脂质组学案例分析
疾病研究：血浆靶向脂质组学轮廓谱研究提高二型糖尿病病人中患心血管疾病的传统风险因子的预测能力

研究对象：人
分析检测平台：LC ESI-MS/MS
期刊：Circulation
影响因子：17.047
发表时间：2016

摘要：
Background: Clinical lipid measurements do not show the full complexity of the altered lipid metabolism associated with diabetes or cardiovascular disease. Lipidomics enables the assessment of hundreds of lipid species as potential markers for disease risk. Methods: Plasma lipid species (310) were measured by a targeted lipidomic analysis with liquid chromatography electrospray ionisation-tandem mass spectrometry on a case-cohort (n=3,779) subset from the ADVANCE (Action in Diabetes and Vascular disease: preterAx and diamicroN- MR Controlled Evaluation) trial. The-case cohort was 61% male with a mean age of 67. All participants had type 2 diabetes mellitus with one or more additional cardiovascular risk factors and 35% had a history of macrovascular disease. Weighted Cox regression was used to identify lipid species associated with future cardiovascular events (non-fatal myocardial infarction, non- fatal stroke and cardiovascular death) and cardiovascular death during a five year follow-up period. Multivariable models combining traditional risk factors with lipid species were optimized using the Akaike information criteria. C-statistics and net reclassification indices (NRI) were calculated within a five-fold cross validation framework. Results: Sphingolipids, phospholipids (including lyso- and ether- species), cholesteryl esters, and glycerolipids were associated with future cardiovascular events and cardiovascular death. The addition of 7 lipid species to a base model (14 traditional risk factors and medications) to predict cardiovascular events increased the C statistic from 0.680 (95% confidence interval [CI], 0.678–0.682) to 0.700 (95% CI, 0.698–0.702; P<0.0001) with a corresponding continuous NRI of 0.227 (95% CI, 0.219–0.235). The prediction of cardiovascular death was improved with the incorporation of 4 lipid species into the base model, showing an increase in the C statistic from 0.740 (95% CI, 0.738–0.742) to 0.760 (95% CI, 0.757–0.762; P<0.0001) and a continuous net reclassification index of 0.328 (95% CI, 0.317–0.339). The results were validated in a subcohort with type 2 diabetes mellitus (n=511) from the LIPID trial (Long-Term Intervention With Pravastatin in Ischemic Disease). Conclusions: The improvement in the prediction of cardiovascular events, above traditional risk factors, demonstrates the potential of plasma lipid species as biomarkers for cardiovascular risk stratification in diabetes mellitus.

Keywords: lipids, biomarker, mass spectrometry, cardiovascular outcomes, diabetes mellitus.

一、研究背景：
二型糖尿病（T2D）是一种全球各国经济和健康负担日益增加的疾病，动脉粥样硬化性心血管疾病（CVD）是T2D并发症中致死率非常高的并发症，评估和调控CVD的发生是T2D治疗中的一个重点内容。虽然已经建立了CVD风险打分模型，但是弗雷明汉风险评分低估了T2D患者患CVD的风险，而英国糖尿病风险评分高估了T2D患者患CVD的风险。
传统的脂类物质标记物（总胆固醇、低密度脂蛋白胆固醇、三酰甘油和高密度脂蛋白胆固醇）被用于风险评分，但是这些有限的检测都无法解释T2D及其相关心血管疾病复杂的脂类变化。脂质组学技术的发展以及血浆中越来越多的脂类物质被发现与T2D和心血管疾病密切相关，本文拟通过使用脂质组学的方法研究和评估T2D人群患心血管疾病的风险，希望能够找到较好预测5年后是否会患心血管疾病的脂类物质。