Abstract
Direct infusion high-resolution mass spectrometry (DIHRMS) is a novel, high-throughput approach to rapidly and accurately profile hundreds of lipids in human serum without prior chromatography, facilitating in-depth lipid phenotyping for large epidemiological studies to reveal the detailed associations of individual lipids with coronary heart disease (CHD) risk factors. Intact lipid profiling by DIHRMS was performed on 5662 serum samples from healthy participants in the Pakistan Risk of Myocardial Infarction Study (PROMIS). We developed a novel semi-targeted peak-picking algorithm to detect mass-to-charge ratios in positive and negative ionization modes. We analyzed lipid partial correlations, assessed the association of lipid principal components with established CHD risk factors and genetic variants, and examined differences between lipids for a common genetic polymorphism. The DIHRMS method provided information on 360 lipids (including fatty acyls, glycerolipids, glycerophospholipids, sphingolipids, and sterol lipids), with a median coefficient of variation of 11.6% (range: 5.4–51.9). The lipids were highly correlated and exhibited a range of associations with clinical chemistry biomarkers and lifestyle factors. This platform can provide many novel insights into the effects of physiology and lifestyle on lipid metabolism, genetic determinants of lipids, and the relationship between individual lipids and CHD risk factors.
Highlights
Lipids have many different functions, from membrane components to cell signaling, and are associated with a number of chronic diseases, including coronary heart disease (CHD).[1−4] Atherosclerosis, the main cause of CHD, is associated with lipid accumulation and aggregation, of cholesterol and its derivatives
This study provides a detailed description of the method used for a large-scale lipidomics analysis in 5662 healthy participants in the Pakistan Risk of Myocardial Infarction Study (PROMIS),[10] which is currently among the largest MS-based metabolomics studies
To demonstrate the utility of the direct nanospray-infusion coupled to high-resolution mass spectrometry (DIHRMS) platform to inform lipid research and the genetic determinants of human metabolism, we examined levels of individual lipids associated with rs662799, a common genetic polymorphism in the APOA5−APOC3 gene region that is known to associate with major lipid markers and coronary artery disease (CAD).[13,14]
Summary
Lipids have many different functions, from membrane components to cell signaling, and are associated with a number of chronic diseases, including coronary heart disease (CHD).[1−4] Atherosclerosis, the main cause of CHD, is associated with lipid accumulation and aggregation, of cholesterol and its derivatives. The development of new analytical technologies for the analysis of lipids, in mass spectrometry and data processing,[7] has led to the rise of lipidomics,[8] with the aim of capturing information on a wide range of lipids in a given biological sample, across a large number of individuals.[1] In particular, lipidomic analysis of human blood has the potential to identify the role of specific lipids in diseases, including CHD.[3] There are important prerequisites for any method that uses profiles of serum lipids to study lipid metabolism. Since by definition an open-profiling method does not target particular lipids, it must have the ability to measure and discriminate a wide range of lipids with minimal bias across different lipid species and classes.[9]
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