GENetic characteristics and REsponse to lipid-lowering therapy in familial hypercholesterolemia: GENRE-FH study

Area of Science:

• Genetics and Precision Medicine
• Cardiovascular Disease Research
• Pharmacogenomics

Background:

• Familial Hypercholesterolemia (FH) is a genetic disorder characterized by high LDL-C levels.
• Lipid-lowering therapy (LLT) is crucial for managing FH, but treatment response can vary.
• Genetic factors, including pathogenic variants (PVs), are known to influence LLT efficacy.

Purpose of the Study:

• To investigate the association between pathogenic variants (PVs) and LLT response in Korean FH patients.
• To evaluate the impact of PV characteristics and a 4-SNP score on low-density lipoprotein-cholesterol (LDL-C) reduction.
• To explore correlations between genetic profiles and treatment outcomes for personalized FH management.

Main Methods:

• Analysis of 83 Korean FH patients from a registry, followed for ≥6 months after LLT escalation.
• Assessment of achieved percentage of expected LDL-C reduction and rates of LDL-C <70 mg/dL.
• Evaluation of correlations between treatment response, PV characteristics, and a weighted 4 SNP-based score.

Main Results:

• PV-positive patients showed significantly lower LDL-C reduction compared to PV-negative patients (p=0.007).
• The 4-SNP score correlated inversely with LDL-C reduction (R²=0.045, p=0.048), with higher scores indicating lower response.
• Among evolocumab users, null PVs were associated with lower LDL-C reduction, while defective PVs showed better response.

Conclusions:

• LLT response in FH patients is significantly associated with PV positivity and the 4-SNP score.
• Genetic background, including PV type and SNP score, plays a role in predicting LLT effectiveness.
• These findings support tailored management strategies for FH patients based on their genetic profiles.