HDL Proteomics in Coronary Artery Calcification in Type 1 Diabetes (CACTI) Study

Atherosclerotic cardiovascular disease (CVD) is the major cause of death in patients with type 1 diabetes mellitus (T1DM). Alterations in the HDL proteome associate with prevalent CVD in T1DM. We therefore determined which proteins carried by HDL might predict incident CVD in T1DM patients. Using targeted MS/MS, we quantified 50 proteins in HDL from 181 T1DM subjects enrolled in the prospective Coronary Artery Calcification in Type 1 Diabetes study (CACTI). We used Cox proportional regression analysis and a case-cohort design to test associations of HDL proteins with incident CVD (myocardial infarction, coronary artery bypass grafting, angioplasty, or death from coronary heart disease). Only one HDL protein—SFTPB (pulmonary surfactant protein B)—predicted incident CVD in all of the models tested. In a fully adjusted model that controlled for lipids and other risk factors, the hazard ratio was 2.17 per SD increase of SFTPB (95% confidence interval, 1.12-4.21, P=0.022). Plasma fractionation demonstrated that plasma SFTPB is nearly quantitatively bound to HDL. Although previous studies have shown that high plasma levels of SFTPB associate with prevalent atherosclerosis only in smokers, we found that SFTPB predicted incident CVD in T1DM independently of smoking status. Elevated levels of SFTPB in HDL strongly predicted incident CVD in CACTI subjects independently of a wide range of confounding factors, including smoking status, HDL-C, LDL-C, and triglyceride levels. Because SFTPB is almost quantitatively bound to plasma HDL, our observations support the proposal that SFTPB carried by HDL is a marker—and perhaps mediator—of CVD risk in patients with T1DM.

动脉粥样硬化性心血管疾病（atherosclerotic cardiovascular disease, CVD）是1型糖尿病（type 1 diabetes mellitus, T1DM）患者的首要死亡原因。高密度脂蛋白（HDL）蛋白质组的异常改变与1型糖尿病患者的显性心血管疾病密切相关。为此，本研究旨在明确HDL携带的哪些蛋白质可预测1型糖尿病患者的新发心血管事件。本研究采用靶向串联质谱（targeted MS/MS）技术，对纳入前瞻性1型糖尿病冠状动脉钙化研究（Coronary Artery Calcification in Type 1 Diabetes study, CACTI）的181名T1DM受试者的HDL样本中的50种蛋白质进行了定量检测。我们采用考克斯比例风险回归分析结合病例队列设计，检验HDL蛋白质与新发心血管事件（包括心肌梗死、冠状动脉旁路移植术、血管成形术或冠心病致死）的关联。在所有测试的模型中，仅有一种HDL蛋白质——肺表面活性蛋白B（SFTPB）可有效预测新发心血管事件。在校正了血脂及其他危险因素的完全校正模型中，SFTPB每增加1个标准差，风险比为2.17（95%置信区间：1.12~4.21，P=0.022）。血浆分级分离实验证实，血浆中几乎所有的SFTPB均与HDL特异性结合。既往研究仅显示，血浆SFTPB水平升高仅在吸烟者中与显性动脉粥样硬化相关，但本研究发现，SFTPB可独立于吸烟状态预测T1DM患者的新发心血管事件。HDL中SFTPB水平升高可强烈预测CACTI研究受试者的新发心血管事件，且不受吸烟状态、高密度脂蛋白胆固醇（HDL-C）、低密度脂蛋白胆固醇（LDL-C）及甘油三酯水平等多种混杂因素的影响。鉴于SFTPB几乎全部与血浆HDL结合，本研究结果支持“HDL携带的SFTPB可作为T1DM患者心血管疾病风险的标志物——甚至可能是风险介导因子”这一假说。