Diagnosis of Familial Dysbetalipoproteinemia Based on the Lipid Abnormalities Driven by APOE2/E2 Genotype

Abstract Background Familial dysbetalipoproteinemia (FDBL) is a monogenic disease due to variants in APOE with a highly variable phenotype. Current diagnostic lipid-based methods have important limitations. The objective is twofold: to define characteristics of dysbetalipoproteinemia (DBL) based on the analysis of APOE in patients from a lipid unit and in a sample from the general population, and to propose a screening algorithm for FDBL. Methods Lipids and APOE genotype from consecutive unrelated subjects from Miguel Servet University Hospital (MSUH) (n = 3603), subjects from the general population participants of the Aragon Workers’ Health Study (AWHS) (n = 4981), and selected subjects from external lipid units (Ext) (n = 390) were used to define DBL criteria and to train and validate a screening tool. Results Thirty-five subjects from MSUH, 21 subjects from AWHS, and 31 subjects from Ext were APOE2/2 homozygous. The combination of non high-density lipoprotein cholesterol (non-HDLc)/apoB ≥1.7 plus triglycerides/apoB ≥1.35, in mg/dL (non-HDLc [mmol/L]/apolipoprotein B (apoB) [g/L] ≥4.4 and triglycerides [mmol/L]/apoB [g/L] ≥3.5), provided the best diagnostic performance for the identification of subjects with hyperlipidemia and APOE2/2 genotype (sensitivity 100% in the 3 cohorts, and specificity 92.8% [MSUH], 80.9% [AWHS], and 77.6% [Ext]). This improves the performance of previous algorithms. Similar sensitivity and specificity were observed in APOE2/2 subjects receiving lipid-lowering drugs. Conclusions The combination of non-HDLc/apoB and triglycerides/apoB ratios is a valuable tool to diagnose DBL in patients with hyperlipidemia with or without lipid-lowering drugs. FDBL diagnosis requires DBL and the presence of a compatible APOE genotype. Most adult APOE2/2 subjects express DBL, making FDBL as common as familial hypercholesterolemia in the population.