Putative Candidate Drug Targets for Sarcopenia-Related Traits Identified Through Mendelian Randomization Analysis of the Blood Proteome.
Putative Candidate Drug Targets for Sarcopenia-Related Traits Identified Through Mendelian Randomization Analysis of the Blood Proteome.
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DOI：
10.3389/fgene.2022.923429
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发表时间：
2022
影响因子：
3.7
通讯作者：
中科院分区：
文献类型：
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作者：
目的：肌少症的日益流行仍然是全球卫生保健系统面临的一个持续挑战。治疗方法的缺乏鼓励了人类蛋白质组学的发现，以寻找潜在的治疗靶点。血浆蛋白作为人体蛋白质组的主要组成部分之一，在功能上与机体各器官联系，调节生物过程，介导整体稳态，在衰老、慢性疾病等多种复杂过程中起着至关重要的作用。通过对血浆蛋白质组进行系统的因果分析，我们试图揭示肌少症的病因机制并发现药物靶点。方法：利用四项血液蛋白全基因组关联研究数据和英国生物银行肌肉减少症相关性状的数据，我们采用双样本孟德尔随机化（MR）分析来评估310种血浆蛋白作为肌肉减少症相关性状的可能因果介质：阑尾瘦质量（ALM）和握力（左右）。然后，我们对已确定的推定因果蛋白进行了双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784种疾病的推定致病蛋白进行了全现象MR分析，以测试这些蛋白对其他疾病可能产生的副作用。结果：五种血浆蛋白被确定为肌少症相关性状的推定因果介质。具体来说，白细胞免疫球蛋白样受体亚家族B成员2 （LILRB2）、抗菌素（ASPN）和接触素-2 （CNTN2）对阑尾瘦质量有潜在的因果影响，外腺苷-核糖基转移酶4 （ART4）和超氧化物歧化酶2 （SOD2）分别对握力有推测的因果影响。五种推定的因果蛋白中没有一种与肌少症相关特征具有反向因果关系，也没有发现对其他疾病的副作用。结论：我们确定了5种血浆蛋白，它们可能是肌少症的潜在新药物靶点。我们的研究证明了双样本MR分析在识别和优先考虑复杂疾病的假定潜在治疗靶点方面的价值。
Purpose: 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. Methods: 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. Results: 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. Conclusion: 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.
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DOI：
10.1002/jcsm.12121
发表时间：
2017-02
期刊：
Journal of cachexia, sarcopenia and muscle
影响因子：
--
作者：
Gonzalez-Freire M;Semba RD;Ubaida-Mohien C;Fabbri E;Scalzo P;Højlund K;Dufresne C;Lyashkov A;Ferrucci L
通讯作者：
Ferrucci L
影响因子：
7.7
作者：
Bowden J;Del Greco M F;Minelli C;Davey Smith G;Sheehan NA;Thompson JR
通讯作者：
Thompson JR
肥胖，代谢产物和大肠癌风险：孟德尔随机研究。
影响因子：
9.3
作者：
Bull CJ;Bell JA;Murphy N;Sanderson E;Davey Smith G;Timpson NJ;Banbury BL;Albanes D;Berndt SI;Bézieau S;Bishop DT;Brenner H;Buchanan DD;Burnett-Hartman A;Casey G;Castellví-Bel S;Chan AT;Chang-Claude J;Cross AJ;de la Chapelle A;Figueiredo JC;Gallinger SJ;Gapstur SM;Giles GG;Gruber SB;Gsur A;Hampe J;Hampel H;Harrison TA;Hoffmeister M;Hsu L;Huang WY;Huyghe JR;Jenkins MA;Joshu CE;Keku TO;Kühn T;Kweon SS;Le Marchand L;Li CI;Li L;Lindblom A;Martín V;May AM;Milne RL;Moreno V;Newcomb PA;Offit K;Ogino S;Phipps AI;Platz EA;Potter JD;Qu C;Quirós JR;Rennert G;Riboli E;Sakoda LC;Schafmayer C;Schoen RE;Slattery ML;Tangen CM;Tsilidis KK;Ulrich CM;van Duijnhoven FJB;van Guelpen B;Visvanathan K;Vodicka P;Vodickova L;Wang H;White E;Wolk A;Woods MO;Wu AH;Campbell PT;Zheng W;Peters U;Vincent EE;Gunter MJ
通讯作者：
Gunter MJ
影响因子：
46.9
作者：
通讯作者：
--
影响因子：
2.1
作者：
Bowden J;Davey Smith G;Haycock PC;Burgess S
通讯作者：
Burgess S