Impact of clinical signs and genetic diagnosis of familial hypercholesterolaemia on the prevalence of coronary artery...

Area of Science:

• Cardiovascular Medicine
• Genetics
• Biochemistry

Background:

• Familial hypercholesterolaemia (FH) is a genetic disorder characterized by extremely high levels of low-density lipoprotein (LDL) cholesterol.
• The independent impact of clinical signs (xanthoma, family history) and genetic mutation status on coronary artery disease (CAD) risk, beyond LDL cholesterol levels, requires further elucidation.

Purpose of the Study:

• To evaluate the combined effect of clinical FH signs and FH mutation status on CAD risk in individuals with severely elevated LDL cholesterol.
• To determine if clinical signs and genetic diagnosis add to the risk prediction provided by LDL cholesterol alone.

Main Methods:

• Sequenced three genes (LDLR, APOB, PCSK9) in 636 patients with severe hypercholesterolaemia (LDL cholesterol ≥180 mg/dL or ≥140 mg/dL for <15 years).
• Assessed the presence of clinical FH signs (xanthoma and/or family history).
• Compared CAD prevalence across four groups: no FH mutation/no clinical signs, clinical signs only, FH mutation only, and both clinical signs and FH mutation, adjusting for known risk factors.

Main Results:

• Subjects with clinical FH signs or FH mutations had 3- to 4-fold increased odds of CAD compared to those without.
• Individuals with both clinical FH signs and FH mutations exhibited over an 11-fold higher odds of developing CAD.
• These associations remained significant after adjusting for LDL cholesterol and other risk factors.

Conclusions:

• Positive clinical signs and genetic mutation status for FH have an additive effect on CAD risk.
• Integrating clinical assessment with genetic testing improves CAD risk stratification in patients with elevated LDL cholesterol.