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

Area of Science:

• Genetics and Molecular Biology
• Cardiovascular Medicine
• Population Health

Background:

• The APOE p.(Leu167del) variant is a rare cause of autosomal dominant hypercholesterolemia.
• A comprehensive phenotypic profile and frequency of this variant are not well-defined.

Purpose of the Study:

• To characterize phenotypic differences between p.(Leu167del) carriers and individuals with primary hypercholesterolemia or familial hypercholesterolemia (FH).
• To estimate the frequency of the APOE p.(Leu167del) variant in diverse populations.

Main Methods:

• Phenotypic data analyzed from the Hospital Universitario Miguel Servet (HUMS) cohort (n=6489).
• Allele frequency estimated using HUMS, Aragon Workers Health Study (AWHS, n=5678), and international datasets (GnomAD, TOPMed, 100 K Genomes Project).
• Carrier profiles assessed via HUMS data and systematic literature review.

Main Results:

• APOE p.(Leu167del) carriers exhibited higher HDL, LDL, and non-HDL cholesterol, and lower Lp(a) compared to noncarriers.
• Compared to FH patients with LDLR, APOB, or PCSK9 variants, carriers had higher triglycerides and HDL, but lower LDL and Lp(a).
• The variant frequency is ~1:12,000 in the general population and ~2.5% in FH patients.

Conclusions:

• APOE p.(Leu167del) is associated with hypercholesterolemia, presenting lower LDL cholesterol than typical FH.
• The findings support p.(Leu167del) as a cause of FH, recommending its inclusion in genetic screening, especially in Caucasian populations.