BACKGROUND:Hypertension, a complex condition, is primarily defined based on blood pressure readings without involving its pathophysiological mechanisms. We aimed to identify biomarkers through a proteomic approach, thereby enhancing the future definition of hypertension with insights into its molecular mechanisms.METHODS:The discovery analysis included 1560 participants, aged 55 to 74 years at baseline, from the KORA (Cooperative Health Research in the Region of Augsburg) S4/F4/FF4 cohort study, with 3332 observations over a median of 13.4 years of follow-up. Generalized estimating equations were used to estimate the associations of 233 plasma proteins with hypertension and systolic blood pressure (SBP). For validation, proteins significantly associated with hypertension or SBP in the discovery analysis were validated in the KORA Age1/Age2 cohort study (1024 participants, 1810 observations). A 2-sample Mendelian randomization analysis was conducted to infer causalities of validated proteins with SBP.RESULTS:Discovery analysis identified 49 proteins associated with hypertension and 99 associated with SBP. Validation in the KORA Age1/Age2 study replicated 7 proteins associated with hypertension and 23 associated with SBP. Three proteins, NT-proBNP (N-terminal pro-B-type natriuretic peptide), KIM1 (kidney injury molecule 1), and OPG (osteoprotegerin), consistently showed positive associations with both outcomes. Five proteins demonstrated potential causal associations with SBP in Mendelian randomization analysis, including NT-proBNP and OPG.CONCLUSIONS:We identified and validated 7 hypertension-associated and 23 SBP-associated proteins across 2 cohort studies. KIM1, NT-proBNP, and OPG demonstrated robust associations, and OPG was identified for the first time as associated with blood pressure. For NT-proBNP (protective) and OPG, causal associations with SBP were suggested.

中文翻译：

---

蛋白质组学与高血压和收缩压的关联：KORA S4/F4/FF4 和 KORA Age1/Age2 队列研究


背景：高血压是一种复杂的疾病，主要根据血压读数来定义，而不涉及其病理生理机制。我们的目标是通过蛋白质组学方法识别生物标志物，从而通过深入了解高血压的分子机制来增强未来对高血压的定义。 方法：发现分析包括来自 KORA（合作健康研究中心）的 1560 名参与者，基线年龄为 55 至 74 岁。奥格斯堡地区）S4/F4/FF4 队列研究，在平均 13.4 年的随访期间进行了 3332 次观察。使用广义估计方程来估计 233 种血浆蛋白与高血压和收缩压 (SBP) 的关联。为了进行验证，在 KORA Age1/Age2 队列研究（1024 名参与者，1810 个观察值）中验证了发现分析中与高血压或 SBP 显着相关的蛋白质。进行 2 个样本孟德尔随机化分析，以推断已验证蛋白质与 SBP 的因果关系。结果：发现分析确定了 49 种与高血压相关的蛋白质和 99 种与 SBP 相关的蛋白质。 KORA Age1/Age2 研究中的验证复制了 7 种与高血压相关的蛋白质和 23 种与 SBP 相关的蛋白质。 NT-proBNP（N 端 B 型利尿钠肽原）、KIM1（肾损伤分子 1）和 OPG（骨保护素）这三种蛋白始终与这两种结果呈正相关。在孟德尔随机化分析中，包括 NT-proBNP 和 OPG 在内的 5 种蛋白质被证明与 SBP 存在潜在因果关系。结论：我们在 2 项队列研究中鉴定并验证了 7 种高血压相关蛋白和 23 种 SBP 相关蛋白。 KIM1、NT-proBNP 和 OPG 表现出强大的关联性，并且首次发现 OPG 与血压相关。对于 NT-proBNP（保护性）和 OPG，建议与 SBP 存在因果关系。