Shengli Clinical Medical College of Fujian Medical University, Fuzhou, People's Republic of China.
Department of Geriatric Medicine, Fujian Provincial Hospital, Fuzhou, People's Republic of China.
BMC Med Genomics. 2024 Feb 21;17(1):59. doi: 10.1186/s12920-024-01826-6.
Heart failure (HF) is a prevalent clinical syndrome with diverse etiologies. It is crucial to identify novel therapeutic targets based on underlying causes. Here, we aimed to use proteome-wide Mendelian randomization (MR) analyses to identify the associations between genetically predicted elevated levels of circulating proteins and distinct HF outcomes, along with specific HF etiologies.
Protein quantitative trait loci (pQTL) data for circulating proteins were sourced from the Atherosclerosis Risk in Communities (ARIC) study, encompassing 7,213 individuals and profiling 4,657 circulating proteins. Genetic associations for outcomes were obtained from the HERMES Consortium and the FinnGen Consortium. Colocalization analysis was employed to assess the impact of linkage disequilibrium on discovered relationships. For replication, two-sample MR was conducted utilizing independent pQTL data from the deCODE study. Multivariable MR (MVMR) and two-step MR were further conducted to investigate potential mediators.
Two proteins (PCSK9 and AIDA) exhibited associations with HF in patients with coronary heart disease (CHD), and four proteins (PCSK9, SWAP70, NCF1, and RELT) were related with HF in patients receiving antihypertensive medication. Among these associations, strong evidence from subsequent analyses supported the positive relationship between genetically predicted PCSK9 levels and the risk of HF in the context of CHD. Notably, MVMR analysis revealed that CHD and LDL-C did not exert a complete mediating effect in this relationship. Moreover, two-step MR results yielded valuable insights into the potential mediating proportions of CHD or LDL-C in this relationship.
Our findings provide robust evidence supporting the association between PCSK9 and concomitant HF and CHD. This association is partly elucidated by the influence of CHD or LDL-C, underscoring the imperative for additional validation of this connection and a thorough exploration of the mechanisms through which PCSK9 directly impacts ischemic HF.
心力衰竭（HF）是一种常见的临床综合征，具有多种病因。根据潜在病因确定新的治疗靶点至关重要。在这里，我们旨在使用基于全蛋白质组的孟德尔随机分析（MR）来识别循环蛋白水平升高与不同心力衰竭结局以及特定心力衰竭病因之间的关联。
循环蛋白的蛋白质数量性状基因座（pQTL）数据来源于动脉粥样硬化风险社区（ARIC）研究，包括 7213 个人，分析了 4657 种循环蛋白。结果的遗传关联来自 HERMES 联盟和 FinnGen 联盟。共定位分析用于评估连锁不平衡对发现关系的影响。为了复制，使用 deCODE 研究中的独立 pQTL 数据进行了两样本 MR。进一步进行多变量 MR（MVMR）和两步 MR 以研究潜在的介质。
两种蛋白（PCSK9 和 AIDA）与冠心病（CHD）患者的 HF 相关，四种蛋白（PCSK9、SWAP70、NCF1 和 RELT）与接受抗高血压药物治疗的 HF 相关。在这些关联中，随后的分析提供了强有力的证据支持 CHD 背景下遗传预测的 PCSK9 水平与 HF 风险之间的正相关关系。值得注意的是，MVMR 分析表明，CHD 和 LDL-C 并未在这种关系中完全发挥中介作用。此外，两步 MR 结果深入了解了 CHD 或 LDL-C 在这种关系中潜在的中介比例。
我们的研究结果提供了强有力的证据，支持 PCSK9 与同时发生的 HF 和 CHD 之间的关联。这种关联部分由 CHD 或 LDL-C 的影响来解释，这强调了需要进一步验证这种联系，并深入探讨 PCSK9 如何直接影响缺血性 HF 的机制。
