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.

Contribution of APOE Genetic Variants to Dyslipidemia

“…In addition to the randomly selected volunteers from AWHS, all subjects with hyperlipidemia, as defined above, and dysbetalipoproteinemia criteria (non-HDLc/apoB≥1.7 plus TG/(apoB)≥1.35, in mg/dL; n=392) at baseline 12 were selected from the total AWHS cohort for APOE gene variant analysis. Among these, 43 subjects had been already studied because they had been included in the previous random cohort study.…”

“…1 Dysbetalipoproteinemia (DBL) was considered when non-HDLc/apoB≥1.7 plus TG/(apoB) ≥1.35, in mg/dL. 12 There were 210 subjects with DBL criteria, all included in the combined hyperlipidemia group.…”

“…• Exon 4 of APOE were sequenced in all consecutive unrelated subjects with primary hyperlipidemia from a lipid unit. 12 were selected from the total AWHS cohort for APOE gene variant analysis. Among these, 43 subjects had been already studied because they had been included in the previous random cohort study.…”

Labordiagnostik von Fettstoffwechselstörungen

“…Ein aus Apo B, non-HDL-C und TG abgeleiteter Index wurde kürzlich für die Diagnose der Typ III-HLP vorgeschlagen und könnte diesbezüglich die Lipoprotein-Elektrophorese oder Ultrazentrifugation ergänzen 79 .…”

Estudio molecular de los polimorfismos comunes del gen apoE asociados con disbetalipoproteinemia familiar y la enfermedad de Alzheimer de inicio tardío

“…Se recuperaron un total de 284 referencias bibliográficas, de las cuales, únicamente un estudio cumplió con los criterios de inclusión 1 . La mayoría de los trabajos fueron descartados por emplear otro tipo de técnicas para el genotipado de apoE, principalmente la reacción en cadena de la polimerasa con análisis del polimorfismo de los fragmentos de restricción (PCR-RLFP) o por secuenciación.…”