Clinical utility of the polygenic LDL-C SNP score in familial hypercholesterolemia

Area of Science:

• Genetics and Genomics
• Cardiovascular Medicine
• Precision Medicine

Background:

• Autosomal dominant Familial Hypercholesterolemia (FH) is caused by mutations in LDLR, APOB, or PCSK9, but these are found in only ~40% of diagnosed patients.
• A polygenic aetiology, involving common LDL-C raising variants, is suspected in the remaining FH cases.
• Previous research identified a 12-SNP LDL-C score based on common variants associated with elevated LDL-C.

Purpose of the Study:

• To validate the 12-SNP LDL-C score in diverse European-Caucasian populations.
• To determine the prevalence of polygenic aetiology in FH patients lacking identifiable mutations in known FH genes.
• To assess the clinical utility of differentiating monogenic and polygenic causes of FH for treatment decisions.

Main Methods:

• Utilized a 12-SNP LDL-C score derived from genome-wide association studies.
• Validated the score in adult and pediatric FH cohorts from multiple countries with European-Caucasian populations.
• Analyzed genetic data to identify mutations in LDLR, APOB, and PCSK9, and assessed polygenic scores.

Main Results:

• The 12-SNP LDL-C score demonstrated validity across different European-Caucasian populations.
• A polygenic explanation is the most likely cause of hypercholesterolaemia in over 80% of FH patients without detectable LDLR, APOB, or PCSK9 mutations.
• Low polygenic scores may indicate mutations in novel genes, warranting further whole exome/genome sequencing.
• Distinguishing monogenic vs. polygenic FH supports tailored, less aggressive treatment pathways for non-mutation cases.

Conclusions:

• The 12-SNP LDL-C score is a valid tool for assessing polygenic hypercholesterolaemia in FH.
• Identifying the genetic aetiology (monogenic vs. polygenic) of FH enables precision medicine approaches.
• Genomic information guides more appropriate and cost-effective lipid-lowering treatment strategies.