Mechanism of the Molecular Pathophysiology for Familial Hypercholesterolemia

Familial hypercholesterolemia (FH) is characterized by high serum low-density lipoprotein cholesterol (LDL-C) levels from birth, tendon/skin xanthomas, and premature coronary artery disease. The prevalence of FH is 1 per 300 individuals in the general population. FH is caused by a pathogenic (rare) variant in the LDL receptor (LDLR), apolipoprotein B (APOB), and proprotein convertase subtilisin/kexin type 9 (PCSK9) genes. In Japan, there has been only one reported case of a family with FH caused by the known APOB p.(Arg3527Gln) variant. Those without pathogenic variants in the LDLR or PCSK9 genes account for approximately 36% of patients with FH. Novel causative genes/variants of FH have been explored in patients with FH worldwide, but no gene variants with a large effect size have been found. Polygenic hypercholesterolemia accounts for approximately 10% of patients with clinical FH. We performed whole-exome sequencing in 122 families without pathogenic variants in the LDLR and PCSK9 genes. However, we could not find novel causative genes/variants of FH via family analysis. We examined all the APOB variants and showed that the low-frequency APOB p.(Pro955Ser) variant has a moderate effect size in FH patients via functional analysis of hepatocytes. We also reported that low-frequency PCSK9 variants contribute to the severity of the FH phenotype in patients with FH harboring an LDLR pathogenic variant. Thus, the combination of low-frequency variants and age, environmental factors such as diet, or other genetic factors contribute to the severity of or variability in the FH phenotype.