Methylation status of LDLR, PCSK9 and LDLRAP1 is associated with cardiovascular events in familial hypercholesterolemia

Aim: Methylation of LDLR, PCSK9 and LDLRAP1 CpG sites was assessed in patients with familial hypercholesterolemia (FH). Methods: DNA methylation of was analyzed by pyrosequencing in 131 FH patients and 23 normolipidemic (NL) subjects. Results: LDLR, PCSK9 and LDLRP1 methylation was similar between FH patients positive (MD) and negative (non-MD) for pathogenic variants in FH-related genes. LDLR and PCSK9 methylation was higher in MD and non-MD groups than NL subjects (p LDLR, PCSK9 and LDLRAP1 methylation profiles were associated with clinical manifestations and cardiovascular events in FH patients (p Conclusion: Differential methylation of LDLR, PCSK9 and LDLRAP1 is associated with hypercholesterolemia and cardiovascular events. This methylation profile maybe useful as a biomarker and contribute to the management of FH. Familial hypercholesterolemia (FH) is a monogenic disease that results in increased plasma LDL cholesterol and cardiovascular risk. FH is caused by deleterious variants in APOB, LDLR, PCSK9 and LDLRAP1 that can be identified using high-throughput genomic sequencing technology. DNA methylation is an epigenetic mechanism of gene expression regulation. Hypermethylation of promoter region results in downregulation of gene expression, reducing protein synthesis. Promoter methylation of genes involved in cholesterol homeostasis is associated with variability in blood lipids and may explain the phenotypic profile of patients without a causal variant of FH. Methylation of LDLR, PCSK9 and LDLRAP1 loci is not associated molecular diagnosis of FH (presence of a FH-causing variant). Methylation of LDLR and PCSK9 CpG sites is higher in FH patients than normolipidemic subjects. LDLR, PCSK9 and LDLRAP1 methylation profiles are associated with clinical manifestations and cardiovascular events in FH patients. This study identified potential epigenomic biomarkers that could be useful for cardiovascular risk assessment and therapy management in FH. Future studies should consider larger samples, influence of lipid-lowering drugs and other environmental factors, and explore other epigenetic mechanisms such as post-translational histone modifications and non-coding RNAs.