Contribution of APOE Genetic Variants to Dyslipidemia.

Autor:	Bea AM; Hospital Universitario Miguel Servet, IIS Aragón, CIBERCV, Spain (A.M.B., V.M.-B., I.L.-M., M.L., P.F.-C., F.C., A.C.)., Larrea-Sebal A; Biofisika Institute (UPV/EHU, CSIC), University of the Basque Country, Leioa, Spain (A.L.-S., C.M.).; Fundación Biofísica Bizkaia, Leioa, Spain (A.L.-S.)., Marco-Benedi V; Hospital Universitario Miguel Servet, IIS Aragón, CIBERCV, Spain (A.M.B., V.M.-B., I.L.-M., M.L., P.F.-C., F.C., A.C.).; Universidad de Zaragoza, Spain (V.M.-B., I.L.-M., M.L., B.M.-F., S.O., F.C.)., Uribe KB; Department of Biochemistry and Molecular Biology, UPV/EHU, University of the Basque Country, Bilbao, Spain (K.B.U., U.G.-G., C.M.).; Center for Cooperative Research in Biomaterials (CIC biomaGUNE), Basque Research and Technology Alliance (BRTA), Donostia-San Sebastián, Spain (K.B.U.)., Galicia-Garcia U; Department of Biochemistry and Molecular Biology, UPV/EHU, University of the Basque Country, Bilbao, Spain (K.B.U., U.G.-G., C.M.)., Lamiquiz-Moneo I; Hospital Universitario Miguel Servet, IIS Aragón, CIBERCV, Spain (A.M.B., V.M.-B., I.L.-M., M.L., P.F.-C., F.C., A.C.).; Universidad de Zaragoza, Spain (V.M.-B., I.L.-M., M.L., B.M.-F., S.O., F.C.)., Laclaustra M; Hospital Universitario Miguel Servet, IIS Aragón, CIBERCV, Spain (A.M.B., V.M.-B., I.L.-M., M.L., P.F.-C., F.C., A.C.).; Universidad de Zaragoza, Spain (V.M.-B., I.L.-M., M.L., B.M.-F., S.O., F.C.)., Moreno-Franco B; Universidad de Zaragoza, Spain (V.M.-B., I.L.-M., M.L., B.M.-F., S.O., F.C.)., Fernandez-Corredoira P; Hospital Universitario Miguel Servet, IIS Aragón, CIBERCV, Spain (A.M.B., V.M.-B., I.L.-M., M.L., P.F.-C., F.C., A.C.)., Olmos S; Universidad de Zaragoza, Spain (V.M.-B., I.L.-M., M.L., B.M.-F., S.O., F.C.).; Aragon Institute of Engineering Research (I3A), Universidad de Zaragoza, Spain (S.O.)., Civeira F; Hospital Universitario Miguel Servet, IIS Aragón, CIBERCV, Spain (A.M.B., V.M.-B., I.L.-M., M.L., P.F.-C., F.C., A.C.).; Universidad de Zaragoza, Spain (V.M.-B., I.L.-M., M.L., B.M.-F., S.O., F.C.)., Martin C; Hospital Universitario Miguel Servet, IIS Aragón, CIBERCV, Spain (A.M.B., V.M.-B., I.L.-M., M.L., P.F.-C., F.C., A.C.).; Department of Biochemistry and Molecular Biology, UPV/EHU, University of the Basque Country, Bilbao, Spain (K.B.U., U.G.-G., C.M.)., Cenarro A; Hospital Universitario Miguel Servet, IIS Aragón, CIBERCV, Spain (A.M.B., V.M.-B., I.L.-M., M.L., P.F.-C., F.C., A.C.).; Instituto Aragonés de Ciencias de la Salud (IACS), Zaragoza, Spain (A.C.).
Jazyk:	angličtina
Zdroj:	Arteriosclerosis, thrombosis, and vascular biology [Arterioscler Thromb Vasc Biol] 2023 Jun; Vol. 43 (6), pp. 1066-1077. Date of Electronic Publication: 2023 Apr 13.
DOI:	10.1161/ATVBAHA.123.318977
Abstrakt:	Background: apo (apolipoprotein) E has crucial role in lipid metabolism. The genetic variation in APOE gene is associated with monogenic disorders and contributes to polygenic hypercholesterolemia and to interindividual variability in cholesterol. APOE rare variants may be involved in the phenotype of genetic hyperlipidemias. Methods: Exon 4 of APOE were sequenced in all consecutive unrelated subjects with primary hyperlipidemia from a Lipid Unit (n=3667) and 822 random subjects from the Aragon Workers Health Study. Binding affinity of VLDL (very low-density lipoprotein) to LDL receptor of pathogenic predicted apoE variants was analyzed in vitro. Lipoprotein particle number, size, and composition were studied by nuclear magnetic resonance. Results: In addition to common polymorphisms giving rise to APOE2 and APOE4, 14 gene variants were found in exon 4 of APOE in 65 subjects. p.(Leu167del) in 8 patients with isolated hypercholesterolemia and in 8 patients with combined hyperlipidemia. Subjects with p.(Arg121Trp), p.(Gly145Asp), p.(Arg154Ser), p.(Arg163Cys), p.(Arg165Trp), and p.(Arg168His) variants met dysbetalipoproteinemia lipid criteria and were confirmed by nuclear magnetic resonance. VLDL affinity for the LDL receptor of p.(Arg163Cys) and p.(Arg165Trp) heterozygous carriers had intermedium affinity between APOE2/2 and APOE3/3. p.(Gly145Asp) and p.(Pro220Leu) variants had higher affinity than APOE3/3. Conclusions: APOE genetic variation contributes to the development of combined hyperlipidemia, usually dysbetalipoproteinemia, and familial hypercholesterolemia. The lipid phenotype in heterozygous for dysbetalipoproteinemia-associated mutations is milder than the homozygous APOE2/2-associated phenotype. Subjects with dysbetalipoproteinemia and absence of APOE2/2 are good candidates for the study of pathogenic variants in APOE . However, more investigation is required to elucidate the significance of rarer variants of apoE. Competing Interests: Disclosures None.
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu