School of Public Health, Peking University, Beijing, China.
Peking University Center for Public Health and Epidemic Preparedness & Response, Beijing, China.
Heart. 2024 Sep 25;110(20):1208-1215. doi: 10.1136/heartjnl-2024-324050.
Integration of large proteomics and genetic data in population-based studies can provide insights into discovery of novel biomarkers and potential therapeutic targets for cardiometabolic diseases (CMD). We aimed to synthesise existing evidence on the observational and genetic associations between circulating proteins and CMD.
PubMed, Embase and Web of Science were searched until July 2023 for potentially relevant prospective observational and Mendelian randomisation (MR) studies investigating associations between circulating proteins and CMD, including coronary heart disease, stroke, type 2 diabetes, heart failure, atrial fibrillation and atherosclerosis. Two investigators independently extracted study characteristics using a standard form and pooled data using random effects models.
50 observational, 25 MR and 10 studies performing both analyses were included, involving 26 414 160 non-overlapping participants. Meta-analysis of observational studies revealed 560 proteins associated with CMD, of which 133 proteins were associated with ≥2 CMDs (ie, pleiotropic). There were 245 potentially causal protein biomarkers identified in MR pooled results, involving 23 pleiotropic proteins. IL6RA and MMP12 were each causally associated with seven diseases. 22 protein-disease pairs showed directionally concordant associations in observational and MR pooled estimates. Addition of protein biomarkers to traditional clinical models modestly improved the accuracy of predicting incident CMD, with the highest improvement for heart failure (ΔC-index ~0.2). Of the 245 potentially causal proteins (291 protein-disease pairs), 3 pairs were validated by evidence of drug development from existing drug databases, 288 pairs lacked evidence of drug development and 66 proteins were drug targets approved for other indications.
Combined analyses of observational and genetic studies revealed the potential causal role of several proteins in the aetiology of CMD. Novel protein biomarkers are promising targets for drug development and risk stratification.
CRD42022350327.
在基于人群的研究中整合大规模蛋白质组学和遗传数据，可以深入了解心血管代谢疾病 (CMD) 新型生物标志物和潜在治疗靶点的发现。我们旨在综合现有观察性和遗传关联研究的证据，探讨循环蛋白与 CMD 之间的关系。
检索 PubMed、Embase 和 Web of Science，以获取截至 2023 年 7 月可能相关的前瞻性观察性和孟德尔随机化 (MR) 研究，这些研究调查了循环蛋白与 CMD（包括冠心病、中风、2 型糖尿病、心力衰竭、心房颤动和动脉粥样硬化）之间的关联。两位研究者独立使用标准表格提取研究特征，并使用随机效应模型汇总数据。
纳入了 50 项观察性研究、25 项 MR 研究和 10 项同时进行这两种分析的研究，涉及 26414160 个非重叠参与者。观察性研究的荟萃分析显示，与 CMD 相关的蛋白有 560 种，其中 133 种蛋白与≥2 种 CMD 相关（即多效性）。MR 汇总结果中确定了 245 种潜在的因果蛋白生物标志物，其中 23 种蛋白具有多效性。IL6RA 和 MMP12 分别与 7 种疾病相关。22 种蛋白-疾病对在观察性和 MR 汇总估计中显示出方向一致的关联。将蛋白生物标志物添加到传统的临床模型中，可适度提高预测 CMD 事件的准确性，心力衰竭的改善幅度最大（ΔC 指数约为 0.2）。在 245 种潜在的因果蛋白（291 种蛋白-疾病对）中，有 3 对通过现有药物数据库中药物开发的证据得到验证，288 对缺乏药物开发的证据，66 种蛋白是其他适应症批准的药物靶点。
观察性和遗传研究的综合分析显示，几种蛋白在 CMD 的发病机制中具有潜在的因果作用。新型蛋白生物标志物是药物开发和风险分层的有前途的靶点。
PROSPERO 注册号：CRD42022350327。
