Clinical School of Pediatrics, Tianjin Medical University, Tianjin, China.
Department of Pulmonology, Tianjin Children's Hospital (Children's Hospital of Tianjin University), Machang Compus, 225 Machang Road, Hexi District, Tianjin, 300074, China.
J Transl Med. 2024 Oct 29;22(1):978. doi: 10.1186/s12967-024-05782-8.
Asthma poses a significant global health challenge, characterized by high rates of morbidity and mortality. Despite available treatments, many severe asthma patients remain poorly managed, highlighting the need for novel therapeutic strategies. This study aims to identify potential drug targets for asthma by examining the influence of circulating plasma proteins on asthma risk.
This study employs summary-data-based Mendelian randomization (MR) and two-sample MR methods to investigate the association between 2940 plasma proteins from the UK Biobank study and asthma. The analysis includes discovery (FinnGen cohort) and replication (GERA cohort) phases, with Bayesian colocalization used to validate the relationships between proteins and asthma. Furthermore, protein-protein interaction and druggability assessments were conducted on high-evidence strength protein biomarkers, and candidate drug prediction and molecular docking were performed for proteins without targeted drugs. Given the complexity of asthma pathogenesis, the study also explores the relationships between plasma proteins and asthma-related endpoints (e.g., obesity-related asthma, infection-related asthma, childhood asthma) to identify potential therapeutic targets for different subtypes.
In the discovery cohort, 75 plasma proteins were associated with asthma, including IL1RAP, IL1RL1, IL6, CXCL5, and CXCL8. Additionally, 6 proteins (IL4R, LTB, CASP8, MAX, PCDH12, and SCLY) were validated through co-localization analysis and validation cohort. The assessment of drug targetability revealed potential drug targets for IL4R, CASP8, and SCLY, while candidate drugs were predicted for LTB and MAX proteins. MAX exhibited strong binding affinity with multiple small molecules indicating a highly stable interaction and significant druggability potential. Analysis of the 75 proteins with 9 asthma-related endpoints highlighted promising targets such as DOK2, ITGAM, CA1, BTN2A1, and GZMB.
These findings elucidate the link between asthma, its related endpoints, and plasma proteins, advancing our understanding of molecular pathogenesis and treatment strategies. The discovery of potential therapeutic targets offers new insights into asthma drug target research.
哮喘是一个全球性的重大健康挑战，其特点是发病率和死亡率高。尽管有可用的治疗方法，但许多严重的哮喘患者仍未得到妥善管理，这突显了需要新的治疗策略。本研究旨在通过研究循环血浆蛋白对哮喘风险的影响，来确定哮喘的潜在药物靶点。
本研究采用基于汇总数据的孟德尔随机化（MR）和两样本 MR 方法，研究来自英国生物库研究的 2940 种血浆蛋白与哮喘之间的关联。该分析包括发现（FinnGen 队列）和复制（GERA 队列）阶段，使用贝叶斯共定位来验证蛋白与哮喘之间的关系。此外，对高证据强度的蛋白生物标志物进行蛋白-蛋白相互作用和可成药性评估，并对没有靶向药物的蛋白进行候选药物预测和分子对接。鉴于哮喘发病机制的复杂性，本研究还探索了血浆蛋白与哮喘相关终点（如肥胖相关哮喘、感染相关哮喘、儿童哮喘）之间的关系，以确定不同亚型的潜在治疗靶点。
在发现队列中，有 75 种血浆蛋白与哮喘相关，包括 IL1RAP、IL1RL1、IL6、CXCL5 和 CXCL8。此外，通过共定位分析和验证队列验证了 6 种蛋白（IL4R、LTB、CASP8、MAX、PCDH12 和 SCLY）。药物靶标评估揭示了 IL4R、CASP8 和 SCLY 的潜在药物靶点，同时预测了 LTB 和 MAX 蛋白的候选药物。MAX 与多种小分子表现出强烈的结合亲和力，表明其具有高度稳定的相互作用和显著的成药性潜力。对与 9 个哮喘相关终点的 75 种蛋白进行分析，突出了 DOK2、ITGAM、CA1、BTN2A1 和 GZMB 等有前途的靶点。
这些发现阐明了哮喘及其相关终点与血浆蛋白之间的联系，提高了我们对分子发病机制和治疗策略的认识。潜在治疗靶点的发现为哮喘药物靶点研究提供了新的见解。
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