A new phenotypic classification system for dyslipidemias based on the standard lipid panel

Sampson et al. Lipids in Health and Disease https://doi.org/10.1186/s12944-021-01585-8 (2021) 20:170 RESEARCH Open Access A new phenotypic classification system for dyslipidemias based on the standard lipid panel Maureen Sampson1 , Rami A. Ballout2, Daniel Soffer3, Anna Wolska2, Sierra Wilson2, Jeff Meeusen4, Leslie J. Donato4, Erica Fatica4, James D. Otvos5, Eliot A. Brinton6, Robert S. Rosenson7, Peter Wilson8, Marcelo Amar2, Robert Shamburek2, Sotirios K. Karathanasis2 and Alan T. Remaley2* Abstract Background: Dyslipoproteinemias can be classified by their distinct lipoprotein patterns, which helps determine atherosclerotic cardiovascular disease (ASCVD) risk and directs lipid management but this has required advanced laboratory testing. Objective: To develop a new algorithm for classifying lipoprotein disorders that only relies on the standard lipid panel. Methods: Lipid thresholds for defining the different lipoprotein phenotypes were derived for Non-HighDensity Lipoprotein-Cholesterol (NonHDL-C) and Triglycerides (TG) to be concordant when possible with the current US Multi-Society guidelines for blood cholesterol management. Results: The new classification method categorizes patients into all the classical Fredrickson-like phenotypes except for Type III dysbetalipoproteinemia. In addition, a new hypolipidemic phenotype (Type VI) due to genetic mutations in apoB-metabolism is described. The validity of the new algorithm was confirmed by lipid analysis by NMR (N = 11,365) and by concordance with classification by agarose gel electrophoresis/betaquantification (N = 5504). Furthermore, based on the Atherosclerosis Risk in Communities (ARIC) cohort (N = 14,742), the lipoprotein phenotypes differ in their association with ASCVD (TypeV>IIb > IVb > IIa > IVa > normolipidemic) and can be used prognostically as risk enhancer conditions in the management of patients. Conclusions: We describe a clinically useful lipoprotein phenotyping system that is only dependent upon the standard lipid panel. It, therefore, can be easily implemented for increasing compliance with current guidelines and for improving the care of patients at risk for ASCVD. * Correspondence: 2 Lipoprotein Metabolism Laboratory, Translational Vascular Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, 10 Center Drive, Bldg. 10/Rm. 2C433, Bethesda, MD 20892, USA Full list of author information is available at the end of the article © The Author(s). 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Sampson et al. Lipids in Health and Disease (2021) 20:170 Page 2 of 21 Highlights A new algorithm is described for categorizing dyslipidemic patients into Fredrickson-like lipoprotein phenotypes except for Type III. The new lipoprotein phenotypes were validated by NMR-lipoprotein analysis and by agarose gel electrophoresis/beta-quantification in a large number of subjects. The new lipoprotein phenotyping system identifies high-risk cardiovascular patients and helps direct clinical management. A major advance is that the new lipoprotein phenotypes are based on just the standard lipid panel, and thus can be automatically calculated by the clinical laboratory and widely implemented. Keywords: Cholesterol, LDL, Lipids, Lipoproteins, Genetics, Cardiovascular disease Background Elevated plasma lipids, in particular total cholesterol (TC) and triglycerides (TG), increase the risk of atherosclerotic cardiovascular disease (ASCVD); hence, their measurement is integral to ASCVD risk assessment and prevention [1]. The levels of TC and TG in plasma are influenced by a complex network of metabolic pathways, which when disturbed by disease or environmental influences, will alter the concentration of the various lipoproteins that transport these lipids in the circulation. Perturbations in the normal physiologic level of plasma lipoproteins were first noted over 50 years ago by Donald S. Fredrickson and colleagues, whose observations became the foundation for the first phenotypic classification of lipoprotein disorders [2–6]. The three main classes of apolipoprotein B (apoB)-containing lipoprotein particles are Low-Density Lipoproteins (LDL), Very-Low Density Lipoproteins (VLDL) and chylomicrons. Nearly all possible permutations for elevations in these lipoproteins, taken one or two at a time, comprise the classic Fredrickson classification system. Three of these phenotypes are characterized by an increase in a single type of lipoprotein, namely Type I (chylomicrons), Type IIa (LDL), and Type IV (VLDL). In the Types IIb and V phenotypes, two classes of lipoproteins are increased, and thus they are sometimes called mixed dyslipoproteinemias. In Type IIb, there is an increase in both VLDL and LDL, whereas in Type V both VLDL and chylomicrons are increased. The only other possible permutation for simultaneous elevations in two lipoprotein classes would be an increase in LDL and chylomicrons, but this pattern has only been described in a single case report [7]. The other remaining Fredrickson phenotype is Type III. It is a relatively uncommon disorder characterized by the accumulation of cholesterol-enriched remnant particles, due to impaired apoE-mediated hepatic clearance of partially lipolyzed VLDL and chylomicrons [8]. It is important to note that the Fredrickson classification system does not address dyslipidemias related to low HDL-C or elevated Lp(a). The Fredrickson classification was originally established by separating lipoproteins by density gradient ultracentrifugation (beta-quantification), but later it was mostly performed by the more convenient method of agarose gel electrophoresis [9]. Although the classification of Fredrickson lipoprotein phenotypes is still used for didactic purposes, it is currently only available in specialty reference laboratories and is no longer widely used in clinical practice [9]. The gradual discontinuation of detailed lipoprotein phenotypi (...truncated)