BACKGROUND Circulating proteins in blood are involved in various physiological processes, but their contributions to blood pressure regulation remain partially understood. In traditional observational studies, identifying circulating proteins causally associated with blood pressure is challenging because of potentially unmeasured confounding and possible reverse causality. METHODS Two-sample Mendelian randomization analyses were conducted to estimate the causal effects of 2270 circulating proteins (data sourced from 8 genome-wide association studies) on diastolic blood pressure, systolic blood pressure, and pulse pressure. Colocalization analyses were then used to investigate whether the circulating proteins and blood pressure traits shared causal genetic variants. To further verify the findings, we subsequently performed Steiger filtering analyses, annotation of protein-altering variants, assessment of overlap between protein quantitative trait loci and expression quantitative trait loci, protein-protein interaction and functional enrichment analyses, and drug target evaluation. To provide more potential biomarkers, we further evaluated the epidemiological associations of 2923 circulating proteins with blood pressure and hypertension by cross-sectional and longitudinal analyses using individual data in the UK Biobank. RESULTS Mendelian randomization and colocalization analyses identified 121 circulating proteins with putative causal effects on at least 1 blood pressure trait. Many of the identified proteins are enriched in the pathways relevant to blood pressure regulation, and a majority of these proteins are either known drug targets or druggable candidates. CONCLUSIONS This study has uncovered numerous circulating proteins potentially causally associated with blood pressure, providing insights into the regulatory mechanisms of blood pressure and potential therapeutic targets to facilitate blood pressure management.

中文翻译：

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鉴定与血压相关的循环蛋白质。


背景 血液中的循环蛋白质参与各种生理过程，但它们对血压调节的贡献仍部分了解。在传统的观察性研究中，识别与血压因果相关的循环蛋白具有挑战性，因为可能存在无法测量的混杂和可能的反向因果关系。方法 进行双样本孟德尔随机化分析，以估计 2270 种循环蛋白 （数据来源于 8 项全基因组关联研究） 对舒张压、收缩压和脉压的因果影响。然后使用共定位分析来研究循环蛋白和血压性状是否共享致病遗传变异。为了进一步验证这些发现，我们随后进行了 Steiger 过滤分析、蛋白质改变变体的注释、蛋白质数量性状位点和表达数量性状位点之间的重叠评估、蛋白质-蛋白质相互作用和功能富集分析，以及药物靶点评估。为了提供更多潜在的生物标志物，我们使用英国生物样本库中的个人资料，通过横断面和纵向分析进一步评估了 2923 种循环蛋白与血压和高血压的流行病学关联。结果 孟德尔随机化和共定位分析确定了 121 种循环蛋白，这些蛋白对至少 1 种血压特征具有推定的因果影响。许多已鉴定的蛋白质富含与血压调节相关的通路，并且这些蛋白质中的大多数是已知的药物靶点或可成药的候选者。 结论 本研究发现了许多与血压可能因果相关的循环蛋白，为血压的调节机制和促进血压管理的潜在治疗靶点提供了见解。