APOB to Estimated APOB Ratio for Screening for the APOE2 Genotype

Area of Science:

• Lipidology
• Genetics
• Cardiovascular Disease Epidemiology

Background:

• Familial dysbetalipoproteinemia (FDB) is a genetic disorder associated with the apolipoprotein E (APOE) ɛ2/ɛ2 genotype.
• This genotype leads to impaired remnant lipoprotein clearance and elevated atherosclerotic cardiovascular disease (ASCVD) risk.
• Current methods for identifying the ɛ2/ɛ2 genotype and associated ASCVD risk are suboptimal.

Purpose of the Study:

• To develop a screening test for the APOE ɛ2/ɛ2 genotype using routine lipid tests.
• To identify individuals with the ɛ2/ɛ2 genotype who are at the highest risk for ASCVD.
• To evaluate the performance of a novel apolipoprotein B (APOB) estimation equation.

Main Methods:

• A primary prevention cohort (n=298,249) from the UK Biobank was analyzed.
• Genotyping was used to classify patients as ɛ2/ɛ2 positive or negative.
• Lipid profiles, apolipoprotein B (APOB) levels, and ASCVD events were assessed over a 15-year follow-up.

Main Results:

• The ratio of measured apolipoprotein B (APOB) to estimated APOB (eAPOB) demonstrated high accuracy in identifying the ɛ2/ɛ2 genotype (AUC: 0.990).
• The APOB/eAPOB ratio outperformed other lipid tests and ratios for genotype identification, irrespective of FDB phenotype.
• Established risk equations (PCE and PREVENT) were most effective in identifying patients with higher ASCVD risk (AUCs ~0.70).

Conclusions:

• The APOB/eAPOB ratio serves as an accurate and efficient screening tool for the APOE ɛ2/ɛ2 genotype.
• Conventional ASCVD risk equations remain the preferred method for stratifying risk in patients with the ɛ2/ɛ2 genotype.
• This study provides a novel approach to identify individuals at risk for FDB and subsequent ASCVD.