Genetics of Hypercholesterolemia: Comparison Between Familial Hypercholesterolemia and Hypercholesterolemia...

Area of Science:

• Cardiovascular Medicine
• Genetics
• Metabolic Disorders

Background:

• Severe hypercholesterolemia (HC), characterized by elevated LDL cholesterol (LDL-C) above 190 mg/dl or the 95th percentile, is a significant risk factor for atherosclerotic cardiovascular disease (ASCVD), particularly ischemic heart disease (IHD).
• Familial hypercholesterolemia (FH) is a genetic form of severe HC caused by single gene variants (e.g., LDLR, APOB, PCSK9, ApoE), leading to extreme LDL-C levels and early-onset IHD.
• Polygenic hypercholesterolemia (PH) accounts for a substantial portion of severe HC cases, resulting from the cumulative effect of multiple genetic variants, though its diagnosis, prevalence, and cardiovascular risk are less understood.

Purpose of the Study:

• To differentiate between genetic causes of severe hypercholesterolemia, specifically familial hypercholesterolemia (FH) and polygenic hypercholesterolemia (PH).
• To highlight the varying cardiovascular risks associated with different forms of severe HC.
• To emphasize the importance of early detection and aggressive lipid-lowering treatment for severe HC to prevent ASCVD.

Main Methods:

• Review of current literature on the definition, genetic basis, diagnosis, and cardiovascular risk of severe hypercholesterolemia.
• Comparison of diagnostic and screening recommendations for FH versus PH.
• Analysis of treatment guidelines for managing severe HC, including target LDL-C levels.

Main Results:

• FH, caused by single gene variants, presents the highest cardiovascular risk, followed by PH and other forms of HC.
• Cascade screening is recommended for FH relatives, while only first-degree relatives of other HC cases are advised for LDL-C screening due to lack of PH genetic consensus.
• High-intensity lipid-lowering treatment aiming for LDL-C <100 mg/dl or a ≥50% reduction is recommended for all severe HC patients for primary ASCVD prevention.

Conclusions:

• Severe HC, encompassing FH and PH, necessitates prompt management to mitigate ASCVD risk.
• Genetic testing and targeted screening strategies are vital for identifying individuals at high risk.
• Aggressive lipid-lowering therapies are essential for primary prevention of ASCVD in patients with severe hypercholesterolemia, with intensified treatment for those with existing ASCVD or additional risk factors.