This article is available online at http://www.jlr.org Circulating lipids, their biosynthesis, metabolism, and biological functions are intimately involved in many complex disease processes ( 1 ). Traditional clinical chemistry uses measurements of total cholesterol, triglycerides, and HDL as tools for determining health status and disease risk. The tests for these lipids are low cost, high throughput, and well established. The development of soft ionization techniques, particularly electrospray ionization has proven to be a watershed for lipidomics, allowing the detection and quantifi cation of individual molecular species. Recently, the Lipid Maps Consortium described a detailed analysis of the plasma lipidome, reporting on the concentration of nearly 600 lipids in pooled human plasma from healthy individuals ( 1, 2 ). This analysis highlighted the complexity of the plasma lipidome and the potential of plasma lipid profi ling for disease classifi cation, risk assessment, and to uncover changes in lipid metabolism associated with disease states. To date, plasma lipid profi ling has been used to identify lipidomic biomarkers associated with a variety of diseases and activities related to obesity ( 3 ), hypertension ( 4 ), smoking ( 5 ), cystic fi brosis ( 6 ), weight loss ( 7 ), and type 2 diabetes ( 8 ). These studies have, in general, have been conducted using relatively small cohorts (<100 participants) ( 3, 4, 6, 7 ) and/or limited coverage of the lipidome (<100 species) ( 4, 6, 8 ).Abstract We have performed plasma lipid profi ling using liquid chromatography electrospray ionization tandem mass spectrometry on a population cohort of more than 1,000 individuals. From 10 l of plasma we were able to acquire comparative measures of 312 lipids across 23 lipid classes and subclasses including sphingolipids, phospholipids, glycerolipids, and cholesterol esters (CEs) in 20 min. Using linear and logistic regression, we identifi ed statistically signifi cant associations of lipid classes, subclasses, and individual lipid species with anthropometric and physiological measures. In addition to the expected associations of CEs and triacylglycerol with age, sex, and body mass index (BMI), ceramide was signifi cantly higher in males and was independently associated with age and BMI. Associations were also observed for sphingomyelin with age but this lipid subclass was lower in males. Lysophospholipids were associated with age and higher in males, but showed a strong negative association with BMI. Many of these lipids have previously been associated with chronic diseases including cardiovascular disease and may mediate the interactions of age, sex, and obesity with disease risk. -Weir, J. M., G.

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The relationship between lipid metabolism with prediabetes (impaired fasting glucose and impaired glucose tolerance) and type 2 diabetes mellitus is poorly defined. We hypothesized that a lipidomic analysis of plasma lipids might improve the understanding of this relationship. We performed lipidomic analysis measuring 259 individual lipid species, including sphingolipids, phospholipids, glycerolipids and cholesterol esters, on fasting plasma from 117 type 2 diabetes, 64 prediabetes and 170 normal glucose tolerant participants in the Australian Diabetes, Obesity and Lifestyle Study (AusDiab) then validated our findings on 1076 individuals from the San Antonio Family Heart Study (SAFHS). Logistic regression analysis of identified associations with type 2 diabetes (135 lipids) and prediabetes (134 lipids), after adjusting for multiple covariates. In addition to the expected associations with diacylglycerol, triacylglycerol and cholesterol esters, type 2 diabetes and prediabetes were positively associated with ceramide, and its precursor dihydroceramide, along with phosphatidylethanolamine, phosphatidylglycerol and phosphatidylinositol. Significant negative associations were observed with the ether-linked phospholipids alkylphosphatidylcholine and alkenylphosphatidylcholine. Most of the significant associations in the AusDiab cohort (90%) were subsequently validated in the SAFHS cohort. The aberration of the plasma lipidome associated with type 2 diabetes is clearly present in prediabetes, prior to the onset of type 2 diabetes. Lipid classes and species associated with type 2 diabetes provide support for a number of existing paradigms of dyslipidemia and suggest new avenues of investigation.

Objective-Traditional risk factors for coronary artery disease (CAD) fail to adequately distinguish patients who have atherosclerotic plaques susceptible to instability from those who have more benign forms. Using plasma lipid profiling, this study aimed to provide insight into disease pathogenesis and evaluate the potential of lipid profiles to assess risk of future plaque instability. Methods and Results-Plasma lipid profiles containing 305 lipids were measured on 220 individuals (matched healthy controls, nϭ80; stable angina, nϭ60; unstable coronary syndrome, nϭ80) using electrospray-ionisation tandem mass spectrometry. ReliefF feature selection coupled with an L2-regularized logistic regression based classifier was used to create multivariate classification models which were verified via 3-fold cross-validation (1000 repeats). Models incorporating both lipids and traditional risk factors provided improved classification of unstable CAD from stable CAD (C-statisticϭ0.875, 95% CI 0.874 -0.877) compared with models containing only traditional risk factors (Cstatisticϭ0.796, 95% CI 0.795-0.798). Many of the lipids identified as discriminatory for unstable CAD displayed an association with disease acuity (severity), suggesting that they are antecedents to the onset of acute coronary syndrome. Key Words: acute coronary syndromes Ⅲ atherosclerosis Ⅲ lipids Ⅲ risk factors Ⅲ biomarker A cute coronary syndromes (unstable angina, myocardial infarction, and many cases of sudden cardiac death) are almost invariably the result of atherosclerotic plaque disruption and subsequent thrombosis (atherothrombosis). Although plaque accumulation and development is progressive throughout life, plaques may cycle between being stable and unstable throughout the disease process. Accurate identification of those at risk for unstable coronary syndromes is an important prerequisite to targeted treatment and prevention. However, current screening is limited by the predictive power of available tests, the high cost of these tests, or a combination of both. Furthermore, the ability of these tests to subclassify patients with CAD as having stable or unstable disease has been limited. Conclusion-PlasmaRisk assessment for coronary artery disease (CAD) is currently performed by the evaluation of traditional risk factors (eg, smoking status, body mass index, cholesterol level, blood pressure); by direct measures of arterial structural changes associated with atherosclerosis, such as carotid intima-medial thickness and the coronary artery calcification score; or by testing for myocardial ischemia using stress testing. For the most part, the addition of circulating biomarkers has added little to risk assessment by conventional methods, although the recent reports by Blankenberg et al 1 indicate that risk scores incorporating multiple biomarkers can improve on conventional risk models, and the report of Schnabel et al 2 suggests that this strategy may also be useful in the setting of stable CAD. The development of noninvasive screening tests that c...

URL: https://clinicaltrials.gov. Unique identifier: NCT00145925.