Mediating Mendelian randomization in the proteome identified potential drug targets for obesity-related allergic asthma.

IF 2.7 3区 生物学
Jiannan Lin, Shuwen Lu, Xiaoyu Zhao
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引用次数: 0

Abstract

Background: With the development of the economy, the number of obese patients has been increasing annually worldwide. The proportion of asthma patients associated with obesity is also gradually rising. However, the pathogenesis of obesity-related asthma remains incompletely understood, and conventional pharmacological treatments generally show limited efficacy.

Objective: This study aims to explore the causal relationship between obesity and allergic asthma, elucidate the pathogenesis of obesity-related asthma, and identify the plasma proteins involved in its development, providing new insights for clinical interventions.

Methods: In this study, we employed a two-step approach for mediation Mendelian randomization (MR) analysis, utilizing stringent selection criteria to identify instrumental variables (IVs). This approach was used to assess the causal impact of obesity on allergic asthma and to validate the plasma proteins identified as mediating factors. We further explored the functions and enriched pathways of the mediating proteins using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Finally, we conducted drug-targeted MR analysis to evaluate the potential of each mediator plasma proteins as a drug target gene. If significant heterogeneity remained among the IVs, we applied the weighted median method as the primary analytical tool. Otherwise, we utilized the inverse variance weighted (IVW) method as the main analytical approach. Additionally, we conducted various sensitivity analyses and statistical tests to further illustrate the robustness of the observed associations.

Results: The research findings indicate a causal relationship between obesity and allergic asthma. Plasma proteins such as TPST1, ROR1, and DAPK1 mediate this relationship, with TPST1 accounting for over 10% of the mediation effect. GO and KEGG analyses show that the genes corresponding to these mediator proteins are primarily enriched in pathways related to responses to stimuli, carbohydrate synthesis and metabolism, regulation of certain protein activities, and synaptic connections. The drug-targeted MR analysis suggests that SIGLEC12, BOLA1, HOMER2, and TPST1 all have the potential to be drug target genes.

Conclusion: This study suggests that obese patients defined by BMI may promote the development of allergic asthma by influencing the expression of plasma proteins such as TPST1, ROR1, and DAPK1. Furthermore, some of these plasma proteins, including TPST1, could potentially serve as therapeutic targets for treating allergic asthma in these patients. However, further research is needed to explore their therapeutic potential and the mechanisms underlying their effects.

Clinical trial number: Not applicable.

在蛋白质组中介导孟德尔随机化确定了肥胖相关过敏性哮喘的潜在药物靶点。
背景:随着经济的发展,世界范围内肥胖患者的数量逐年增加。与肥胖相关的哮喘患者比例也在逐渐上升。然而,肥胖相关哮喘的发病机制仍不完全清楚,传统的药物治疗通常疗效有限。目的:探讨肥胖与变应性哮喘的因果关系,阐明肥胖相关性哮喘的发病机制,鉴定参与变应性哮喘发病的血浆蛋白,为临床干预提供新的思路。方法:在本研究中,我们采用两步法进行中介孟德尔随机化(MR)分析,使用严格的选择标准来识别工具变量(IVs)。该方法用于评估肥胖对过敏性哮喘的因果影响,并验证被确定为介导因子的血浆蛋白。我们利用基因本体(GO)和京都基因与基因组百科全书(KEGG)分析进一步探索了介导蛋白的功能和富集途径。最后,我们进行了药物靶向MR分析,以评估每种介质血浆蛋白作为药物靶基因的潜力。如果IVs之间仍然存在显著的异质性,我们采用加权中位数法作为主要分析工具。除此之外,我们采用逆方差加权(IVW)方法作为主要的分析方法。此外,我们进行了各种敏感性分析和统计检验,以进一步说明观察到的关联的稳健性。结果:研究结果表明肥胖与过敏性哮喘之间存在因果关系。血浆蛋白如TPST1、ROR1、DAPK1介导了这一关系,其中TPST1介导作用占10%以上。GO和KEGG分析表明,与这些中介蛋白对应的基因主要富集于与刺激反应、碳水化合物合成和代谢、某些蛋白质活性调节和突触连接相关的途径中。药物靶向MR分析提示SIGLEC12、BOLA1、HOMER2和TPST1都有成为药物靶基因的潜力。结论:本研究提示BMI定义的肥胖患者可能通过影响血浆蛋白TPST1、ROR1、DAPK1的表达促进变应性哮喘的发生。此外,其中一些血浆蛋白,包括TPST1,可能潜在地作为治疗这些患者过敏性哮喘的治疗靶点。然而,还需要进一步的研究来探索它们的治疗潜力和作用机制。临床试验号:不适用。
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来源期刊
Hereditas
Hereditas Biochemistry, Genetics and Molecular Biology-Genetics
CiteScore
3.80
自引率
3.70%
发文量
0
期刊介绍: For almost a century, Hereditas has published original cutting-edge research and reviews. As the Official journal of the Mendelian Society of Lund, the journal welcomes research from across all areas of genetics and genomics. Topics of interest include human and medical genetics, animal and plant genetics, microbial genetics, agriculture and bioinformatics.
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