Unit of Medical Epidemiology, Department of Surgical Sciences, Uppsala University, Dag Hammarskjölds väg 14 B, 75185, Uppsala, Sweden.
Unit of Cardiovascular and Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
Eur Heart J. 2024 Nov 14;45(43):4647-4657. doi: 10.1093/eurheartj/ehae658.
Few population-based cohort studies, including both men and women, have explored circulating proteins associated with incident myocardial infarction (MI). This study investigated the relationships between circulating cardiometabolic-related proteins and MI risk using cohort-based and Mendelian randomization (MR) analyses and explored potential sex-specific differences.
The discovery cohort included 11 751 Swedish adults (55-93 years). Data on 259 proteins assessed with Olink proximity extension assays, biochemical, and questionnaire-based information were used. Participants were followed up for incident MI and death over 8 years through linkage to Swedish registers. Replication analyses were conducted on the UK Biobank sample (n = 51 613). In MR analyses, index cis-genetic variants strongly related to the proteins were used as instrumental variables. Genetic association summary statistic data for MI were obtained from the CARDIoGRAMplusC4D consortium and FinnGen.
Forty-five proteins were associated with incident MI in discovery and replication samples following adjustment for potential confounders and multiple testing. In the secondary analysis, 13 of the protein associations were sex-specific, with most associations identified among women. In MR analysis, genetically predicted higher levels of renin, follistatin, and retinoic acid receptor responder protein 2 were linked to an increased risk of MI. Tissue factor pathway inhibitor, tumor necrosis factor receptors 1 and 2, placenta growth factor had an inverse association with MI.
This study identified both new and confirmed previously established associations between circulating proteins and incident MI and, for the first time, suggested sex-specific patterns in multiple protein-MI associations.
少数基于人群的队列研究，包括男性和女性，都探讨了与心肌梗死（MI）事件相关的循环蛋白。本研究通过基于队列的和孟德尔随机化（MR）分析，调查了与心肌梗死风险相关的循环心脏代谢相关蛋白的关系，并探讨了潜在的性别特异性差异。
发现队列包括 11751 名瑞典成年人（55-93 岁）。使用 Olink 接近延伸测定法评估了 259 种蛋白质的数据，以及生化和基于问卷的信息。参与者通过与瑞典登记册的链接，在 8 年内跟踪观察心肌梗死和死亡的发生情况。在英国生物银行样本（n=51613）中进行了复制分析。在 MR 分析中，将与蛋白质密切相关的指数顺式遗传变异作为工具变量。从 CARDIoGRAMplusC4D 联盟和 FinnGen 获得了 MI 的遗传关联汇总统计数据。
在发现和复制样本中，经过潜在混杂因素和多次检验调整后，有 45 种蛋白与心肌梗死事件相关。在二次分析中，有 13 种蛋白与性别相关，大多数关联发生在女性中。在 MR 分析中，遗传预测的肾素、卵泡抑素和维甲酸受体应答蛋白 2 水平升高与 MI 风险增加相关。组织因子途径抑制剂、肿瘤坏死因子受体 1 和 2、胎盘生长因子与 MI 呈负相关。
本研究鉴定了循环蛋白与心肌梗死之间的新的和已确认的关联，并首次提出了多种蛋白与心肌梗死之间的性别特异性模式。
