Population Health Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute (S.T., J.S., M.C., H.G., G.P.), McMaster University, Hamilton, ON, Canada.
Department of Molecular Biology, Medical Biochemistry and Pathology, Laval University, Quebec City, Canada (S.T.).
Circ Genom Precis Med. 2020 Feb;13(1):e002605. doi: 10.1161/CIRCGEN.119.002605. Epub 2020 Jan 12.
Hypertension is a common modifiable risk factor for cardiovascular disease and mortality. Pathophysiological mechanisms leading to hypertension remain incompletely understood. Mendelian randomization (MR) allows the evaluation of the causal role of markers by minimizing the risk of biases such as reverse causation and confounding. We aimed to identify novel circulating proteins associated with blood pressure through a comprehensive screen of 227 blood biomarkers using MR.
Genetic determinants of 227 biomarkers were identified in ORIGIN (Outcome Reduction With Initial Glargine Intervention; URL: http://www.clinicaltrials.gov. Unique identifier: NCT00069784) participants (N=4147) and combined with genetic effects on systolic blood pressure, diastolic blood pressure, mean arterial pressure, and pulse pressure from the International Consortium for Blood Pressure (74 064 individuals) using MR. Results were replicated in the UK Biobank (up to 319 103 individuals) and using another biomarker dataset (N=3301). MR analyses with cardiovascular risk factors and outcomes as well as other biomarkers were performed to further evaluate the mechanisms involved.
Six biomarkers were associated with blood pressure using MR after adjustment for multiple hypothesis testing. Relationships between NT-proBNP (N-terminal Pro-B-type natriuretic peptide), systolic blood pressure, and diastolic blood pressure confirmed previous reports. Novel circulating proteins associated with blood pressure were also identified. uPA (urokinase-type plasminogen activator) was related to systolic blood pressure; ADM (adrenomedullin) was related to systolic blood pressure and pulse pressure; IL (interleukin) 16 was related to diastolic blood pressure; cFn (cellular fibronectin) and IGFBP3 (insulin-like growth factor-binding protein 3) were related to pulse pressure. With the exception of IL16 and diastolic blood pressure (=0.58), these relationships were validated in the UK Biobank (<0.0001). Further MR analyses with cardiovascular risk factors and outcomes showed relationships between NT-proBNP and large-artery atherosclerotic stroke, IGFBP3 and diabetes mellitus as well as cFn and body mass index.
We identified novel biomarkers associated with blood pressure using MR. These markers could prove useful for risk assessment and as potential therapeutic targets.
高血压是心血管疾病和死亡率的常见可改变危险因素。导致高血压的病理生理机制仍不完全清楚。孟德尔随机化（MR）通过使用 MR 对 227 种血液生物标志物进行全面筛选，可评估标志物的因果作用，从而最大程度地降低反向因果关系和混杂等偏倚的风险。我们旨在通过使用 MR 对 227 种血液生物标志物进行全面筛选，确定与血压相关的新型循环蛋白。
在 ORIGIN（初始甘精胰岛素干预的结局降低；URL：http://www.clinicaltrials.gov. 唯一标识符：NCT00069784）参与者（N=4147）中确定了 227 种生物标志物的遗传决定因素，并与国际血压联合会（74 064 人）的收缩压、舒张压、平均动脉压和脉搏压的遗传效应相结合使用 MR。结果在英国生物库（最多 319 103 人）和另一个生物标志物数据集（N=3301）中进行了复制。还进行了心血管风险因素和结果以及其他生物标志物的 MR 分析，以进一步评估所涉及的机制。
使用 MR 进行多重假设检验调整后，有 6 种生物标志物与血压相关。NT-proBNP（氨基末端 pro-B 型利钠肽）、收缩压和舒张压之间的关系证实了先前的报告。还确定了与血压相关的新型循环蛋白。uPA（尿激酶型纤溶酶原激活物）与收缩压相关；ADM（肾上腺髓质素）与收缩压和脉搏压相关；IL（白细胞介素）16 与舒张压相关；cFn（细胞纤连蛋白）和 IGFBP3（胰岛素样生长因子结合蛋白 3）与脉搏压相关。除了 IL16 和舒张压（=0.58）之外，这些关系在英国生物库中得到了验证（<0.0001）。使用心血管风险因素和结果进行的进一步 MR 分析表明，NT-proBNP 与大动脉粥样硬化性卒中、IGFBP3 与糖尿病以及 cFn 与体重指数之间存在关系。
我们使用 MR 确定了与血压相关的新型生物标志物。这些标志物可用于风险评估和作为潜在的治疗靶点。
