Metabolomic Profiling of Cholesterol Efflux Capacity in a Multiethnic Population: Insights From MESA.
Metabolomic Profiling of Cholesterol Efflux Capacity in a Multiethnic Population: Insights From MESA.
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多种族人群中胆固醇流出能力的代谢组学分析：来自梅萨的见解。
DOI：
10.1161/atvbaha.122.318222
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发表时间：
2023-10
影响因子：
8.7
通讯作者：
Rohatgi, Anand
中科院分区：
文献类型：
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作者：
Hunter, Wynn G.;Smith, Alexander G.;Pinto, Rui C.;Saldanha, Suzanne;Gangwar, Anamika;Pahlavani, Mandana;Deodhar, Sneha;Wilkins, John;Pandey, Ambarish;Herrington, David;Greenland, Philip;Tzoulaki, Ioanna;Rohatgi, Anand
胆固醇外排能力受损（CEC）是一种与动脉粥样硬化性心血管疾病相关的新型脂质代谢特征。CEC变异的机制尚不清楚。我们评估了循环代谢物与CEC的关系，以促进对胆固醇外排调节中代谢途径的理解。MESA（多种族动脉粥样硬化研究）的参与者在基线时接受了核磁共振代谢组分析和CEC测量（N=3543）。使用标准线性回归分析评估代谢物与CEC的关联。使用重复ElasticNet和多层感知器回归来评估CEC的代谢物谱预测性能。使用Shapley加性解释值确定了CEC预测的重要特征。较大的CEC与由VLDL（极低密度脂蛋白）和HDL（高密度脂蛋白）的最大颗粒亚类组成的代谢物簇及其组成的载脂蛋白A1、载脂蛋白A2、磷脂和胆固醇组分显著相关（β= 0.072-0.081； P<0.001）。代谢物谱在线性和非线性分析中预测体外CEC的准确性较差（R2<0.02; Spearman ρ<0.18）。CEC预测最重要的特征是种族，与其他种族相比，黑人参与者的CEC显著较低。我们发现了CEC、VLDL和HDL的最大颗粒亚类及其组成载脂蛋白和脂质之间的独立关联。代谢物和传统的临床危险因素仍然无法解释CEC的很大一部分变异，这支持了对CEC的基因组、蛋白质组学和磷脂组学决定因素的进一步研究。
Impaired cholesterol efflux capacity (CEC) is a novel lipid metabolism trait associated with atherosclerotic cardiovascular disease. Mechanisms underlying CEC variation are unknown. We evaluated associations of circulating metabolites with CEC to advance understanding of metabolic pathways involved in cholesterol efflux regulation. Participants enrolled in the MESA (Multi-Ethnic Study of Atherosclerosis) who underwent nuclear magnetic resonance metabolome profiling and CEC measurement (N=3543) at baseline were included. Metabolite associations with CEC were evaluated using standard linear regression analyses. Repeated ElasticNet and multilayer perceptron regression were used to assess metabolite profile predictive performance for CEC. Features important for CEC prediction were identified using Shapley Additive Explanations values. Greater CEC was significantly associated with metabolite clusters composed of the largest-sized particle subclasses of VLDL (very-low-density lipoprotein) and HDL (high-density lipoprotein), as well as their constituent apo A1, apo A2, phospholipid, and cholesterol components (β=0.072–0.081; P<0.001). Metabolite profiles had poor accuracy for predicting in vitro CEC in linear and nonlinear analyses (R2<0.02; Spearman ρ<0.18). The most important feature for CEC prediction was race, with Black participants having significantly lower CEC compared with other races. We identified independent associations among CEC, the largest-sized particle subclasses of VLDL and HDL, and their constituent apolipoproteins and lipids. A large proportion of variation in CEC remained unexplained by metabolites and traditional clinical risk factors, supporting further investigation into genomic, proteomic, and phospholipidomic determinants of CEC.