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

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This study was supported by grants PI 18/01777,PI 19/00694 from the Spanish Ministry of Economy and Competitiveness, CIBERCV and Gobierno de Aragon B-14. These projects are co-funded by the Instituto de Salud Carlos III and the European Regional Development Fund (ERDF) of the European UnionA way to make Europe. Biobank of the Aragon HealthSystem (PT17/0015/0039).

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Vinals, CAuthor

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Article

Publicated to:Clinical Chemistry. 69 (2): 140-148 - 2023-02-01 69(2), DOI: 10.1093/clinchem/hvac213

Authors: Bea, Ana M; Cenarro, Ana; Marco-Benedi, Victoria; Laclaustra, Martin; Martin, Cesar; Ibarretxe, Daiana; Pinto, Xavier; Arrobas, Teresa; Vinals, Clara; Civeira, Fernando; Olmos, Salvador

Affiliations

Aragon Institute of Engineering Research (I3A), Universidad de Zaragoza, Zaragoza, Spain. - Author

Biofisika Institute (UPV/EHU, CSIC), Leioa, Spain. - Author

Centro de Investigación Biomédica en Red Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), Madrid, Spain. - Author

Departamento de Medicina, Psiquiatría y Dermatología, Universidad de Zaragoza, Zaragoza, Spain. - Author

Department of Biochemistry and Molecular Biology, Universidad del País Vasco UPV/EHU, Bilbao, Spain. - Author

Endocrinology Department, Hospital Clinic de Barcelona, Barcelona, Spain. - Author

Fdn Biofis Bizkaia, Leioa, Spain - Author

Fundación Biofisika Bizkaia, Leioa, Spain. - Author

Hosp Clin Barcelona, Endocrinol Dept, Avda Isabel La Catolica 1 3, Barcelona 50009, Spain - Author

Hosp Univ Miguel Servet, IIS Aragon, CIBERCV, Zaragoza, Spain - Author

Hosp Virgen Macarena, Lab Nutr & RCV, Lab Bioquim Clin, Seville, Spain - Author

Hospital Universitario Miguel Servet, IIS Aragón, CIBERCV, Zaragoza, Spain. - Author

Inst Aragones Ciencias Salud IACS, Mol Res Lab, Zaragoza, Spain - Author

Inst Invest Biomed August Pi i Sunyer IDIBAPS, Barcelona, Spain - Author

Inst Salud Carlos III ISCIII, Ctr Invest Biomed Red Fisiopatol Obes & Nutr CIBER, Madrid, Spain - Author

Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain. - Author

Laboratorio de Nutrición y RCV, Laboratorio de Bioquímica Clínica, Hospital Virgen Macarena, Sevilla, Spain. - Author

Molecular Research Laboratory, Instituto Aragones de Ciencias de la Salud (IACS), Zaragoza, Spain. - Author

Unidad de Lípidos, Servicio de Medicina Interna, Hospital Universitario de Bellvitge-Idibell, Universidad de Barcelona, CiberObn, Barcelona, Spain. - Author

Unitat de Medicina Vascular i Metabolisme (UVASMET) Hospital Universitari Sant Joan, IISPV, CIBERDEM, Universitat Rovira i Virgili, Reus, Tarragona, Spain. - Author

Univ Barcelona, Hosp Univ Bellvitge Idibell, Serv Med Interna, CiberObn,Unidada Lipidos, Barcelona, Spain - Author

Univ Basque Country, CSIC, Biofis Inst, Leioa, Spain - Author

Univ Pais Vasco UPV EHU, Dept Biochem & Mol Biol, Bilbao, Spain - Author

Univ Rovira i Virgili, IISPV, CIBERDEM, Unitat Med Vasc Metab UVASMET Hosp Univ St Joan, Reus, Tarragona, Spain - Author

Univ Zaragoza, Aragon Inst Engn Res I3A, Zaragoza, Spain - Author

Univ Zaragoza, Dept Med Psiquiatria & Dermatol, Zaragoza, Spain - Author

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.

Keywords

associationexpressionhypercholesterolemiaAdultAlgorithmApolipoprotein bApolipoprotein eApolipoprotein e2Apolipoproteins bApolipoproteins eArea under the curveArticleAssociationBiochemical analysisBody massCholesterolCohort analysisCombination drug therapyControlled studyDiagnostic accuracyDiagnostic test accuracy studyDisease classificationExpressionFalse negative resultFalse positive resultFemaleFenofibrateGenetic analysisGeneticsGenotypeHigh density lipoprotein cholesterolHumanHumansHydroxymethylglutaryl coenzyme a reductase inhibitorHypercholesterolemiaHyperlipidemiaHyperlipidemiasHyperlipoproteinemia type 3Hyperlipoproteinemia type iiiIii hyperlipoproteinemiaLipidLipid fingerprintingLow density lipoprotein cholesterolMajor clinical studyMalePhenotypeReceiver operating characteristicSensitivity and specificityTriacylglycerolTriglycerides

Quality index

Bibliometric impact. Analysis of the contribution and dissemination channel

The work has been published in the journal Clinical Chemistry due to its progression and the good impact it has achieved in recent years, according to the agency WoS (JCR), it has become a reference in its field. In the year of publication of the work, 2023, it was in position 1/31, thus managing to position itself as a Q1 (Primer Cuartil), in the category Medical Laboratory Technology. Notably, the journal is positioned above the 90th percentile.

From a relative perspective, and based on the normalized impact indicator calculated from World Citations provided by WoS (ESI, Clarivate), it yields a value for the citation normalization relative to the expected citation rate of: 3.25. This indicates that, compared to works in the same discipline and in the same year of publication, it ranks as a work cited above average. (source consulted: ESI Nov 14, 2024)

This information is reinforced by other indicators of the same type, which, although dynamic over time and dependent on the set of average global citations at the time of their calculation, consistently position the work at some point among the top 50% most cited in its field:

Weighted Average of Normalized Impact by the Scopus agency: 1.64 (source consulted: FECYT Feb 2024)
Field Citation Ratio (FCR) from Dimensions: 7.34 (source consulted: Dimensions May 2025)

Specifically, and according to different indexing agencies, this work has accumulated citations as of 2025-05-16, the following number of citations:

WoS: 10
Scopus: 10
Europe PMC: 3
OpenCitations: 7

Impact and social visibility

Leadership analysis of institutional authors