HDL proteomics on CPROBE samples

Patients with chronic kidney disease (CKD) are at high risk for cardiovascular disease (CVD). However, traditional lipid risk factors, including low HDL levels, cannot completely explain the increased risk. Altered HDL proteome is linked with both CVD and CKD, but the role of HDL proteins in incident CVD events in CKD is unknown. In this prospective case-control study, we used targeted proteomics to quantify 31 proteins in HDL from 92 subjects (46 incident new CVD and 46 one-to-one matched controls) at various stages of CKD. We tested associations of HDL proteins with incident CVD using matched logistic regression analysis. In unadjusted models, levels of six HDL proteins (APOA1, APOA4, APOC3, LCAT, PON1, and PON3) significantly associated with incident CVD. No significant associations were found for HDL-C. In the fully adjusted model for clinical confounders and lipid levels, we observed an inverse association between levels of PON1, PON3, and LCAT in HDL and incident CVD. Odds ratios (per 1-SD) were 0.38 (0.18-0.97, P=0.042), 0.42 (0.20-0.92, P=0.031), and 0.30 (0.11-0.83, P=0.020) for PON1, PON3, and LCAT, respectively. APOA4 remained associated with incident CVD in CKD patients in models adjusted for clinical confounders and lipid levels but lost significance with the addition of CRP and proteinuria in the model. In conclusion, levels of four HDL proteins, PON1, PON3, LCAT, and APOA4, were inversely associated with incident CVD events in CKD subjects. Our observations indicate that HDL’s protein cargo but not HDL-C levels can serve as a marker—and perhaps mediator—for elevated CVD risk in CKD patients.

慢性肾病（chronic kidney disease, CKD）患者具有较高的心血管疾病（cardiovascular disease, CVD）风险。然而，包括低高密度脂蛋白（high-density lipoprotein, HDL）水平在内的传统脂质风险因素无法完全解释这种风险升高的现象。HDL蛋白组的改变与CVD和CKD均相关，但HDL蛋白在CKD患者新发CVD事件中的作用尚不清楚。在这项前瞻性病例对照研究中，我们采用靶向蛋白质组学技术对92名不同CKD分期受试者（46例新发CVD患者和46例一对一匹配的对照者）的HDL中31种蛋白质进行了定量分析。我们通过配对逻辑回归分析检验了HDL蛋白与新发CVD之间的关联。在未调整模型中，6种HDL蛋白（APOA1、APOA4、APOC3、LCAT、PON1和PON3）的水平与新发CVD显著相关。未发现HDL-C水平与新发CVD存在显著关联。在调整了临床混杂因素和脂质水平的完全调整模型中，我们观察到HDL中PON1、PON3和LCAT的水平与新发CVD呈负相关。PON1、PON3和LCAT的比值比（每1个标准差）分别为0.38（0.18-0.97，P=0.042）、0.42（0.20-0.92，P=0.031）和0.30（0.11-0.83，P=0.020）。在调整了临床混杂因素和脂质水平的模型中，APOA4仍与CKD患者的新发CVD相关，但在模型中加入C反应蛋白（C-reactive protein, CRP）和蛋白尿后，这种相关性不再显著。综上，HDL中的四种蛋白质（PON1、PON3、LCAT和APOA4）水平与CKD受试者的新发CVD事件呈负相关。我们的观察结果表明，HDL的蛋白质组分而非HDL-C水平可作为CKD患者CVD风险升高的标志物——或许也是介导因素。