Chen Yi-Lin, Wang Ji-Jing, You Jia, Cheng Ji-Yun, Li Ze-Yu, Ge Yi-Jun, Yao Bing-Ran, He Xiao-Yu, Guo Yu, Zhang Yi, Chen Shi-Dong, Yang Liu, Wu Xin-Rui, Wu Bang-Sheng, Zhang Ya-Ru, Cui Mei, Dong Qiang, Feng Jian-Feng, Tian Mei, Cheng Wei, Yu Jin-Tai
Department of Neurology and National Center for Neurological Disorders, Huashan Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, Shanghai 200433, China.
Huashan Hospital & Human Phenome Institute, Fudan University, Shanghai 200433, China.
Protein Cell. 2025 Aug 6. doi: 10.1093/procel/pwaf072.
Cardiovascular disease (CVD) research is hindered by limited comprehensive analyses of plasma proteome across disease subtypes. Here, we systematically investigated the associations between plasma proteins and cardiovascular outcomes in 53,026 UK Biobank participants over a 14-year follow-up. Association analyses identified 3,089 significant associations involving 892 unique protein analytes across 13 CVD outcomes. The most notable associations included NT-proBNP for atrial fibrillation (P = 6.31 × 10-313), followed by NPPB (P = 1.03 × 10-164) and GDF15 for heart failure (P = 1.21 × 10-166). Among 445 unique proteins significantly linked to 18 cardiovascular metrics, LEP (RVEDV: β = -9.03, P = 2.76 × 10-51) and FABP4 (RVEDV: β = -10.18, P = 2.42 × 10-32) emerged as the strongest correlates of cardiac structure and function. Our integrated prediction model performed excellently across the majority of CVD outcomes, achieving an AUC of 0.86 for abdominal aneurysm. Two-sample Mendelian randomization analysis revealed 225 proteins causally linked to CVDs, with LPA showing the strongest coronary artery disease association (OR = 1.13 [1.10-1.17], P = 2.38 × 10-15), many of which are targets of existing drugs, suggesting repurposing opportunities. Mediation analysis revealed broad-spectrum mediators (e.g., IGFBP4 and GDF15, each influencing 9 cardiovascular outcomes) and outcome-specific protein mediators, with modifiable risk factors such as smoking and BMI predominantly mediating protein-CVD associations.This comprehensive longitudinal study provides unprecedented insights into plasma proteome influences on cardiovascular health interactions, offering novel perspectives for CVD diagnosis, prediction, and prevention.
心血管疾病（CVD）研究因对疾病亚型血浆蛋白质组缺乏全面综合分析而受到阻碍。在此，我们对53026名英国生物银行参与者进行了为期14年的随访，系统地研究了血浆蛋白与心血管结局之间的关联。关联分析确定了3089个显著关联，涉及13种心血管疾病结局的892种独特蛋白质分析物。最显著的关联包括用于房颤的N末端脑钠肽前体（NT-proBNP）（P = 6.31×10⁻³¹³），其次是用于心力衰竭的NPPB（P = 1.03×10⁻¹⁶⁴）和生长分化因子15（GDF15）（P = 1.21×10⁻¹⁶⁶）。在与18种心血管指标显著相关的445种独特蛋白质中，瘦素（LEP）（右心室舒张末期容积：β = -9.03，P = 2.76×10⁻⁵¹）和脂肪酸结合蛋白4（FABP4）（右心室舒张末期容积：β = -10.18，P = 2.42×10⁻³²）成为心脏结构和功能的最强相关因素。我们的综合预测模型在大多数心血管疾病结局中表现出色，腹主动脉瘤的曲线下面积（AUC）达到0.86。两样本孟德尔随机化分析揭示了225种与心血管疾病有因果关系的蛋白质，其中脂蛋白A（LPA）与冠状动脉疾病的关联最强（比值比[OR] = 1.13 [1.10 - 1.17]，P = 2.38×10⁻¹⁵），其中许多是现有药物的靶点，提示有重新利用药物的机会。中介分析揭示了广谱中介因子（如胰岛素样生长因子结合蛋白4[IGFBP4]和GDF15，各影响9种心血管疾病结局）和特定结局的蛋白质中介因子，吸烟和体重指数等可改变的风险因素主要介导蛋白质与心血管疾病的关联。这项全面的纵向研究为血浆蛋白质组对心血管健康相互作用的影响提供了前所未有的见解，为心血管疾病的诊断、预测和预防提供了新的视角。
