APOE p.(Leu167del) variant in hypercholesterolemia: Prevalence & phenotypic expression

Bello-Álvarez, Daniel ; Cenarro, Ana ; Bea, Ana M. ; Marco-Benedí, Victoria (Universidad de Zaragoza) ; Jarauta, Estíbaliz (Universidad de Zaragoza) ; Ortiz-Palma, Pedro ; Ortega, Emilio ; González-Lleó, Ana M. ; Civeira, Fernando (Universidad de Zaragoza)

Resumen: BACKGROUND.The APOE p.(Leu167del) variant has been identified as a rare cause of autosomal dominant hypercholesterolemia. A comprehensive phenotypic profile of carriers remains undefined, and its frequency has not been systematically studied.
OBJECTIVE To characterize the phenotypic differences between p.(Leu167del) carriers among individuals with primary hypercholesterolemia and those with familial hypercholesterolemia (FH), and to estimate the variant's frequency in different populations.
MEDTHODS Phenotypic differences were assessed from the Lipid Unit cohort of the Hospital Universitario Miguel Servet (HUMS, n = 6489). The allele frequency of the p.(Leu167del) variant was estimated using data from the HUMS and Aragon Workers Health Study (AWHS, n = 5678), a cohort of working adults, and international cohorts: GnomAD (n ≈ 807,162), TOPMed (n ≈ 180,000), 100 K Genomes Project (n ≈ 85,000). To characterize the profile of carriers, data from the HUMS cohort and a systematic review of the published literature were also used. RESULTS Carriers showed significantly higher high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and non-HDL cholesterol and lower lipoprotein(a) [Lp(a)] concentrations compared to noncarriers with primary hypercholesterolemia. In comparison with FH patients carrying LDL receptor (LDLR), apolipoprotein B (APOB), or proprotein convertase subtilisin/kexin type 9 ( PCSK9 ) variants, carriers displayed higher triglycerides and HDL cholesterol but lower LDL cholesterol and Lp(a). The APOE p.(Leu167del) frequency is approximately 1 in 12,000 individuals in the general population and about 2.5% of FH. CONCLUSION The study confirmed the association of APOE p.(Leu167del) with hypercholesterolemia but with lower LDL cholesterol than subjects with FH. These findings support p.(Leu167del) as a cause of FH and its inclusion in the genetic screening for FH, particularly in Caucasian populations

Idioma: Inglés

DOI: 10.1016/j.jacl.2025.09.016

Año: 2025

Publicado en: Journal of Clinical Lipidology 19, 6 (2025), 1637-1645
ISSN: 1933-2874

Financiación: info:eu-repo/grantAgreement/ES/ISCIII-MINECO/PI19-00694
Financiación: info:eu-repo/grantAgreement/ES/ISCIII-MINECO/PI22-01595

Tipo y forma: Article (Published version)

Área (Departamento): Area Medicina (Dpto. Medicina, Psiqu. y Derm.)