Plasma Proteomic Insights for Identification of Novel Predictors and Potential Drug Targets in Atrial Fibrillation: A Prospective Cohort Study and Mendelian Randomization Analysis.

IF 9.1 1区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS
Xiaodong Peng, Yukun Li, Nian Liu, Shijun Xia, Xin Li, Yiwei Lai, Liu He, Caihua Sang, Jianzeng Dong, Changsheng Ma
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引用次数: 0

Abstract

Background: Currently, there are no reliable methods for predicting and preventing atrial fibrillation (AF) in its early stages. This study aimed to identify plasma proteins associated with AF to discover biomarkers and potential drug targets.

Methods: The UK Biobank Pharma Proteomics Project examined 2923 circulating proteins using the Olink platform, forming the basis of this prospective cohort study. The UK Biobank Pharma Proteomics Project included a randomly selected discovery cohort and the consortium-selected replication cohort. The study's end point was incident AF, identified using International Classification of Diseases, Tenth Revision codes. The association between plasma proteins and incident AF was evaluated using Cox proportional hazard models in both cohorts. Proteins present in both cohorts underwent Mendelian randomization analysis to delineate causal connections, utilizing cis-protein quantitative trait loci as genetic tools. The predictive efficacy of the identified proteins for AF was assessed using the area under the receiver operating characteristic curve, and their druggability was explored.

Results: Data from 38 784 participants were included in this study. Incident AF cases were identified in the discovery cohort (1894; 5.5%) within a median follow-up of 14.5 years and in the replication cohort (451; 10.6%) within a median follow-up of 14.4 years. Twenty-one proteins linked to AF were identified in both cohorts. Specifically, COL4A1 (collagen IV α-1; odds ratio, 1.11 [95% CI, 1.04-1.19]; false discovery rate, 0.016) and RET (proto-oncogene tyrosine-protein kinase receptor Ret; odds ratio, 0.96 [95% CI, 0.94-0.98]; false discovery rate, 0.013) demonstrated a causal link with AF, and RET is druggable. COL4A1 improved the short- and long-term predictive performance of established AF models, as evidenced by significant enhancements in the area under the receiver operating characteristic, integrated discrimination improvement, and net reclassification index, all with P values below 0.05.

Conclusions: COL4A1 and RET are associated with the development of AF. RET is identified as a potential drug target for AF prevention, while COL4A1 serves as a biomarker for AF prediction. Future studies are needed to evaluate the effectiveness of targeting these proteins to reduce AF risk.

用于识别心房颤动新预测因子和潜在药物靶点的血浆蛋白质组学见解:前瞻性队列研究和孟德尔随机分析
背景:目前,还没有可靠的方法在早期预测和预防心房颤动(AF)。这项研究旨在鉴定与房颤相关的血浆蛋白,以发现生物标记物和潜在的药物靶点:英国生物库药物蛋白质组学项目利用 Olink 平台检测了 2923 种循环蛋白质,为这项前瞻性队列研究奠定了基础。英国生物库医药蛋白质组学项目包括随机挑选的发现队列和联盟挑选的复制队列。研究终点是使用《国际疾病分类》第十版代码确定的房颤事件。在两个队列中使用 Cox 比例危险模型评估了血浆蛋白与心房颤动发病率之间的关系。利用顺式蛋白质定量性状位点作为遗传工具,对两个队列中存在的蛋白质进行孟德尔随机分析,以确定因果关系。利用接收者操作特征曲线下面积评估了已识别蛋白质对房颤的预测功效,并探讨了其可药用性:结果:本研究纳入了 53 032 名参与者的数据。在中位随访 14.5 年的发现队列(1894 例;5.5%)和中位随访 14.4 年的复制队列(451 例;10.6%)中发现了房颤病例。两个队列中均发现了 21 种与房颤相关的蛋白质。具体来说,COL4A1(胶原蛋白 IV α-1;几率比为 1.11 [95% CI, 1.04-1.19];错误发现率为 0.016)和 RET(原癌基因酪氨酸蛋白激酶受体 Ret;几率比为 0.96 [95% CI, 0.94-0.98];错误发现率为 0.013)与心房颤动有因果关系,而 RET 是可以药物治疗的。COL4A1改善了已建立的房颤模型的短期和长期预测性能,这体现在接收者操作特征下面积、综合辨别改进和净再分类指数的显著提高,所有P值均低于0.05:COL4A1和RET与房颤的发生有关。结论:COL4A1和RET与心房颤动的发生有关,RET被认为是预防心房颤动的潜在药物靶点,而COL4A1则是预测心房颤动的生物标志物。未来的研究需要评估以这些蛋白为靶点降低房颤风险的有效性。
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来源期刊
CiteScore
13.70
自引率
4.80%
发文量
187
审稿时长
4-8 weeks
期刊介绍: Circulation: Arrhythmia and Electrophysiology is a journal dedicated to the study and application of clinical cardiac electrophysiology. It covers a wide range of topics including the diagnosis and treatment of cardiac arrhythmias, as well as research in this field. The journal accepts various types of studies, including observational research, clinical trials, epidemiological studies, and advancements in translational research.
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