[Mechanism of the Molecular Pathophysiology for Familial Hypercholesterolemia]

Area of Science:

• Genetics and Molecular Biology
• Cardiovascular Medicine
• Biochemistry

Background:

• Familial hypercholesterolemia (FH) is a prevalent genetic disorder characterized by elevated low-density lipoprotein cholesterol (LDL-C) from birth, leading to xanthomas and premature cardiovascular disease.
• Established genetic causes include variants in LDLR, APOB, and PCSK9 genes, yet a significant portion of FH cases remain genetically unexplained.
• Approximately 36% of FH patients lack identified pathogenic variants in LDLR or PCSK9, highlighting the need to explore other genetic contributors.

Purpose of the Study:

• To identify novel causative genes and variants for Familial hypercholesterolemia (FH) in patients lacking pathogenic variants in LDLR and PCSK9.
• To investigate the functional impact of identified variants, specifically focusing on the APOB gene.
• To understand the contribution of low-frequency variants and other factors to the variability and severity of the FH phenotype.

Main Methods:

• Whole-exome sequencing was performed on 122 families with FH but without known pathogenic variants in LDLR or PCSK9.
• Comprehensive analysis of all APOB variants was conducted, followed by functional analysis of hepatocytes for the APOB p.(Pro955Ser) variant.
• Investigation into the role of low-frequency PCSK9 variants in patients with existing LDLR pathogenic variants.

Main Results:

• Whole-exome sequencing did not reveal novel causative genes or variants for FH through family analysis.
• Functional analysis demonstrated that the low-frequency APOB p.(Pro955Ser) variant has a moderate effect size in FH patients.
• Low-frequency PCSK9 variants were found to contribute to the severity of the FH phenotype in individuals with an LDLR pathogenic variant.

Conclusions:

• The APOB p.(Pro955Ser) variant is identified as a contributor to FH, exhibiting a moderate effect size.
• The severity and variability of the FH phenotype are influenced by a combination of low-frequency genetic variants, age, environmental factors (e.g., diet), and potentially other genetic factors.
• Further research is needed to fully elucidate the complex genetic architecture underlying Familial hypercholesterolemia.