德尔随机化分析，以评估性状值可能影响蛋白质水平的潜在反向因果关系。最后，我们对已确定的可能具有因果关系的蛋白质针对784种疾病进行了全表型孟德尔随机化分析，以测试这些蛋白质对其他疾病可能产生的副作用。五种血浆蛋白被确定为肌肉减少症相关性状可能的因果中介因素。具体而言，白细胞免疫球蛋白样受体亚家族B成员2（LILRB2）、骨桥蛋白（ASPN）和接触蛋白2（CNTN2）对四肢瘦体重具有潜在的因果效应，而胞外ADP核糖基转移酶4（ART4）和超氧化物歧化酶2（SOD2）分别对握力具有推定的因果效应。这五种可能具有因果关系的蛋白质中，没有一种与肌肉减少症相关性状存在反向因果关系，也未发现对其他疾病有副作用。我们确定了五种血浆蛋白，它们可能作为肌肉减少症潜在的新型药物靶点。我们的研究证明了两样本MR分析在识别和优先确定复杂疾病潜在治疗靶点方面的价值。
