Department of Medical Sciences Uppsala University Sweden.
Division of Cardiovascular Medicine Department of Medicine Stanford University School of Medicine Stanford CA.
J Am Heart Assoc. 2021 Dec 7;10(23):e023330. doi: 10.1161/JAHA.121.023330. Epub 2021 Nov 30.
Background We recently reported a link between plasma levels of 2 of 84 cardiovascular disease (CVD)-related proteins and the 3 major CVDs, myocardial infarction, ischemic stroke, and heart failure. The present study investigated whether measurement of almost 10 times the number of proteins could lead to discovery of additional risk markers for CVD. Methods and Results We measured 742 proteins using the proximity extension assay in 826 male participants of ULSAM (Uppsala Longitudinal Study of Adult Men) who were free from CVD at the age of 70 years. Cox proportional hazards models were adjusted for age only, as well as all traditional risk factors. During a 12.5-year median follow-up (maximal, 22.0 years), 283 incident CVDs occurred. Forty-one proteins were significantly (false discovery rate <0.05) related to the combined end point of incident CVD, with N-terminal pro-brain natriuretic peptide as the top finding, while 53 proteins were related to incident myocardial infarction. A total of 13 and 16 proteins were significantly related to incident ischemic stroke and heart failure, respectively. Growth differentiation factor 15, 4-disulfide core domain protein 2, and kidney injury molecule were related to all of the 3 major CVD outcomes. A lasso selection of 11 proteins improved discrimination of incident CVD by 5.0% (=0.0038). Conclusions Large-scale proteomics seem useful for the discovery of new risk markers for CVD and to improve risk prediction in an elderly population of men. Further studies are needed to replicate the findings in independent samples of both men and women of different ages.
背景 我们最近报道了 84 种与心血管疾病（CVD）相关蛋白中的 2 种的血浆水平与 3 种主要 CVD（心肌梗死、缺血性卒中和心力衰竭）之间的关联。本研究探讨了测量近 10 倍数量的蛋白是否可以发现 CVD 的其他风险标志物。
方法和结果 我们使用邻近延伸测定法在 826 名 ULSAM（乌普萨拉成年男性纵向研究）男性参与者中测量了 742 种蛋白，这些参与者在 70 岁时没有 CVD。Cox 比例风险模型仅调整了年龄以及所有传统危险因素。在中位随访 12.5 年（最长 22.0 年）期间，发生了 283 例 CVD 事件。41 种蛋白与复合 CVD 终点显著相关（假发现率<0.05），其中 N 端脑钠肽前体为最高发现，而 53 种蛋白与心肌梗死相关。共有 13 种和 16 种蛋白分别与缺血性卒中和心力衰竭的发生显著相关。生长分化因子 15、4 二硫键核心域蛋白 2 和肾损伤分子与所有 3 种主要 CVD 结局均相关。lasso 选择 11 种蛋白可使 CVD 发生的判别提高 5.0%（=0.0038）。
结论 大规模蛋白质组学似乎可用于发现 CVD 的新风险标志物，并改善老年男性人群的风险预测。需要进一步的研究来复制在不同年龄的男性和女性的独立样本中的发现。
