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

BACKGROUND: Familial hypercholesterolemia (FH) is diagnosed based on clinical signs of FH, including family history and/or xanthomas, or pathogenic FH-variant. OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: Among patients with severe hypercholesterolemia, clinical and genetic signatures of FH are useful for risk discrimination for CAD beyond their hypercholesterolemia.