# Significance of Clinical and Genetic Signatures of Familial Hypercholesterolemia Among Patients With Severe Hypercholesterolemia

## TL;DR

This study shows that clinical and genetic signs of familial hypercholesterolemia help predict heart disease risk beyond cholesterol levels in patients with severe hypercholesterolemia.

## Contribution

The study demonstrates that FH signatures improve CAD risk prediction beyond LDL cholesterol in severe hypercholesterolemia patients.

## Key findings

- Patients with FH-variant or clinical signs had higher CAD risk compared to non-FH patients.
- Those with both clinical signs and FH-variant had over 5 times higher CAD risk after adjusting for other factors.
- Baseline LDL cholesterol levels were significantly higher in patients with FH signs.

## Abstract

Familial hypercholesterolemia (FH) is diagnosed based on clinical signs of FH, including family history and/or xanthomas, or pathogenic FH-variant.

The authors aimed to clarify whether these signatures are associated with coronary artery disease (CAD) events beyond low density lipoprotein (LDL) cholesterol level among patients with severe hypercholesterolemia.

We retrospectively reviewed the data of patients with severe hypercholesterolemia (LDL cholesterol ≥180 mg/dL) aged ≥15 years (N = 1,273; male, n = 631) admitted to Kanazawa University Hospital between 2000 and 2022. We divided the patients into 4 groups based on clinical signs of FH and/or presence of FH-variant and assessed the factors associated with CAD events using the Cox proportional hazard model.

We identified 144 CAD events during the 12.4-year median follow-up. Baseline LDL cholesterol level in patients with any signs of FH tended to be significantly higher than non-FH patients. Compared with the reference group of patients without any signs of FH, patients with FH-variant or clinical signs of FH had significantly higher HRs of developing CAD events (HR: 1.44; 95% CI: 1.02-1.86; P = 0.007 and HR: 2.27; 95% CI: 1.41-3.13; P < 0.001, respectively), whereas those with clinical signs of FH and FH-variant had more than 5-fold higher HR for CAD (HR: 5.02; 95% CI: 2.60-7.44; P < 0.001) after adjusting for known risk factors, including LDL cholesterol year score.

Among patients with severe hypercholesterolemia, clinical and genetic signatures of FH are useful for risk discrimination for CAD beyond their hypercholesterolemia.